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ABSTRACT: Accumulating evidence suggests that neuroimmune interactions contribute to pathological pain. Transient receptor potential melastatin 2 (TRPM2) is a nonselective Ca²⁺-permeable cation channel that acts as a sensor for reactive oxygen species. TRPM2 is expressed abundantly in immune cells and is important in inflammatory processes. The results of the present study show that TRPM2 plays a crucial role in inflammatory and neuropathic pain. While wild-type and TRPM2 knock-out mice showed no difference in their basal sensitivity to mechanical and thermal stimulation, nocifensive behaviors in the formalin test were reduced in TRPM2 knock-out mice. In carrageenan-induced inflammatory pain and sciatic nerve injury-induced neuropathic pain models, mechanical allodynia and thermal hyperalgesia were attenuated in TRPM2 knock-out mice. Carrageenan-induced inflammation and sciatic nerve injury increased the expression of TRPM2 mRNA in the inflamed paw and around the injured sciatic nerve, respectively. TRPM2 deficiency diminished the infiltration of neutrophils and the production of chemokine (C-X-C motif) ligand-2 (CXCL2), a major chemokine that recruits neutrophils, but did not alter the recruitment of F4/80-positive macrophages in the inflamed paw or around the injured sciatic nerve. Microglial activation after nerve injury was suppressed in the spinal cord of TRPM2 knock-out mice. Furthermore, CXCL2 production and inducible nitric oxide synthase induction were diminished in cultured macrophages and microglia derived from TRPM2 knock-out mice. Together, these results suggest that TRPM2 expressed in macrophages and microglia aggravates peripheral and spinal pronociceptive inflammatory responses and contributes to the pathogenesis of inflammatory and neuropathic pain.
Journal of Neuroscience 03/2012; 32(11):3931-41. · 7.11 Impact Factor
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ABSTRACT: The glial glutamate transporter GLT-1 is abundantly expressed in astrocytes and is crucial for glutamate removal from the synaptic cleft. Decreases in glutamate uptake activity and expression of spinal glutamate transporters are reported in animal models of pathological pain. However, the lack of available specific inhibitors and/or activators for GLT-1 makes it difficult to determine the roles of spinal GLT-1 in inflammatory and neuropathic pain. In this study, we examined the effect of gene transfer of GLT-1 into the spinal cord with recombinant adenoviruses on the inflammatory and neuropathic pain in rats.
Intraspinal infusion of adenoviral vectors expressing the GLT-1 gene increased GLT-1 expression in the spinal cord 2-21 days after the infusion. Transgene expression was primarily localized to astrocytes. The spinal GLT-1 gene transfer had no effect on acute mechanical and thermal nociceptive responses in naive rats, whereas it significantly reduced the inflammatory mechanical hyperalgesia induced by hindlimb intraplantar injection of carrageenan/kaolin. Spinal GLT-1 gene transfer 7 days before partial sciatic nerve ligation recovered the extent of the spinal GLT-1 expression in the membrane fraction that was decreased following the nerve ligation, and prevented the induction of tactile allodynia. However, the partial sciatic nerve ligation-induced allodynia was not reversed when the adenoviruses were infused 7 or 14 days after the nerve ligation.
These results suggest that overexpression of GLT-1 on astrocytes in the spinal cord by recombinant adenoviruses attenuates the induction, but not maintenance, of inflammatory and neuropathic pain, probably by preventing the induction of central sensitization, without affecting acute pain sensation. Upregulation or functional enhancement of spinal GLT-1 could be a novel strategy for the prevention of pathological pain.
Molecular Pain 01/2009; 4:65. · 3.53 Impact Factor
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ABSTRACT: Several lines of evidence suggest that activation of spinal mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinase (ERK) and p38 MAPK, contributes to the induction and maintenance of chronic pain. We recently reported that an intrathecal (i.t.) administration of ATP evoked tactile allodynia, which lasted more than 1 week in rats. The long-lasting allodynia was induced by activation of spinal P2X 2/3-receptors, and the induction and early phase of maintenance, but not the late phase, was mediated, at least in part, by the activation of spinal glial cells. In this study, we examined the involvement of spinal ERK and p38 MAPK in each phase of i.t. ATP-evoked long-lasting allodynia. I.t. administration of ATP (100 nmol) markedly increased phosphorylated ERK, which peaked at 1-8 h before gradually decreasing to a level that was sustained until 7 d after administration. In contrast, only a slight increase in phosphorylated p38 MAPK was observed. Consistent with the increased phosphorylation of MAPKs, the ERK kinase MEK inhibitor, U0126 (3 nmol), attenuated the induction phase (co-administration with ATP) and early maintenance phase (1-d post-ATP administration) of the i.t. ATP-evoked allodynia, but not the late maintenance phase (7-d post-ATP administration), while the p38 MAPK inhibitor, SB203580 (10 microg), had little effect. These results suggest that the induction phase and early maintenance phase, but not the late maintenance phase of long-lasting allodynia is mediated by the activation of ERK, rather than by the activation of p38 MAPK, in the spinal cord. These findings are informative for elucidating the mechanisms underlying the pathogenesis of chronic pain.
Biological & Pharmaceutical Bulletin 06/2008; 31(6):1164-8. · 1.66 Impact Factor
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