Molecular Pain via MedWorm.com

Cannabinoid-mediated modulation of neuropathic pain and microglial accumulation in a model of murine type I diabetic peripheral neuropathic pain

Molecular Pain — Wed, 17 Mar 2010 00:00:00 +0100

Conclusions: The prevention of microglial accumulation and activation in the dorsal spinal cord was associated with limited development of a neuropathic pain state. Cannabinoids demonstrated antinociceptive effects in this mouse model of DPN. These results suggest that such interventions may also benefit humans with DPN, and their early introduction may also modify the development of the NeP state. (Source: Molecular Pain)

Nitric oxide synthase modulates CFA-induced thermal hyperalgesia through cytokine regulation in mice

Molecular Pain — Tue, 02 Mar 2010 00:00:00 +0100

Conclusion: These findings lead us to propose that inhibition of NOS modulates inflammatory thermal hyperalgesia by regulating cytokine expression. (Source: Molecular Pain)

Expression genetics identifies spinal mechanisms supporting formalin late phase behaviors

Molecular Pain — Thu, 11 Feb 2010 00:00:00 +0100

Conclusions: Wide differences in pain behaviors, including those resulting from the injection of formalin, can be observed in inbred strains of mice suggesting strong genetic influences. Correlating levels of gene expression in tissues established to be mechanistically implicated in the expression of specific behaviors can identify genes involved in the behaviors of interest. Comparing formalin late phase behavior levels with spinal cord gene expression yielded several plausible gene candidates, including the Mapk8 gene. Additional molecular and pharmacologic evidence confirmed a functional role for this gene in supporting formalin late phase responses. (Source: Molecular Pain)

Facilitation of synaptic transmission and pain responses by CGRP in the amygdala of normal rats

Molecular Pain — Mon, 08 Feb 2010 00:00:00 +0100

Calcitonin gene-related peptide (CGRP) plays an important role in peripheral and central sensitization. CGRP also is a key molecule in the spino-parabrachial-amygdaloid pain pathway. Blockade of CGRP1 receptors in the spinal cord or in the amygdala has antinociceptive effects in different pain models. Here we studied the electrophysiological mechanisms of behavioral effects of CGRP in the amygdala in normal animals without tissue injury.Whole-cell patch-clamp recordings of neurons in the latero-capsular division of the central nucleus of the amygdala (CeLC) in rat brain slices showed that CGRP (100 nM) increased excitatory postsynaptic currents (EPSCs) at the parabrachio-amygdaloid (PB-CeLC) synapse, the exclusive source of CGRP in the amygdala. Consistent with a postsynaptic mechanism of ...

Alteration of primary afferent activity following inferior alveolar nerve transection in rats

Molecular Pain — Wed, 03 Feb 2010 00:00:00 +0100

Conclusions: These data suggest that the increase in both TTX-S INa and TTX-R INa and the decrease in IA and Ik in small/medium TG neurons in IAN-transected rats are involved in the activation of spike generation, resulting in hyperexcitability of A delta -IAN fibers innervating the mental region after IAN transection. (Source: Molecular Pain)

Trigeminal injury causes kappa opioid-dependent allodynic, glial and immune cell responses in mice

Molecular Pain — Fri, 29 Jan 2010 00:00:00 +0100

Conclusions: These results show that kappa opioid receptor system has different effects after pIONL in CNS and PNS: KOR activation promotes CNS astrocytosis and microglial or stem cell proliferation but inhibits macrophage proliferation in PNS. The trigeminal central root has a key role in the etiology and treatment of trigeminal neuralgia, and these newly identified responses may provide new targets for developing pain therapies. (Source: Molecular Pain)

Behavioral and anatomical characterization of the bilateral sciatic nerve chronic constriction (bCCI) injury: correlation of anatomic changes and responses to cold stimuli

Molecular Pain — Wed, 27 Jan 2010 00:00:00 +0100

Conclusions: These results confirm the usefulness of cold testing in bCCI rats, a new approach using CCI to model neuropathic pain, and suggest a potential value of studying the roles of dorsal horn CCK and substance P in chronic neuropathic pain. Compared to human subjects with neuropathic pain, responses to cold stimuli in rats with bCCI may be a useful model of neuropathic pain. (Source: Molecular Pain)

Regulation of AMPA receptors in spinal nociception

Molecular Pain — Thu, 21 Jan 2010 00:00:00 +0100

The functional properties of alpha-amino-3-hydroxy-5-methy-4-isoxazole propionate (AMPA) receptors in different brain regions, such as hippocampus and cerebellum, have been well studied in vitro and in vivo. The AMPA receptors present a unique characteristic in the mechanisms of subunit regulation during LTP (long-term potentiation) and LTD (long-term depression), which are involved in the trafficking, altered composition and phosphorylation of AMPA receptor subunits. Accumulated data have demonstrated that spinal AMPA receptors play a critical role in the mechanism of both acute and persistent pain. However, less is known about the biochemical regulation of AMPA receptor subunits in the spinal cord in response to painful stimuli. Recent studies have shown that some important regulatory pr...

Effects of Parecoxib and Fentanyl on nociception-induced cortical activity

Molecular Pain — Thu, 21 Jan 2010 00:00:00 +0100

Conclusion: Cortical activity was modulated by nociceptive stimulation in anesthetized rats. Fentanyl showed a strong inhibitory effect on the nociceptive-stimulus induced cortical activity while parecoxib had no significant effect. (Source: Molecular Pain)

Ryanodine receptors contribute to the induction of nociceptive input-evoked long-term potentiation in the rat spinal cord slice

Molecular Pain — Wed, 20 Jan 2010 00:00:00 +0100

Conclusions: These data indicate that activation of presynaptic RyRs play a crucial role in the induction of LTP in the spinal pain pathway, probably through enhancement of transmitter release. (Source: Molecular Pain)

Down-regulation of Toll-like receptor 4 gene expression by short interfering RNA attenuates bone cancer pain in a rat model

Molecular Pain — Wed, 20 Jan 2010 00:00:00 +0100

Conclusions: TLR4 might be the main mediator in the induction of bone cancer pain. Further study of this early, specific, and innate CNS/microglial response, and how it leads to sustained glial/neuronal hypersensitivity, might lead to new therapies for the prevention and treatment of bone cancer pain syndromes. (Source: Molecular Pain)

Differential involvement of trigeminal transition zone and laminated subnucleus caudalis in orofacial deep and cutaneous hyperalgesia: the effects of interleukin-10 and glial inhibitors

Molecular Pain — Mon, 21 Dec 2009 00:00:00 +0100

Conclusion: These results support the hypothesis that the Vi/Vc transition zone is involved in deep orofacial injury and suggest that glial inhibition and interruption of the cytokine cascade after inflammation may provide pain relief. (Source: Molecular Pain)

Characterization of intrinsic properties of cingulate pyramidal neurons in adult mice after nerve injury

Molecular Pain — Wed, 16 Dec 2009 00:00:00 +0100

The anterior cingulate cortex (ACC) is important for cognitive and sensory functions including memory and chronic pain. Glutamatergic excitatory synaptic transmission undergo long-term potentiation the ACC pyramidal cells after peripheral injury. Less information is available for the possible long-term changes in neuronal action potentials or intrinsic properties. In the present study, we characterized cingulate pyramidal cells in the layer II/III of the ACC in adult mice. We then examined possible long-term changes in intrinsic properties of the ACC pyramidal cells after peripheral nerve injury. In the control mice, we found that there are three major types of pyramidal cells according to their action potential firing pattern: (i) regular spiking (RS) cells (24.7%), intrinsic bursting (IB...

Peripheral non-viral MIDGE vector-driven delivery of beta-endorphin in inflammatory pain

Molecular Pain — Mon, 14 Dec 2009 00:00:00 +0100

Conclusion: Although MIDGE vectors circumvent side-effects associated with classical viral and plasmid vectors, the current POMC-MIDGE-NLS did not result in reliable analgesic effectiveness in our pain model. This was possibly associated with insufficient and variable efficacy in transfection and/or beta-endorphin production. Our data point at the importance of the reproducibility of gene therapy strategies for the control of chronic pain. (Source: Molecular Pain)

Differential regulation of immune responses and macrophage/neuron interactions in the dorsal root ganglion in young and adult rats following nerve injury

Molecular Pain — Thu, 10 Dec 2009 00:00:00 +0100

Conclusions: The results show, for the first time, a major difference in the neuroimmune response to nerve injury in the dorsal root ganglion of young and adult rats. Differential analysis reveals a new set of immune related genes in the ganglia, that are differentially regulated in adult neuropathic pain, and that are consistent with the selective activation of macrophages around adult, but not young large A sensory neurons post injury. These differences may contribute to the reduced incidence of neuropathic pain in infants. (Source: Molecular Pain)

Conditional gene deletion reveals functional redundancy of GABAB receptors in peripheral nociceptors in vivo

Molecular Pain — Thu, 19 Nov 2009 00:00:00 +0100

Conclusions: This study addressed contribution of GABAB receptors expressed on primary afferent nociceptive fibers to the modulation of pain. We observed that neither the development of acute and chronic pain nor the analgesic effects of a systematically-delivered GABAB agonist was significantly changed upon a specific deletion of GABAB receptors from peripheral nociceptive neurons in vivo. This lets us conclude that GABAB receptors in the peripheral nervous system play a less important role than those in the central nervous system in the regulation of pain. (Source: Molecular Pain)

Effective relief of neuropathic pain by adeno-associated virus-mediated expression of a small hairpin RNA against GTP cyclohydrolase 1

Molecular Pain — Wed, 18 Nov 2009 00:00:00 +0100

Conclusions: Therefore, the data suggests that GCH1 levels can be reduced by introducing rAAV-shGCH1, leading to pain relief. Based on the results, we propose that GCH1 modulation may be developed as a clinically applicable gene therapy strategy to treat neuropathic pain. (Source: Molecular Pain)

Different forms of glycine- and GABAA-receptor mediated inhibitory synaptic transmission in mouse superficial and deep dorsal horn neurons

Molecular Pain — Wed, 18 Nov 2009 00:00:00 +0100

Conclusions: Together these data show that Gly- and GABAARs with clearly differing physiological properties and cannabinoid-sensitivity contribute to fast synaptic inhibition in mouse SDH and DDH. (Source: Molecular Pain)

Oxaliplatin-induced loss of phosphorylated heavy neurofilament subunit neuronal immunoreactivity in rat DRG tissue

Molecular Pain — Wed, 18 Nov 2009 00:00:00 +0100

Background: Oxaliplatin and related chemotherapeutic drugs cause painful chronic peripheral neuropathies in cancer patients. We investigated changes in neuronal size profiles and neurofilament immunoreactivity in L5 dorsal root ganglion (DRG) tissue of adult female Wistar rats after multiple-dose treatment with oxaliplatin, cisplatin, carboplatin or paclitaxel. Results: After treatment with oxaliplatin, phosphorylated neurofilament heavy subunit (pNF-H) immunoreactivity was reduced in neuronal cell bodies, but unchanged in nerve fibres, of the L5 DRG. Morphometric analysis confirmed significant changes in the number (-75%; P (Source: Molecular Pain)

Antinociceptive action of oxytocin involves inhibition of potassium channel currents in lamina II neurons of the rat spinal cord

Molecular Pain — Thu, 12 Nov 2009 00:00:00 +0100

Conclusions: This effect of OT on the firing profile of lamina II neurons is in good agreement with the antinociceptive and analgesic properties of OT described in vivo. (Source: Molecular Pain)

Differential role of the menthol-binding residue Y745 in the antagonism of thermally gated TRPM8 channels

Molecular Pain — Tue, 03 Nov 2009 00:00:00 +0100

Conclusions: In summary, we identify structural elements on the TRPM8 channel that are critical for the action of channel antagonists, providing valuable information for the future design of new, specific modulator compounds. (Source: Molecular Pain)

In vivo evidence that truncated trkB.T1 participates in nociception

Molecular Pain — Thu, 29 Oct 2009 00:00:00 +0100

Brain-Derived Neurotrophic Factor (BDNF) is a central nervous system modulator of nociception. In animal models of chronic pain, BDNF exerts its effects on nociceptive processing by binding to the full-length receptor tropomyosin-related kinase B (trkB.FL) and transducing intracellular signaling to produce nocifensive behaviors. In addition to trkB.FL, the trkB locus also produces a widely-expressed alternatively-spliced truncated isoform, trkB.T1. TrkB.T1 binds BDNF with high affinity; however the unique 11 amino acid intracellular cytoplasmic tail lacks the kinase domain of trkB.FL. Recently, trkB.T1 was shown to be specifically up-regulated in a model of HIV-associated neuropathic pain, potentially implicating trkB.T1 as a modulator of nociception. Here, we report that trkB.T1 mRNA and ...

Morphine modulation of pain processing in medial and lateral pain pathways

Molecular Pain — Mon, 12 Oct 2009 23:00:00 +0100

Conclusions: These results suggest that morphine exerts analgesic effects through suppressing both sensory and affective dimensions of pain. (Source: Molecular Pain)

Dynamic regulation of the endocannabinoid system: implications for analgesia

Molecular Pain — Wed, 07 Oct 2009 23:00:00 +0100

The analgesic effects of cannabinoids are well documented, but these are often limited by psychoactive side-effects. Recent studies indicate that the endocannabinoid system is dynamic and altered under different pathological conditions, including pain states. Changes in this receptor system include altered expression of receptors, differential synthesis pathways of endocannabinoids by various cell types and multiple pathways of catabolism and the generation of biologically active metabolites, which may be engaged under different conditions. This review discusses the evidence that pain states alter the endocannabinoid receptor system at key sites involved in pain processing and how these changes may inform the development of cannabinoid based analgesics. (Source: Molecular Pain)

Involvement of S-nitrosylation of actin in inhibition of neurotransmitter release by nitric oxide

Molecular Pain — Mon, 28 Sep 2009 23:00:00 +0100

Conclusions: The present study demonstrates that actin is a major S-nitrosylated protein in the spinal cord and suggests that NO directly regulates neurotransmitter release by S-nitrosylation in addition to the well-known phosphorylation by cGMP-dependent protein kinase. (Source: Molecular Pain)

Delayed onset of changes in soma action potential genesis in nociceptive A-beta DRG neurons in vivo in a rat model of osteoarthritis

Molecular Pain — Sun, 27 Sep 2009 23:00:00 +0100

Clinical data on osteoarthritis suggest widespread changes in sensory function. The present study was done to investigate the possible changes specifically in functionally-identified Abeta-fiber nociceptive primary sensory dorsal root ganglion (DRG) neurons in a rat surgical derangement model of knee osteoarthritis. We have previously found that this model undergoes structural changes in the joint and gait changes as indicated in the incapacitance test. Intracellular recordings were made from L4 Abeta nociceptive DRG neurons in vivo at two stages of development: one month and two months following model induction. Action potential (AP) configuration was compared between neurons in control animals vs. OA animals. At one month, the only change observed was in Abeta nociceptors that lacked ide...

Do genetic predictors of pain sensitivity associate with persistent widespread pain?

Molecular Pain — Tue, 22 Sep 2009 23:00:00 +0100

In conclusion, there was no evidence of association between proposed functional SNPs, previously reported to influence pain sensitivity, in GCH1 and OPRM1 with CWP. Further evidence of null association in large independent cohorts is required to truly exclude these SNPs as genetic risk factors for CWP. (Source: Molecular Pain)

Large A-fiber activity is required for microglial proliferation and p38 MAPK activation in the spinal cord: different effects of resiniferatoxin and bupivacaine on spinal microglial changes after spared nerve injury

Molecular Pain — Mon, 21 Sep 2009 23:00:00 +0100

Conclusions: (1) Blocking peripheral input in TRPV1-positive fibers (presumably C-fibers) is not enough to prevent nerve injury-induced spinal microglia activation. (2) Peripheral input from large myelinated fibers is important for microglial activation. (3) Microglial activation is associated with mechanical allodynia. (Source: Molecular Pain)

NMDA receptor subunit expression and PAR2 receptor activation in colospinal afferent neurons (CANs) during inflammation induced visceral hypersensitivity

Molecular Pain — Mon, 21 Sep 2009 23:00:00 +0100

Conclusions: Our data show that inflammation causes an up-regulation of the NMDA receptor and the activation of the PAR2 receptor expressed on CANs. These changes correlate with a decrease in balloon pressure in response to colorectal distention in non-RTX and RTX lesioned animals. Therefore, these data suggest that CANs contribute to visceral hypersensitivity during inflammation. (Source: Molecular Pain)

Nociception-induced spatial and temporal plasticity of synaptic connection and function in the hippocampal formation of rats: a multi-electrode array recording

Molecular Pain — Mon, 21 Sep 2009 23:00:00 +0100

Conclusion: Peripheral persistent nociception produces great impact upon the higher brain structures that lead to not only temporal plasticity, but also spatial plasticity of synaptic connection and function in the HF. The spatial plasticity of synaptic activities is more complex than the temporal plasticity, comprising of enlargement of synaptic connection size at network level, deformed fEPSP at local circuit level and, increased synaptic efficacy at cellular level. In addition, the multi-synaptic model established in the present investigation may open a new avenue for future studies of pain-related brain dysfunctions at the higher level of the neuromatrix. (Source: Molecular Pain)

Recombinant adeno-associated virus serotype 6 (rAAV2/6)-mediated gene transfer to nociceptive neurons through different routes of delivery

Molecular Pain — Mon, 07 Sep 2009 23:00:00 +0100

Conclusion: We have found that rAAV2/6 is an efficient vector to deliver transgenes to nociceptive neurons in mice. Furthermore, the characterization of the transduction profile may facilitate gene transfer studies to dissect mechanisms behind neuropathic pain. (Source: Molecular Pain)

Short-term synaptic plasticity in the nociceptive thalamic-anterior cingulate pathway

Molecular Pain — Thu, 03 Sep 2009 23:00:00 +0100

Conclusion: The potentiation of ACC neuronal activity induced by thalamic bursting suggest that short-term synaptic plasticities enable the processing of nociceptive information from the medial thalamus and this temporal response variability is particularly important in pain because temporal maintenance of the response supports cortical integration and memory formation related to noxious events. Moreover, these modifications of cingulate synapses appear to regulate afferent signals that may be important to the transition from acute to chronic pain conditions associated with persistent peripheral noxious stimulation. Enhanced and maintained nociceptive activities in cingulate cortex, therefore, can become adverse and it will be important to learn how to regulate such changes in thalamic fir...

Tumor necrosis factor- alpha (TNF-alpha) enhances functional thermal and chemical responses of TRP cation channels in human synoviocytes

Molecular Pain — Wed, 19 Aug 2009 23:00:00 +0100

Conclusion: TNF-a provides differentially enhanced synoviocyte TRPV1 and TRPV4 expression and [Ca2+]i response dependent on the TRP stimulus and time after exposure. Augmented relevance of TRPV1 and TRPV4 as inflammatory conditions persist would provide calcium mediated cell signaling required for pathophysiological responses of synoviocytes in inflammatory pain states. (Source: Molecular Pain)

Increased chemokine signaling in a model of HIV1-associated peripheral neuropathy

Molecular Pain — Tue, 11 Aug 2009 23:00:00 +0100

Painful distal sensory polyneuropathy (DSP) is the most common neurological complication of HIV1 infection. Although infection with the virus itself carries an incidence of DSP, patients are more likely to become symptomatic following initiation of nucleoside reverse transcriptase inhibitor (NRTI) treatment. The chemokines, monocyte chemoattractant protein-1 (MCP1/CCL2) and stromal derived factor-1 (SDF1/CXCL12) and their respective receptors, CCR2 and CXCR4, have been implicated in HIV1 related neuropathic pain mechanisms including NRTI treatment in rodents. Utilizing a rodent model that incorporates both the viral coat protein, gp120, and the NRTI, 2'3'-dideoxycytidine (ddC), we examined the degree to which chemokine receptor signaling via CCR2 and CXCR4 potentially influences the result...

Subtype-specific regulation of P2X3 and P2X2/3 receptors by phosphoinositides in peripheral nociceptors

Molecular Pain — Mon, 10 Aug 2009 23:00:00 +0100

Conclusion: Our findings indicate a functional regulation of homomeric P2X3 and heteromeric P2X2/3 ATP receptors by phosphoinositides in the plasma membrane of DRG nociceptors, based on subtype-specific mechanisms of direct and indirect lipid sensing. (Source: Molecular Pain)

Roles of the AMPA receptor subunit GluA1 but not GluA2 in synaptic potentiation and activation of ERK in the anterior cingulate cortex

Molecular Pain — Sun, 09 Aug 2009 23:00:00 +0100

Cortical areas including the anterior cingulate cortex (ACC) are important for pain and pleasure. Recent studies using genetic and physiological approaches have demonstrated that the investigation of basic mechanism for long-term potentiation (LTP) in the ACC may reveal key cellular and molecular mechanisms for chronic pain in the cortex. Glutamate N-methyl D-aspartate (NMDA) receptors in the ACC are critical for the induction of LTP, including both NR2A and NR2B subunits. However, cellular and molecular mechanisms for the expression of ACC LTP have been less investigated. Here, we report that the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit, GluA1 but not GluA2 contributes to LTP in the ACC using genetic manipulated mice lacking GluA1 or GluA2 gene. Fur...

Descending serotonergic facilitation and the antinociceptive effects of pregabalin in a rat model of osteoarthritic pain

Molecular Pain — Thu, 06 Aug 2009 23:00:00 +0100

Conclusion: These data suggest descending serotonergic facilitation plays a role in mediating the brush and innocuous mechanical punctate evoked neuronal responses in MIA rats, suggesting an adaptive change in the excitatory serotonergic drive modulating low threshold evoked neuronal responses in MIA-induced OA pain. This alteration in excitatory serotonergic drive, alongside an increase in alpha2delta-1 mRNA levels, may underlie pregabalin's state dependent effects in this model of chronic pain. (Source: Molecular Pain)

Proinflammatory-activated trigeminal satellite cells promote neuronal sensitization: relevance for migraine pathology

Molecular Pain — Wed, 05 Aug 2009 23:00:00 +0100

Conclusions: These findings indicate that satellite cells contribute to migraine-related neurochemical events and are induced to do so by autocrine/paracrine stimuli (such as IL-1beta and NO). The responsiveness of IL-1beta to CGRP creates the potential for a positive feedback loop and, thus, a plurality of targets for therapeutic intervention in migraine. (Source: Molecular Pain)

The endogenous hydrogen sulfide producing enzyme cystathionine-beta synthase contributes to visceral hypersensitivity in a rat model of irritable bowel syndrome

Molecular Pain — Wed, 05 Aug 2009 23:00:00 +0100

Conclusion: Our results suggest that upregulation of CBS expression in colonic DRG neurons and H2S signaling may play an important role in developing CVH, thus identifying a specific neurobiological target for the treatment of CVH in functional bowel syndromes. (Source: Molecular Pain)

Antinociception induced by chronic glucocorticoid treatment is correlated to local modulation of spinal neurotransmitter content

Molecular Pain — Thu, 23 Jul 2009 23:00:00 +0100

Conclusions: These data indicate that corticosteroids modulate nociception since chronic corticosteroid treatment alters the expression of neuropeptides involved in nociceptive transmission at the spinal cord level. As previously observed in some supraspinal areas, the exclusive GR activation resulted in more profound and sustained behavioural and neurochemical changes, than the one observed with a mixed ligand of corticosteroid receptors. These results might be of relevance for the pharmacological management of certain types of chronic pain, in which corticosteroids are used as adjuvant analgesics. (Source: Molecular Pain)

Translocation of neuronal nitric oxide synthase to the plasma membrane by ATP is mediated by P2X and P2Y receptors

Molecular Pain — Sun, 19 Jul 2009 23:00:00 +0100

Conclusions: ATP is involved in nNOS translocation mediated by protein kinase C via activation of P2X and P2Y receptors and nNOS translocation may be an action mechanism of ATP in nocieptive processing in the spinal cord.. (Source: Molecular Pain)

Expression and function of proton-sensing G-protein-coupled receptors in inflammatory pain

Molecular Pain — Mon, 13 Jul 2009 23:00:00 +0100

Conclusions: Each subtype of the OGR1 family was expressed differently, which may reflect differences between models in duration and magnitude of hyperalgesia. Given that TDAG8 and TRPV1 expression increased after CFA-induced inflammation and that TDAG8 activation can lead to TRPV1 sensitization, it suggests that high concentrations of protons after inflammation may not only directly activate proton-sensing ion channels (such as TRPV1) to cause pain but also act on proton-sensing GPCRs to regulate the development of hyperalgesia. (Source: Molecular Pain)

Evidence for a role of NTS2 receptors in the modulation of tonic pain sensitivity

Molecular Pain — Sun, 05 Jul 2009 23:00:00 +0100

Conclusion: The present study provides the first demonstration that activation of NTS2 receptors produces analgesia in the persistent inflammatory pain model of formalin. The dichotomy between these two classes of compounds also indicates that both NTS1 and NTS2 receptors are involved in tonic pain inhibition and implies that these two NT receptors modulate the pain-induced behavioral responses by acting on distinct spinal and/or supraspinal neural circuits. In conclusion, development of NT agonists targeting both NTS1 and NTS2 receptors could be useful for chronic pain management. (Source: Molecular Pain)

Minocycline treatment inhibits microglial activation and alters spinal levels of endocannabinoids in a rat model of neuropathic pain

Molecular Pain — Tue, 30 Jun 2009 23:00:00 +0100

Activation of spinal microglia contributes to aberrant pain responses associated with neuropathic pain states. Endocannabinoids (ECs) are present in the spinal cord, and inhibit nociceptive processing; levels of ECs may be altered by microglia which modulate the turnover of endocannabinoids in vitro. Here, we investigate the effect of minocycline, an inhibitor of activated microglia, on levels of the endocannabinoids anandamide and 2-arachidonylglycerol (2-AG), and the related compound N-palmitoylethanolamine (PEA), in neuropathic spinal cord. Selective spinal nerve ligation (SNL) in rats resulted in mechanical allodynia and the presence of activated microglia in the ipsilateral spinal cord. Chronic daily treatment with minocycline (30mg/kg, ip for 14 days) significantly reduced the develo...

Genetic variation in the serotonin transporter gene (5-HTTLPR, rs25531) influences the analgesic response to the short acting opioid Remifentanil in humans

Molecular Pain — Tue, 30 Jun 2009 23:00:00 +0100

Background: There is evidence from animal studies that serotonin (5-HT) can influence the antinociceptive effects of opioids at the spinal cord level. Therefore, there could be an influence of genetic polymorphisms in the serotonin system on individual variability in response to opioid treatment of pain. The serotonin transporter (5-HTT) is a key regulator of serotonin metabolism and availability and its gene harbors several known polymorphisms that are known to affect 5-HTT expression (e.g. 5-HTTLPR, rs25531). The aim of this study was to investigate if the triallelic 5-HTTLPR influences pain sensitivity or the analgesic effect of opioids in humans. 43 healthy volunteers (12 men, 31 women, mean age 26 years) underwent heat pain stimulations before and after intravenous injection of Remife...

Excitatory neurotransmitters in brain regions in interictal migraine patients

Molecular Pain — Mon, 29 Jun 2009 23:00:00 +0100

Conclusions: These results are consistent with glutamatergic abnormalities in the ACC and insula in migraine patients during their interictal period compared to healthy controls. An alteration in excitatory amino acid neurotransmitters and their derivatives may be a contributing factor for migraineurs for a decrease in sensitivity for migraine or a consequence of the chronic migraine state. Such findings, if extrapolated to other regions of the brain would offer new opportunities to modulate central system as interictal or preemptive medications in these patients. (Source: Molecular Pain)

PKCepsilon-dependent potentiation of TTX-resistant Nav1.8 current by neurokinin-1 receptor activation in rat dorsal root ganglion neurons

Molecular Pain — Mon, 29 Jun 2009 23:00:00 +0100

Conclusions: These data suggest that activation of NK-1 receptor potentiates Nav1.8 sodium current via PKCepsilon-dependent signaling pathway, probably participating in the generation of inflammatory hyperalgesia. (Source: Molecular Pain)

Ethnicity and OPRM variant independently predict pain perception and patient-controlled analgesia usage for post-operative pain

Molecular Pain — Mon, 22 Jun 2009 23:00:00 +0100

Conclusion: Our results suggest that ethnicity and OPRM 118A>G genotype are independent and significant contributors to variation in pain perception and postoperative morphine use in patients undergoing cesarean delivery. (Source: Molecular Pain)

Reactive oxygen species mediate TNFR1 increase after TRPV1 activation in mouse DRG neurons

Molecular Pain — Tue, 16 Jun 2009 23:00:00 +0100

Conclusion: TRPV1 activation increases TNFR1 in cultured mouse DRG neurons through a ROS signaling pathway, a novel sensitization mechanism in DRG neurons. (Source: Molecular Pain)

Challenges of functional imaging research of pain in children

Molecular Pain — Mon, 15 Jun 2009 23:00:00 +0100

Functional imaging has revolutionized the neurosciences. In the pain field it has dramatically altered our understanding of how the brain undergoes significant functional, anatomical and chemical changes in patients with chronic pain. However, most studies have been performed in adults. Because functional imaging is non-invasive and can be performed in awake individuals, applications in children have become more prevalent, but only recently in the pain field. Measures of changes in the brains of children have important implications in understanding neural plasticity in response to acute and chronic pain in the developing brain. Such findings may have implications for treatments in children affected by chronic pain and provide novel insights into chronic pain syndromes in adults. In this r...

An in vivo mouse model of long-term potentiation at synapses between primary afferent C-fibers and spinal dorsal horn neurons: essential role of EphB1 receptor

Molecular Pain — Thu, 11 Jun 2009 23:00:00 +0100

Conclusions: This study provides the first in vivo mouse model of C-LTP that will be valuable for studying synaptic plasticity, central sensitization and hyperalgesia. It further takes advantage of examining functional implications of a specific gene targeted mice and demonstrates that the EphB1 receptor is essential for development of C-LTP. (Source: Molecular Pain)

Formalin-induced behavioural hypersensitivity and neuronal hyperexcitability are mediated by rapid protein synthesis at the spinal level

Molecular Pain — Sun, 07 Jun 2009 04:00:00 +0100

Conclusions: We conclude that mTOR has a role in maintaining persistent inflammatory pain states via mRNA translation and thus protein synthesis. We hypothesise that mTOR may be activated by excitatory neurotransmitter release acting on sensory afferent terminals as well as dorsal horn spinal neurones, which can be further amplified by descending facilitatory systems originating from higher centres in the brain. (Source: Molecular Pain)

Cannabinoid receptor type 2 activation induces a microglial anti-inflammatory phenotype and reduces migration via MKP induction and ERK dephosphorylation

Molecular Pain — Thu, 28 May 2009 04:00:00 +0100

Conclusions: Our results uncover a cellular microglial pathway triggered by CBR2 activation. These data suggest that the reduction of pro-inflammatory factors and microglial migration via MKP-3 induction is part of the mechanism of action of CBR2 agonists. These findings may have clinical implications for further drug development. (Source: Molecular Pain)

NF-kappa B mediated enhancement of potassium currents by the chemokine CXCL1/growth related oncogene in small diameter rat sensory neurons

Molecular Pain — Thu, 28 May 2009 04:00:00 +0100

Conclusions: The results suggest that GRO/KC has important effects in inflammatory processes via its direct actions on sensory neurons, and that activation of NF-kappa B is involved in the GRO/KC-induced enhancement of K currents. (Source: Molecular Pain)

Inhibitory coupling between inhibitory interneurons in the spinal cord dorsal horn

Molecular Pain — Tue, 12 May 2009 04:00:00 +0100

Local inhibitory interneurons in the dorsal horn play an important role in the control of excitability at the segmental level and thus determine how nociceptive information is relayed to higher structures. Regulation of inhibitory interneuron activity may therefore have critical consequences on pain perception. Indeed, disinhibition of dorsal horn neuronal networks disrupts the balance between excitation and inhibition and is believed to be a key mechanism underlying different forms of pain hypersensitivity and chronic pain states. In this context, studying the source and the synaptic properties of the inhibitory inputs that the inhibitory interneurons receive is important in order to predict the impact of drug action at the network level. To address this, we studied inhibitory synaptic tr...

Intrathecal delivery of PDGF produces tactile allodynia through its receptors in spinal microglia

Molecular Pain — Mon, 11 May 2009 04:00:00 +0100

Neuropathic pain is a debilitating pain condition that occurs after nerve damage. Such pain is considered to be a reflection of the aberrant excitability of dorsal horn neurons. Emerging lines of evidence indicate that spinal microglia play a crucial role in neuronal excitability and the pathogenesis of neuropathic pain, but the mechanisms underlying neuron-microglia communications in the dorsal horn remain to be fully elucidated. A recent study has demonstrated that platelet-derived growth factor (PDGF) expressed in dorsal horn neurons contributes to neuropathic pain after nerve injury, yet how PDGF produces pain hypersensitivity remains unknown. Here we report an involvement of spinal microglia in PDGF-induced tactile allodynia. A single intrathecal delivery of PDGF B-chain homodimer (PD...

Antidepressants inhibit P2X4 receptor function: a possible involvement in neuropathic pain relief

Molecular Pain — Thu, 23 Apr 2009 04:00:00 +0100

Conclusions: These results suggest that paroxetine acts as a potent analgesic in the spinal cord via a mechanism independent of its inhibitory effect on serotonin transporters. Powerful inhibition of calcium influx via P2X4 receptors may underlie the analgesic effect of paroxetine, and it is possible that some antidepressants clinically used in patients with neuropathic pain show antiallodynic effects, at least in part via their inhibitory effects on P2X4 receptors. (Source: Molecular Pain)

Pharmacological blockade of TRPA1 inhibits mechanical firing in nociceptors

Molecular Pain — Tue, 21 Apr 2009 04:00:00 +0100

Conclusions: Our data show that acute pharmacological blockade of TRPA1 at the cutaneous receptive field inhibits formalin-evoked activation and markedly reduces mechanically-evoked action potential firing in C fibers. Thus, functional TRPA1 at sensory afferent terminals in skin is required for their responsiveness to both noxious chemical and mechanical stimuli. (Source: Molecular Pain)

High concentrations of morphine sensitize and activate mouse dorsal root ganglia via TRPV1 and TRPA1 receptors

Molecular Pain — Thu, 16 Apr 2009 04:00:00 +0100

Conclusions: Nociceptor activation and sensitization by morphine is conveyed by TRPV1 and TRPA1. (Source: Molecular Pain)

Transforming growth factor-β1 impairs neuropathic pain through pleiotropic effects

Molecular Pain — Fri, 27 Mar 2009 04:00:00 +0100

Conclusion: Our findings revealed that TGF-β1 is effective in the treatment of neuropathic by targeting both neurons and glial cells. We suggest that therapeutic agents such as TGF-β1 having multipotent effects on different types of cells could work in synergy to regain homeostasis in local spinal cord microenvironments, therefore contributing to attenuate neuropathic pain. (Source: Molecular Pain)

Transforming growth factor-beta1 impairs neuropathic pain through pleiotropic effects

Molecular Pain — Fri, 27 Mar 2009 04:00:00 +0100

Conclusion: Our findings revealed that TGF-beta1 is effective in the treatment of neuropathic by targeting both neurons and glial cells. We suggest that therapeutic agents such as TGF-beta1 having multipotent effects on different types of cells could work in synergy to regain homeostasis in local spinal cord microenvironments, therefore contributing to attenuate neuropathic pain. (Source: Molecular Pain)

Plasticity in expression of the glutamate transporters GLT-1 and GLAST in spinal dorsal horn glial cells following partial sciatic nerve ligation

Molecular Pain — Thu, 26 Mar 2009 04:00:00 +0100

Conclusion: These results indicate that the expression of glutamate transporters in astrocytes and microglia are differentially regulated following nerve injury. (Source: Molecular Pain)

Increased peripheral nerve excitability and local NaV1.8 mRNA up-regulation in painful neuropathy

Molecular Pain — Wed, 25 Mar 2009 04:00:00 +0100

Conclusions: Cuff entrapment injury resulted in significantly elevated axonal excitability and increased NaV1.8 immunoreactivity in rat sciatic nerves. The concomitant axonal accumulation of NaV1.8 mRNA may play a role in the pathogenesis of this model of neuropathic pain. (Source: Molecular Pain)

Characterization of NF-kappaB-mediated inhibition of catechol-O-methyltransferase

Molecular Pain — Mon, 16 Mar 2009 04:00:00 +0100

Conclusion: Collectively, our findings provide the first evidence for NF-kappaB-mediated inhibition of COMT expression in the central nervous system, suggesting that COMT contributes to the pathogenesis of inflammatory pain states. (Source: Molecular Pain)

Gz mediates the long-lasting desensitization of brain CB1 receptors and is essential for cross-tolerance with morphine

Molecular Pain — Tue, 10 Mar 2009 04:00:00 +0100

Conclusion: In the brain, cannabinoids can produce analgesic tolerance that is not associated with the loss of surface CB1Rs or their uncoupling from regulated transduction. Neural specific Gz proteins are essential mediators of the analgesic effects of supraspinal CB1R agonists and morphine. These Gz proteins are also responsible for the long-term analgesic tolerance produced by single doses of these agonists, as well as for the cross-tolerance between CB1Rs and MORs. (Source: Molecular Pain)

Peripheral nerve injury sensitizes neonatal dorsal horn neurons to tumor necrosis factor-alpha

Molecular Pain — Mon, 02 Mar 2009 05:00:00 +0100

Conclusions: Developing SDH neurons become susceptible to regulation by TNF-alpha following peripheral nerve injury in the neonate. This may include both a greater efficacy of glutamatergic synapses as well as an increase in the intrinsic excitability of immature dorsal horn neurons. However, neonatal sciatic nerve damage alone did not significantly modulate synaptic transmission or neuronal excitability in the SDH, which could reflect a relatively weak expression of TNF-alpha in the injured spinal cord at early ages. The above data suggest that although the sensitivity of the SDH network to proinflammatory cytokines after nerve injury is present from the first days of life,the profile of spinal cytokine expression under neuropathic conditions may be highly age-dependent. (Source: Molecula...

Mice with cisplatin and oxaliplatin-induced painful neuropathy develop distinct early responses to thermal stimuli

Molecular Pain — Thu, 26 Feb 2009 05:00:00 +0100

Conclusion: We have therefore established a model of platinum drug-induced painful peripheral neuropathy that reflects the differences in early thermal pain responses that are observed in patients treated with either cisplatin or oxaliplatin. This model should be useful in studying the molecular basis for these different pain responses and in designing protective therapeutic strategies. (Source: Molecular Pain)

Effects of removal of dietary polyunsaturated fatty acids on plasma extravasation and mechanical allodynia in a trigeminal neuropathic pain model

Molecular Pain — Wed, 25 Feb 2009 05:00:00 +0100

Conclusions: In summary, PUFA intake reduces CAP-induced neurogenic plasma extravasation in the trigeminal territory, and their removal significantly alters the mechanical allodynia and the plasma extravasation that result from a unilateral CCI-IoN. It is likely that this "protective" effect of dietary lipids is temporary. Also, the presence of contralateral effects of CCI-IoN precludes using the contralateral side as control. (Source: Molecular Pain)

Correlational analysis for identifying genes whose regulation contributes to chronic neuropathic pain

Molecular Pain — Thu, 19 Feb 2009 05:00:00 +0100

Conclusions: Correlational analysis based on in situ hybridization provided evidence that differential regulation of Scn11a and Trpm8 contributes to across-strain variability in pain phenotype. This does not, of course, constitute evidence that the others are unrelated to pain. Correlational analysis based on microarray data yielded a larger "look-up table" of genes whose regulation likely contributes to pain variability. While this list is enriched in genes of potential importance for pain physiology, and is relatively free of the bias inherent in the candidate gene approach, additional steps are required to clarify which transcripts on the list are in fact of functional importance. (Source: Molecular Pain)

Modulation of transient receptor potential vanilloid 4-mediated membrane currents and synaptic transmission by protein kinase C

Molecular Pain — Tue, 10 Feb 2009 05:00:00 +0100

Conclusions: These results indicate that TRPV4 and TRPV1 are co-expressed in certain DRG neurons and TRPV4 can be sensitized by PKC not only in DRG neuronal cell bodies, but also in the central sensory and non-sensory nerve terminals. Co-expression of TRPV1 and TRPV4 ion channels, their modulation of synaptic transmission and their sensitization by PKC may synergistically play a role in nociception. (Source: Molecular Pain)

Enhanced quantal release of excitatory transmitter in anterior cingulate cortex of adult mice with chronic pain

Molecular Pain — Tue, 27 Jan 2009 05:00:00 +0100

The anterior cingulate cortex (ACC) is a forebrain structure that plays important roles in emotion, learning, memory and persistent pain. Our previous studies have demonstrated that the enhancement of excitatory synaptic transmission was induced by peripheral inflammation and nerve injury in ACC synapses. However, little information is available on their presynaptic mechanisms, since the source of the enhanced synaptic transmission could include the enhanced probability of neurotransmitter release at existing release sites and/or increases in the number of available vesicles. The present study aims to perform quantal analysis of excitatory synapses in the ACC with chronic pain to examine the source of these increases. The quantal analysis revealed that both probability of transmitter relea...

Role of spinal cord alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors in complete Freund's adjuvant-induced inflammatory pain

Molecular Pain — Tue, 30 Dec 2008 05:00:00 +0100

Spinal cord alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) mediate acute spinal processing of nociceptive and non-nociceptive information, but whether and how their activation contributes to the central sensitization that underlies persistent inflammatory pain are still unclear. Here, we examined the role of spinal AMPARs in the development and maintenance of complete Freund's adjuvant (CFA)-induced persistent inflammatory pain. Intrathecal application of two selective non-competitive AMPAR antagonists, CFM-2 (25 and 50 ug) and GYKI 52466 (50 ug), significantly attenuated mechanical and thermal hypersensitivities on the ipsilateral hind paw at 2 and 24 h post-CFA injection. Neither CFM-2 nor GYKI 52466 affected the contralateral basal responses to thermal and m...

Genetic variation in the Catechol-O-Methyltransferase (COMT) gene and morphine requirements in cancer patients with pain

Molecular Pain — Thu, 18 Dec 2008 05:00:00 +0100

Conclusion: This study suggests that genetic variability in the COMT gene influence the efficacy of morphine in cancer patients with pain, and that increased understanding of this variability is reached by expanding from analyses of single SNPs to haplotype construction and analyses. (Source: Molecular Pain)

Targeted mutation of EphB1 receptor prevents development of neuropathic hyperalgesia and physical dependence on morphine in mice

Molecular Pain — Fri, 21 Nov 2008 05:00:00 +0100

EphB receptor tyrosine kinases, which play important roles in synaptic connection and plasticity during development and in matured nervous system, have recently been implicated in processing of pain after nerve injury and morphine dependence. Subtypes of the EphB receptors that may contribute to the neuropathic pain and morphine dependence have not been identified. Here we demonstrate that the subtype EphB1 receptor is necessary for development of neuropathic pain and physical dependence on morphine. The results showed that peripheral nerve injury produced thermal hyperalgesia in wild-type (EphB1+/+) control littermate mice, but not in EphB1 receptor homozygous knockout (EphB1-/-) and heterozygous knockdown (EphB1+/-) mice. Hyperalgesia in the wild-type mice was inhibited by intrathecal ad...

FMRI Connectivity Analysis of Acupuncture Effects on an Amygdala-Associated Brain Network

Molecular Pain — Thu, 13 Nov 2008 05:00:00 +0100

Conclusions: Our findings indicate that acupuncture may change this amygdala-specific brain network into a functional state that underlies pain perception and pain modulation. (Source: Molecular Pain)

Sumatriptan inhibits synaptic transmission in the rat midbrain periaqueductal grey

Molecular Pain — Tue, 11 Nov 2008 05:00:00 +0100

Conclusions: These results indicate that sumatriptan inhibits GABAergic and glutamatergic synaptic transmission within the PAG via a 5-HT1B/D receptor mediated reduction in the probability of neurotransmitter release from nerve terminals. These actions overlap those of other analgesics, such as opioids, and provide a mechanism by which centrally acting 5-HT1B and 5-HT1D ligands might lead to novel anti-migraine pharmacotherapies. (Source: Molecular Pain)

Prolonged gabapentin analgesia in an experimental mouse model of fibromyalgia

Molecular Pain — Thu, 06 Nov 2008 05:00:00 +0100

In a new mouse model for generalized pain syndrome, including fibromyalgia, which used intermittent cold stress (ICS), bilateral allodynia in the hindpaw was observed that lasted more than 12 days; thermal hyperalgesia lasted 15 days. During constant cold stress (CCS), mice showed only a transient allodynia. A female prevalence in ICS-induced allodynia was observed in gonadectomized but not in gonad intact mice. Systemic gabapentin showed complete anti-allodynic effects in the ICS model at the one-tenth dose for injury-induced neuropathic pain model, and central gabapentin showed long-lasting analgesia for 4 days in ICS, but not the injury model. These results suggest that the ICS model is useful for the study of generalized pain syndrome. (Source: Molecular Pain)

Quantitative Real-Time PCR detection of TRPV1-4 gene expression in human leukocytes from healthy and hyposensitive subjects.

Molecular Pain — Tue, 04 Nov 2008 05:00:00 +0100

Conclusions: The qRT-PCR assay developed and tested in this study allowed us to determine the relative expression of TRPV1-4 genes in human leukocytes: TRPV3 is the least expressed gene of this pool, followed by TRPV4, TRPV1 and TRPV2. The comparison of TRPV1-4 gene expression between two groups of healthy and hyposensitive subjects highlighted the evident up-regulation of TRPV1, which was almost doubly expressed (1.9X normalized fold induction) in the latter group. All the four house-keeping genes tested in this work (Act-B, GAPDH, hCyPB, HPRT1) were classified as optimal controls and showed a constant expression in human leukocytes samples. We recommend the use of these genes in similar qRT-PCR studies on human blood cells. (Source: Molecular Pain)

Differential regulation of morphine antinociceptive effects by endogenous enkephalinergic system in the forebrain of mice

Molecular Pain — Tue, 30 Sep 2008 04:00:00 +0100

Conclusions: The present results indicate that the endogenous enkephalin system is not involved in acute nociceptive transmission in the spinal cord, S1, and ACC. However, morphine preferentially suppressed supraspinal related nociceptive behavior in KO mice. This effect was reflected in the potentiated differential effects of morphine in the S1 and ACC in KO mice. This potentiation may be due to an up-regulation of opioid receptors. Thus these findings strongly suggest an antagonistic interaction between the endogenous enkephalinergic system and exogenous opioid analgesic actions in the supraspinal brain structures. (Source: Molecular Pain)

Enhancement of Presynaptic Glutamate Release and Persistent Inflammatory Pain by Increasing Neuronal cAMP in the Anterior Cingulate Cortex

Molecular Pain — Mon, 29 Sep 2008 04:00:00 +0100

Both presynaptic and postsynaptic alterations are associated with plastic changes of brain circuits, such as learning and memory, drug addiction and chronic pain. However, the dissection of the relative contributions of pre- and postsynaptic components to brain functions is difficult. We have previously shown peripheral inflammation caused both presynaptic and postsynaptic changes and calcium-stimulated cyclic AMP (cAMP) pathway in the anterior cingulate cortex (ACC) is critical in the synaptic plasticity and behavioral sensitization to pain. It remains to be elucidated whether presynaptic or postsynaptic modulation by cAMP in the ACC could be sufficient for enhancing inflammatory pain. In order to address this question, we took advantage of a novel transgenic mouse model, heterologously e...

The chemokine CXCL1/growth related oncogene increases sodium currents and neuronal excitability in small diameter sensory neurons

Molecular Pain — Wed, 24 Sep 2008 04:00:00 +0100

Conclusions: Many studies on the role of chemokines in pain conditions have focused on their rapid and indirect effects on neurons, via release of inflammatory mediators from immune and glial cells. Our study suggests that GRO/KC may also have important pro-nociceptive effects via its direct actions on sensory neurons, and may induce long-term changes that involve protein synthesis. (Source: Molecular Pain)

The role of cation-dependent chloride transporters in neuropathic pain following spinal cord injury

Molecular Pain — Wed, 17 Sep 2008 04:00:00 +0100

This study investigated the role of two major intracellular Cl- regulatory proteins, Na+-K+-Cl- cotransporter 1 (NKCC1) and K+-Cl- cotransporter 2 (KCC2), in neuropathic pain following spinal cord injury (SCI). Sprague-Dawley rats underwent a contusive SCI at T9 using the MASCIS impactor. The rats developed hyperalgesia between days 21 and 42 post-SCI. Thermal hyperalgesia (TH) was determined by a decrease in hindpaw thermal withdrawal latency time (WLT) between days 21 and 42 post-SCI. Rats with TH were then treated with either vehicle (saline containing 0.25% NaOH) or NKCC1 inhibitor bumetanide (BU, 30mg/kg, i.p.) in vehicle. TH was then re-measured at 1 h post-injection. Administration of BU significantly increased the mean WLT in rats (p < 0.05). The vehicle alone administration group ...

Descending serotonergic controls regulate inflammation-induced mechanical sensitivity and methyl-CpG-binding protein 2 phosphorylation in the rat superficial dorsal horn

Molecular Pain — Mon, 15 Sep 2008 04:00:00 +0100

Conclusions: We conclude that descending serotonergic pathways play a crucial role in regulating gene expression in the dorsal horn and mechanical sensitivity associated with an inflammatory pain state. (Source: Molecular Pain)

Modulation of chloride homeostasis by inflammatory mediators in dorsal root ganglion neurons

Molecular Pain — Tue, 12 Aug 2008 04:00:00 +0100

Conclusion: Our findings indicate that inflammatory mediators impact on Cl- homeostasis in DRG neurons. Inflammatory mediators raise intracellular Cl- levels and, hence, the driving force for depolarizing Cl- efflux. These findings corroborate current concepts for the role of Cl- regulation in the generation of inflammatory hyperalgesia and allodynia. As the intracellular Cl- concentration rises in DRG neurons, afferent signals can be boosted by excitatory Cl- currents in the presynaptic terminals. Moreover, excitatory Cl- currents in peripheral sensory endings may also contribute to the generation or modulation of afferent signals, especially in inflamed tissue. (Source: Molecular Pain)

Modulation of chloride homeostasis by inflammatory mediators in dorsal root ganglion neurons

Molecular Pain — Tue, 12 Aug 2008 04:00:00 +0100

Conclusions: Our findings indicate that inflammatory mediators impact on Cl homeostasis in DRG neurons. Inflammatory mediators raise intracellular Cl levels and, hence, the driving force for depolarizing Cl efflux. These findings corroborate current concepts for the role of Cl regulation in the generation of inflammatory hyperalgesia and allodynia. As the intracellular Cl concentration rises in DRG neurons, afferent signals can be boosted by excitatory Cl currents in the presynaptic terminals. Moreover, excitatory Cl currents in peripheral sensory endings may also contribute to the generation or modulation of afferent signals, especially in inflamed tissue. (Source: Molecular Pain)

Proteomic profiling of neuromas reveals alterations in protein composition and local protein synthesis in hyper-excitable nerves

Molecular Pain — Tue, 12 Aug 2008 04:00:00 +0100

Neuropathic pain may arise following peripheral nerve injury though the molecular mechanisms associated with this are unclear. We used proteomic profiling to examine changes in protein expression associated with the formation of hyper-excitable neuromas derived from rodent saphenous nerves. A two-dimensional difference gel electrophoresis (2D-DIGE) profiling strategy was employed to examine protein expression changes between developing neuromas and normal nerves in whole tissue lysates. We found around 200 proteins which displayed a >1.75-fold change in expression between neuroma and normal nerve and identified 55 of these proteins using mass spectrometry. We also used immunoblotting to examine the expression of low-abundance ion channels Nav1.3, Nav1.8 and calcium channel alpha 2 delta -1...

Pharmacological switch in Aβ-fiber stimulation-induced spinal transmission in mice with partial sciatic nerve injury

Molecular Pain — Fri, 11 Jul 2008 04:00:00 +0100

Conclusion: These results suggest that Aβ-fiber perception is newly transmitted to spinal neurons, which originally receive only Aδ- and C-fiber-mediated pain transmission, through NMDA receptor-mediated mechanisms, in animals with nerve injury. This pharmacological switch in Aβ-fiber spinal transmission could be a mechanism underlying neuropathic allodynia. (Source: Molecular Pain)

Compound heterozygosity in sodium channel Nav1.7 in a family with hereditary erythermalgia

Molecular Pain — Mon, 02 Jun 2008 04:00:00 +0100

Hereditary erythermalgia is a painful and debilitating genetic disorder associated with mutations in voltage-gated sodium channel Nav1.7. We have previously reported a Canadian family segregating erythermalgia consistent with a dominant genetic etiology. Molecular analysis of the proband from the family detected two different missense mutations in Nav1.7. In the present study we have performed a long-term follow-up clinical study of disease progression in three affected family members. A more extensive molecular study has also been completed, analyzing the segregation of the two missense variants in the family. The two variants (P610T, L858F) segregate independently with respect to clinical presentation. Detailed genotype/phenotype correlation suggests that one of the two variants (L858F) ...

Differing alterations of sodium currents in small dorsal root ganglion neurons after ganglion compression and peripheral nerve injury

Molecular Pain — Fri, 30 May 2008 04:00:00 +0100

This study also points to a complexity of hyperexcitability mechanisms contributing to CCD and CCI hyperexcitability in small DRG neurons. (Source: Molecular Pain)

Nav1.7 expression is increased in painful human dental pulp

Molecular Pain — Mon, 21 Apr 2008 04:00:00 +0100

Conclusions: This study identifies the increased axonal expression and augmentation of Nav1.7 at intact and remodeling/demyelinating nodes within the painful human dental pulp where these changes may contribute to constant, increased evoked and spontaneous pain responses that characterize the pain associated with toothache. (Source: Molecular Pain)

Selective activation of microglia in spinal cord but not higher cortical regions following nerve injury in adult mouse

Molecular Pain — Fri, 18 Apr 2008 04:00:00 +0100

Neuronal plasticity along the pathway for sensory transmission including the spinal cord and cortex plays an important role in chronic pain, including inflammatory and neuropathic pain. While recent studies indicate that microglia in the spinal cord are involved in neuropathic pain, a systematic study has not been performed in other regions of the central nervous system (CNS). In the present study, we used heterozygous Cx3cr1GFP/+ mice to characterize the morphological phenotypes of microglia following common peroneal nerve (CPN) ligation. We found that microglia showed a uniform distribution throughout the CNS, and peripheral nerve injury selectively activated microglia in the spinal cord dorsal horn and related ventral horn. In contrast, microglia was not activated in supraspinal regions...

Release of glutamate and CGRP from trigeminal ganglion neurons: Role of calcium channels and 5-HT1 receptor signaling

Molecular Pain — Wed, 16 Apr 2008 04:00:00 +0100

Conclusions: These data suggest that release of both glutamate and CGRP from trigeminal neurons is controlled by calcium channels and modulated by 5-HT signaling in a pertussis-toxin dependent manner and probably via 5-HT1 receptor signaling. This is the first characterization of glutamate release from trigeminal neurons grown in culture. (Source: Molecular Pain)

A computational model for sex-specific genetic architecture of complex traits in humans: Implications for mapping pain sensitivity

Molecular Pain — Wed, 16 Apr 2008 04:00:00 +0100

Understanding differences in the genetic architecture of complex traits between the two sexes has significant implications for evolutionary studies and clinical diagnosis. However, our knowledge about sex-specific genetic architecture is limited largely because of a lack of analytical models that can detect and quantify the effects of sex on the complexity of quantitative genetic variation. Here, we derived a statistical model for mapping DNA sequence variants that contribute to sex-specific differences in allele frequencies, linkage disequilibria, and additive and dominance genetic effects due to haplotype diversity. This model allows a genome-wide search for functional haplotypes and the estimation and test of haplotype by sex interactions and sex-specific heritability. The model, valida...

Vascularization of the dorsal root ganglia and peripheral nerve of the mouse: Implications for chemical-induced peripheral sensory neuropathies

Molecular Pain — Wed, 19 Mar 2008 04:00:00 +0100

Although a variety of industrial chemicals, as well as several chemotherapeutic agents used to treat cancer or HIV, preferentially induce a peripheral sensory neuropathy what remains unclear is why these agents induce a sensory vs. a motor or mixed neuropathy. Previous studies have shown that the endothelial cells that vascularize the dorsal root ganglion (DRG), which houses the primary afferent sensory neurons, are unique in that they have large fenestrations and are permeable to a variety of low and high molecular weight agents. In the present report we used whole-mount preparations, immunohistochemistry, and confocal laser scanning microscopy to show that the cell body-rich area of the L4 mouse DRG has a 7 fold higher density of CD31+ capillaries than cell fiber rich area of the DRG or ...

Influence of TRPV1 on diabetes-induced alterations in thermal pain sensitivity

Molecular Pain — Sat, 01 Mar 2008 05:00:00 +0100

A common complication associated with diabetes is painful or painless diabetic peripheral neuropathy (DPN). The mechanisms and determinants responsible for these peripheral neuropathies are poorly understood. Using both streptozotocin (STZ)-induced and transgene-mediated murine models of type 1 diabetes (T1D), we demonstrate that Transient Receptor Potential Vanilloid 1 (TRPV1) expression varies with the neuropathic phenotype. We have found that both STZ- and transgene-mediated T1D are associated with two distinct phases of thermal pain sensitivity that parallel changes in TRPV1 as determined by paw withdrawal latency (PWL). An early phase of hyperalgesia and a late phase of hypoalgesia are evident. TRPV1-mediated whole cell currents are larger and smaller in dorsal root ganglion (DRG) neu...

Enkephalin-encoding herpes simplex virus-1 decreases inflammation and hotplate sensitivity in a chronic pancreatitis model

Molecular Pain — Thu, 28 Feb 2008 05:00:00 +0100

Conclusions: Thus, clear evidence is provided that site specific HSV-mediated transgene delivery of human cDNA encoding preproenkephalin ameliorates pancreatic inflammation and significantly reduces hypersensitive hotplate responses for an extended time (4-6 weeks) consistent with HSV mediated overexpression, without tolerance or evidence of other opiate related side effects. (Source: Molecular Pain)

Chronic morphine administration enhances nociceptive sensitivity and local cytokine production after incision

Molecular Pain — Fri, 22 Feb 2008 05:00:00 +0100

Conclusions: The enhanced level of nociceptive sensitization seen after incision in animals chronically exposed to morphine is associated with elevated levels of several cytokines previously reported to be relevant to this incisional pain model. The cytokines may be functional in supporting nociceptive sensitization because pentoxifylline reverses both peri-incisional skin cytokine levels and OIH. Opioid administration beginning at the time of incision does not seem to have the same cytokine enhancing effect. Approaches to postoperative pain control involving a reduction of cytokines may be an effective way to control excessive pain in patients chronically using opioids prior to surgical procedures. (Source: Molecular Pain)

Autotaxin, a synthetic enzyme of lysophosphatidic acid (LPA), mediates the induction of nerve-injured neuropathic pain

Molecular Pain — Fri, 08 Feb 2008 05:00:00 +0100

Recently, we reported that lysophosphatidic acid (LPA) induces long-lasting mechanical allodynia and thermal hyperalgesia as well as demyelination and upregulation of pain-related proteins through one of its cognate receptors, LPA1. In addition, mice lacking the LPA1 receptor gene (lpa1-/- mice) lost these nerve injury-induced neuropathic pain behaviors and phenomena. However, since lpa1-/- mice did not exhibit any effects on the basal nociceptive threshold, it is possible that nerve injury-induced neuropathic pain and its machineries are initiated by LPA via defined biosynthetic pathways that involve multiple enzymes. Here, we attempted to clarify the involvement of a single synthetic enzyme of LPA known as autotaxin (ATX) in nerve injury-induced neuropathic pain. Wild-type mice with part...

Expression of AMPA receptor subunits at synapses in laminae I-III of the rodent spinal dorsal horn

Molecular Pain — Wed, 23 Jan 2008 05:00:00 +0100

Conclusions: Our results suggest that virtually all glutamatergic synapses in laminae I-III of adult rat spinal cord contain AMPArs. They show that synapses in laminae I-II contain GluR2 together with GluR1 and/or GluR3, while the long form of GluR4 is restricted to specific neuronal populations, which may include some lamina I projection cells. They also provide further evidence that immunostaining for AMPAr subunits following antigen retrieval is a reliable method for detecting these receptors at glutamatergic synapses. (Source: Molecular Pain)

Hit a new high

Molecular Pain — Mon, 21 Jan 2008 05:00:00 +0100

Over the past three years Molecular Pain has grown steadily and clearly demonstrated its ability to publish novel scientific discoveries in the field of pain research in a timely fashion, hence having a strong and positive impact on pain and neuroscience research. Molecular Pain is now officially tracked by the ISI Web of Science, which allows for the calculation of its impact factor. From this calculation, we have found that Molecular Pain is now ranked at the top among pain journals in the world. (Source: Molecular Pain)

Perineural resiniferatoxin selectively inhibits inflammatory hyperalgesia

Molecular Pain — Wed, 16 Jan 2008 05:00:00 +0100

In this study, we evaluated low, graded, doses of perineural RTX as a method for regional pain control. We hypothesized that this approach can provide long-term, but reversible, blockade of a portion of nociceptive afferent fibers within peripheral nerves when given at a site remote from the neuronal perikarya in the dorsal root ganglia. Following perineural RTX application to the sciatic nerve, we demonstrated a significant inhibition of inflammatory nociception that was dose- and time-dependent. At the same time, treated animals maintained normal proprioceptive sensations and motor control, and other nociceptive responses were largely unaffected. Using a range of mechanical and thermal algesic tests, we found that the most sensitive measure following perineural RTX administration was in...

The effect of deletion of the orphan G - protein coupled receptor (GPCR) gene MrgE on pain-like behaviours in mice

Molecular Pain — Tue, 15 Jan 2008 05:00:00 +0100

Conclusions: The data suggests that MrgE may play a role in selective pain behavioural responses in mice. (Source: Molecular Pain)

Species-specific pharmacology of Trichloro(sulfanyl)ethyl benzamides as transient receptor potential ankyrin 1 (TRPA1) antagonists

Molecular Pain — Mon, 17 Dec 2007 05:00:00 +0100

Agonists of TRPA1 such as mustard oil and its key component AITC cause pain and neurogenic inflammation in humans and pain behavior in rodents. TRPA1 is activated by numerous reactive compounds making it a sensor for reactive compounds in the body. Failure of AITC, formalin and other reactive compounds to trigger pain behavior in TRPA1 knockout mice, as well as the ability of TRPA1 antisense to alleviate cold hyperalgesia after spinal nerve ligation, suggest that TRPA1 is a potential target for novel analgesic agents. Here, we have characterized CHO cells expressing human and rat TRPA1 driven by an inducible promoter. As reported previously, both human and rat TRPA1 are activated by AITC and inhibited by ruthenium red. We have also characterized noxious cold response of these cell lines an...

A role of TRPA1 in mechanical hyperalgesia is revealed by pharmacological inhibition

Molecular Pain — Mon, 17 Dec 2007 05:00:00 +0100

Mechanical hyperalgesia is a clinically-relevant form of pain sensitization that develops through largely unknown mechanisms. TRPA1, a Transient Receptor Potential ion channel, is a sensor of pungent chemicals that may play a role in acute noxious mechanosensation and cold thermosensation. We have developed a specific small molecule TRPA1 inhibitor (AP18) that can reduce cinnameldehyde-induced nociception in vivo. Interestingly, AP18 is capable of reversing CFA-induced mechanical hyperalgesia in mice. Although TRPA1-deficient mice develop normal CFA-induced hyperalgeisa, AP18 is ineffective in the knockout mice, consistent with an on-target mechanism. Therefore, TRPA1 plays a role in sensitization of nociception, and that compensation in TRPA1-deficient mice masks this requirement. (Source...

Delayed functional expression of neuronal chemokine receptors following focal nerve demyelination in the rat: a mechanism for the development of chronic sensitization of peripheral nociceptors

Molecular Pain — Wed, 12 Dec 2007 05:00:00 +0100

Conclusion: These results suggest that the presence of chemokine signaling by both injured and adjacent, uninjured sensory neurons is correlated with the maintenance phase of a persistent pain state, suggesting that chemokine receptor antagonists may be an important therapeutic intervention for chronic pain. (Source: Molecular Pain)

Trafficking of central opioid receptors and descending pain inhibition

Molecular Pain — Tue, 04 Dec 2007 05:00:00 +0100

This article reviews current understanding of the mechanisms underlying the analgesic functions of the emerged DOR through membrane trafficking under certain pathophysiological circumstances. (Source: Molecular Pain)

Requirement of extracellular signal-regulated kinase/mitogen-activated protein kinase for long-term potentiation in adult mouse anterior cingulate cortex

Molecular Pain — Sat, 01 Dec 2007 05:00:00 +0100

In this study, we examined whether LTP in ACC requires the activation of ERK. We found that P42/P44 MAPK inhibitors, PD98059 and U0126, suppressed the induction of cingulate LTP that was induced by presynaptic stimulation with postsynaptic depolarization (the pairing protocol). We also showed that cingulate LTP induced by two other different protocols was also blocked by PD98059. Moreover, we found that these two inhibitors had no effect on the maintenance of cingulate LTP. Inhibitors of c-Jun N-terminal kinase (JNK) and p38, other members of MAPK family, SP600125 and SB203850, suppressed the induction of cingulate LTP generated by the pairing protocol. Thus, our study suggests that the MAPK signaling pathway is involved in the induction of cingulate LTP and plays a critical role in physio...

Neurokinin-1 (NK-1) receptor and brain-derived neurotrophic factor (BDNF) gene expression is differentially modulated in the rat spinal dorsal horn and hippocampus during inflammatory pain

Molecular Pain — Wed, 31 Oct 2007 04:00:00 +0100

Persistent pain produces complex alterations in sensory pathways of the central nervous system (CNS) through activation of various nociceptive mechanisms. However, the effects of pain on higher brain centers, particularly the influence of the stressful component of pain on the limbic system, are poorly understood. Neurokinin-1 (NK-1) receptors and brain-derived neurotrophic factor (BDNF), known neuromediators of hyperalgesia and spinal central sensitization, have also been implicated in the plasticity and neurodegeneration occurring in the hippocampal formation during exposures to various stressors. Results of this study showed that injections of complete Freund's adjuvant (CFA) into the hind paw increased NK-1 receptor and BDNF mRNA levels in the ipsilateral dorsal horn, supporting an imp...

Marked attenuation of inflammatory mediator-induced C-fiber sensitization for mechanical and hypotonic stimuli in TRPV4-/- mice

Molecular Pain — Mon, 29 Oct 2007 04:00:00 +0100

Inflammatory mediators can directly sensitize primary afferent nociceptors to mechanical and osmotic stimuli. Sensitized nociceptors have a lowered threshold of activation and increased spontaneous activity, which result in symptoms of hyperalgesia and pain, respectively. The transient receptor potential vanilloid 4 (TRPV4) ligand-gated ion channel has been implicated in the hyperalgesia for mechanical and osmotic stimuli associated with inflammatory states. To investigate whether TRPV4 directly contributes to the mechanisms of inflammatory mediator sensitization of C-fiber nociceptors, we compared the effect of the injection of simplified inflammatory soup (prostaglandin E2 and serotonin) into the mechanical receptive fields of C-fibers in TRPV4+/+ and TRPV4-/- mice in vivo. Following the...

Roles of TRPV1 and neuropeptidergic receptors in dorsal root reflex-mediated neurogenic inflammation induced by intradermal injection of capsaicin

Molecular Pain — Thu, 25 Oct 2007 04:00:00 +0100

Conclusion: Our data suggest that 1) the generation of DRRs is critical for driving the release of neuropeptides antidromically from primary afferent nociceptors; 2) activation of TRPV1 receptors in primary afferent nociceptors following intradermal capsaicin injection initiates this process; 3) the released CGRP and SP participate in neurogenic inflammation. (Source: Molecular Pain)

Genetic knockout and pharmacologic inhibition of neuronal nitric oxide synthase attenuate nerve injury-induced mechanical hypersensitivity in mice

Molecular Pain — Mon, 08 Oct 2007 04:00:00 +0100

Neuronal nitric oxide synthase (nNOS) is a key enzyme for nitric oxide production in neuronal tissues and contributes to the spinal central sensitization in inflammatory pain. However, the role of nNOS in neuropathic pain remains unclear. The present study combined a genetic strategy with a pharmacologic approach to examine the effects of genetic knockout and pharmacologic inhibition of nNOS on neuropathic pain induced by unilateral fifth lumbar spinal nerve injury in mice. In contrast to wildtype mice, nNOS knockout mice failed to display nerve injury-induced mechanical hypersensitivity. Furthermore, either intraperitoneal (100 mg/kg) or intrathecal (30 ug/5 ul) administration of L-NG-nitro-arginine methyl ester, a nonspecific NOS inhibitor, significantly reversed nerve injury-induced mec...

Transformation of the output of spinal lamina I neurons after nerve injury and microglia stimulation underlying neuropathic pain

Molecular Pain — Thu, 27 Sep 2007 04:00:00 +0100

Conclusions: The transformation of discharge activity and sensory specificity provides an aberrant signal in a primarily nociceptive ascending pathway that may serve as a basis for the symptoms of neuropathic pain. (Source: Molecular Pain)

The activation of nicotinic acetylcholine receptors enhances the inhibitory synaptic transmission in the deep dorsal horn neurons of the adult rat spinal cord

Molecular Pain — Tue, 25 Sep 2007 04:00:00 +0100

Somatosensory information can be modulated by nicotinic acetylcholine receptors (nAChRs) in the superficial dorsal horn of the spinal cord. Nonetheless, the functional significance of nAChRs in the deep dorsal horn of adult animals remains unclear. Using whole-cell patch-clamp recordings from lamina V neurons in the adult rat spinal cord, we investigated whether the activation of nAChRs could modulate the inhibitory synaptic transmission in the deep dorsal horn. In the presence of CNQX and APV to block excitatory glutamatergic synaptic transmission, bath applications of nicotine (100 microM) significantly increased the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) in almost all neurons tested. The effect of nicotine was mimicked by N-methyl-4-(3-pyridinyl)-3-butene-1-a...

Mice left out in the cold: commentary on the phenotype of TRPM8-nulls.

Molecular Pain — Fri, 17 Aug 2007 04:00:00 +0100

Detection of innocuous temperatures allows an organism to select an appropriate environmental climate, while the ability to recognize noxious temperature extremes warns of impending tissue damage. For temperatures considered cold, the menthol receptor TRPM8 is activated when temperatures drop below ~26degreesC, thus making it an intriguing candidate as the molecular mediator of cold perception. However, confirmation of this hypothesis in vivo has eluded researchers until recently. Three independent research groups have reported that mice lacking this single gene are severely impaired in their ability to detect cold temperatures. Remarkably, these animals are deficient in many diverse aspects of cold signaling, including cool and noxious cold perception, injury-evoked sensitization to cold,...

Prostaglandin E2 potentiation of P2X3 receptor mediated currents in dorsal root ganglion neurons

Molecular Pain — Fri, 10 Aug 2007 04:00:00 +0100

Prostaglandin E2 (PGE2) is a well-known inflammatory mediator that enhances the excitability of DRG neurons. Homomeric P2X3 and heteromeric P2X2/3 receptors are abundantly expressed in dorsal root ganglia (DRG) neurons and participate in the transmission of nociceptive signals. The interaction between PGE2 and P2X3 receptors has not been well delineated. We studied the actions of PGE2 on ATP-activated currents in dissociated DRG neurons under voltage-clamp conditions. PGE2 had no effects on P2X2/3 receptor-mediated responses, but significantly potentiated fast-inactivating ATP currents mediated by homomeric P2X3 receptors. PGE2 exerted its action by activating EP3 receptors. To study the mechanism underlying the action of PGE2, we found that the adenylyl cyclase activator, forskolin and th...

Delayed sympathetic dependence in the spared nerve injury (SNI) model of neuropathic pain

Molecular Pain — Tue, 31 Jul 2007 04:00:00 +0100

Conclusions: These results suggest that the early establishment of neuropathic pain-related behavior after distal nerve injury such as in the SNI model is mechanistically independent of the sympathetic system, whereas the system contributes to the maintenance, albeit after a delay of many weeks, of response to cold-related stimuli. (Source: Molecular Pain)

Do motor control genes contribute to interindividual variability in decreased movement in patients with pain?

Molecular Pain — Thu, 26 Jul 2007 04:00:00 +0100

Conclusions: If confirmed, the current results may suggest that a common haplotype in the GABA-A beta-1 subunit acts like an "endogenous muscle relaxant" in some patients with subacute sciatica. Similar methods might be applied a larger set of genes in animal models and human laboratory and clinical studies to understand the causes and prevention of pain-related reduction in movement. (Source: Molecular Pain)

Morphine induces endocytosis of neuronal mu-opioid receptors through the sustained transfer of Galpha subunits to RGSZ2 proteins

Molecular Pain — Tue, 17 Jul 2007 04:00:00 +0100

Conclusion: In the nervous system, morphine induces a strong desensitization before promoting the phosphorylation and recycling of MORs. The long-term sequestering of morphine-activated Galpha subunits by certain RGS proteins reduces the responses to this opioid in neurons. This phenomenon probably increases free Gbetagamma dimers in the receptor environment and leads to GRK phosphorylation and internalization of the MORs. Although, the internalization of the MORs permits the transfer of opioid-activated Galpha subunits to the RGSZ2 proteins, it interferes with the stabilization of this regulatory process and recycled MORs recover the control on these Galpha subunits and opioid tolerance develops slowly. (Source: Molecular Pain)

Frequency-dependent ERK phosphorylation in spinal neurons by electric stimulation of the sciatic nerve and the role in electrophysiological activity

Molecular Pain — Mon, 16 Jul 2007 04:00:00 +0100

The phosphorylation of extracellular signal-regulated kinase (pERK) in DRG and dorsal horn neurons is induced by the C-fiber electrical stimulation to the peripheral nerve. The present study was designed to investigate the expression and modulation of pERK in the rat dorsal horn neurons produced by repetitive electrical stimulation, and its involvement in the electrophysiological activity of dorsal horn neurons. Electrical stimulation of C-fiber intensity at different frequencies was applied to the sciatic nerve; the stimuli-induced pERK expression and the activity in dorsal horn neurons were studied by immunohistochemistry and extracellular recording, respectively. Electrical stimulation of C-fibers (3mA) induced p-ERK expression in dorsal horn neurons in a frequency-dependent manner, ind...

Downregulation of selective microRNAs in trigeminal ganglion neurons following inflammatory muscle pain

Molecular Pain — Fri, 08 Jun 2007 04:00:00 +0100

Active regulation of gene expression in the nervous system plays an important role in the development and/or maintenance of inflammatory pain. MicroRNA (miRNA) negatively regulates gene expression via posttranscriptional or transcriptional inhibition of specific genes. To explore the possible involvement of miRNA in gene regulation during inflammatory pain, we injected complete Freund adjuvant (CFA) unilaterally into the rat masseter muscle and quantified changes in neuron-specific mature miRNAs in the trigeminal ganglion (TG). Real-time reverse-transcription polymerase chain reaction revealed significant, but differential, downregulation of mature miR-10a, -29a, -98, -99a, -124a, -134, and -183 in the ipsilateral mandibular division (V3) of the TG within 4hr after CFA. In contrast, levels...

Neuronal mechanism for neuropathic pain

Molecular Pain — Wed, 06 Jun 2007 04:00:00 +0100

Among different forms of persistent pain, neuropathic pain presents as a most difficult task for basic researchers and clinicians. Despite recent rapid development of neuroscience and modern techniques related to drug discovery, effective drugs based on clear basic mechanisms are still lacking. Here, I will review the basic neuronal mechanisms that maybe involved in neuropathic pain. I will present the problem of neuropathic pain as a rather difficult task for neuroscientists, and we may have to wait for a long time before we fully understand how brain encode, store, and retrieve painful information after the injury. I propose that neuropathic pain as a major brain disease, rather being a clinic problem due to peripheral injury. (Source: Molecular Pain)

Inactivation properties of sodium channel Nav1.8 maintain action potential amplitude in small DRG neurons in the context of depolarization

Molecular Pain — Thu, 31 May 2007 04:00:00 +0100

Conclusions: We conclude that the presence of Nav1.8 allows AP amplitude to be maintained in DRG neurons and their centrally projecting axons even when depolarized within the dorsal horn. (Source: Molecular Pain)

Pharmacological isolation of postsynaptic currents mediated by NR2A- and NR2B-containing NMDA receptors in the anterior cingulate cortex

Molecular Pain — Mon, 30 Apr 2007 04:00:00 +0100

NMDA receptors (NMDARs) are involved in excitatory synaptic transmission and plasticity associated with a variety of brain functions, from memory formation to chronic pain. Subunit-selective antagonists for NMDARs provide powerful tools to dissect NMDAR functions in neuronal activities. Recently developed antagonist for NR2A-containing receptors, NVP-AAM007, triggered debates on its selectivity and involvement of the NMDAR subunits in bi-directional synaptic plasticity. Here, we re-examined the pharmacological properties of NMDARs in the anterior cingulate cortex (ACC) using NVP-AAM007 as well as ifenprodil, a selective antagonist for NR2B-containing NMDARs. By alternating sequence of drug application and examining different concentrations of NVP-AAM007, we found that the presence of NVP-...

Inward currents induced by ischemia in rat spinal cord dorsal horn neurons

Molecular Pain — Wed, 25 Apr 2007 04:00:00 +0100

Hypoxia and ischemia occur in the spinal cord when blood vessels of the spinal cord are compressed under pathological conditions such as spinal stenosis, tumors, and traumatic spinal injury. Here by using spinal cord slice preparations and patch-clamp recordings we investigated the influence of an ischemia-simulating medium on dorsal horn neurons in deep lamina, a region that plays a significant role in sensory hypersensitivity and pathological pain. We found that the ischemia-simulating medium induced large inward currents in dorsal horn neurons recorded. The onset of the ischemia-induced inward currents was age-dependent, being onset earlier in older animals. Increases of sensory input by the stimulation of afferent fibers with electrical impulses or by capsaicin significantly speeded up...

Techniques for assessing knee joint pain in arthritis

Molecular Pain — Wed, 28 Mar 2007 04:00:00 +0100

The assessment of pain is of critical importance for mechanistic studies as well as for the validation of drug targets. This review will focus on knee joint pain associated with arthritis. Different animal models have been developed for the study of knee joint arthritis. Behavioral tests in animal models of knee joint arthritis typically measure knee joint pain rather indirectly. In recent years, however, progress has been made in the development of tests that actually evaluate the sensitivity of the knee joint in arthritis models. They include measurements of the knee extension angle struggle threshold, hind limb withdrawal reflex threshold of knee compression force, and vocalizations in response to stimulation of the knee. A discussion of pain assessment in humans with arthritis pain con...

Behavioural and morphological evidence for the involvement of glial cell activation in delta opioid receptor function: implications for the development of opioid tolerance

Molecular Pain — Mon, 12 Mar 2007 04:00:00 +0100

Previous studies have demonstrated that prolonged morphine treatment in vivo induces the translocation of delta opioid receptors (ORs) from intracellular compartments to neuronal plasma membranes and this trafficking event is correlated with an increased functional competence of the receptor. The mechanism underlying this phenomenon is unknown; however chronic morphine treatment has been shown to involve the activation and hypertrophy of spinal glial cells. In the present study we have examined whether activated glia may be associated with the enhanced delta OR-mediated antinociception observed following prolonged morphine treatment. Accordingly, animals were treated with morphine with or without concomitant administration of propentofylline, an inhibitor of glial activation that was previ...

Lack of influence of GTP cyclohydrolase gene (GCH1) variations on pain sensitivity in humans

Molecular Pain — Wed, 07 Mar 2007 05:00:00 +0100

Conclusions: Considering population stratification, previously reported associations between GCH1 genetic variations and pain sensitivity appear weak or negligible in this well characterized model of pain. (Source: Molecular Pain)

Mechanically-evoked C-fiber activity in painful alcohol and AIDS therapy neuropathy in the rat

Molecular Pain — Fri, 23 Feb 2007 07:00:00 +0100

While altered activities in sensory neurons were noticed in neuropathic pain, caused by highly diverse insults to the peripheral nervous system, such as diabetes, alcohol ingestion, cancer chemotherapy and drugs used to treat AIDS, other infections and autoimmune diseases, as well as trauma, our understanding of how these various peripheral neuropathies manifest as altered neuronal activity is still rudimentary. The recent development of models of several of those neuropathies has, however, now made it possible to address their impact on primary afferent nociceptor function. We compared changes in mechanically-evoked C-fiber activity, in models of painful peripheral neuropathy induced by drinking ethanol (alcohol) or administering 2',3'-dideoxycytidine (ddC), a nucleoside reverse transcrip...

Phosphorylation of ERK in neurokinin 1 receptor-expressing neurons in laminae III and IV of the rat spinal dorsal horn following noxious stimulation

Molecular Pain — Mon, 19 Feb 2007 07:00:00 +0100

Conclusions: Our results demonstrate that lamina III/IV NK1r-immunoreactive neurons show receptor internalisation and ERK phosphorylation after mechanical, thermal or chemical noxious stimuli. (Source: Molecular Pain)

Temperature dependence of erythromelalgia mutation L858F in sodium channel Nav1.7

Molecular Pain — Fri, 19 Jan 2007 07:00:00 +0100

Conclusions: The cooling-dependent shift of the activation midpoint of L858F to more positive potentials brings the threshold of activation of the mutant channels closer to that of wild type Nav1.7 at lower temperatures, and is likely to contribute to the alleviation of painful symptoms upon cooling in affected limbs in patients with this erythromelalgia mutation. (Source: Molecular Pain)

Progress and future of molecular pain

Molecular Pain — Wed, 10 Jan 2007 07:00:00 +0100

Since its launch at the beginning of 2005, Molecular Pain has published pain research articles that cover broad areas including: genetics, molecular and cellular biology, synaptic and neuronal mechanisms, novel animal models and human functional imaging studies. One important feature of Molecular Pain is its high speed in manuscript processing and publication, making the journal one of the best places for pain researchers to publish their novel findings. (Source: Molecular Pain)

FM1-43 is a permeant blocker of mechanosensitive ion channels in sensory neurons and inhibits behavioural responses to mechanical stimuli

Molecular Pain — Sat, 06 Jan 2007 07:00:00 +0100

The molecular identity and pharmacological properties of mechanically gated ion channels in sensory neurons are poorly understood. We show that FM1-43, a styryl dye used to fluorescently label cell membranes, permeates mechanosensitive ion channels in cultured dorsal root ganglion neurons, resulting in blockade of three previously defined subtypes of mechanically activated currents. Blockade and dye uptake is voltage dependent and regulated by external Ca2+. The structurally related larger dye FM3-25 inhibited mechanically activated currents to a lesser degree and did not permeate the channels. In vivo, FMI-43 decreases pain sensitivity in the Randall-Selitto test and increases the withdrawal threshold from von Frey hairs, together suggesting that the channels expressed at the cell body in...

Recent advances in basic neurosciences and brain disease: from synapses to behavior

Molecular Pain — Sat, 30 Dec 2006 07:00:00 +0100

Understanding basic neuronal mechanisms hold the hope for future treatment of brain disease. The 1st international conference on synapse, memory, drug addiction and pain was held in beautiful downtown Toronto, Canada on August 21–23, 2006. Unlike other traditional conferences, this new meeting focused on three major aims: (1) to promote new and cutting edge research in neuroscience; (2) to encourage international information exchange and scientific collaborations; and (3) to provide a platform for active scientists to discuss new findings. Up to 64 investigators presented their recent discoveries, from basic synaptic mechanisms to genes related to human brain disease. This meeting was in part sponsored by Molecular Pain, together with University of Toronto (Faculty of Medicine, Departmen...

Impaired pain sensation in mice lacking prokineticin 2

Molecular Pain — Wed, 15 Nov 2006 07:00:00 +0100

Prokineticins (PKs), consisting of PK1 and PK2, are a pair of newly identified regulatory peptides. Two closely related G-protein coupled receptors, PKR1 and PKR2, mediate the signaling of PKs. PKs/PKRs participate in the regulation of diverse biological processes, ranging from development to adult physiology. A number of studies have indicated the involvement of PKs/PKRs in nociception. Here we show that PK2 is a sensitizer for nociception. Intraplantar injection of recombinant PK2 resulted in a strong and localized hyperalgesia with reduced thresholds to nociceptive stimuli. PK2 mobilizes calcium in dissociated dorsal root ganglion (DRG) neurons. Mice lacking the PK2 gene displayed strong reduction in nociception induced by thermal and chemical stimuli, including capsaicin. However, PK2 ...

Nerve injury induces robust allodynia and ectopic discharges in Nav1.3 null mutant mice

Molecular Pain — Thu, 19 Oct 2006 06:00:00 +0100

Changes in sodium channel activity and neuronal hyperexcitability contribute to neuropathic pain, a major clinical problem. There is strong evidence that the re-expression of the embryonic voltage-gated sodium channel subunit Nav1.3 underlies neuronal hyperexcitability and neuropathic pain.Here we show that acute and inflammatory pain behaviour is unchanged in global Nav1.3 mutant mice. Surprisingly, neuropathic pain also developed normally in the Nav1.3 mutant mouse. To rule out any genetic compensation mechanisms that may have masked the phenotype, we investigated neuropathic pain in two conditional Nav1.3 mutant mouse lines. We used Nav1.8-Cre mice to delete Nav1.3 in nociceptors at E14 and NFH-Cre mice to delete Nav1.3 throughout the nervous system postnatally. Again normal levels of n...