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Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Peripheral nerve injuries that provoke neuropathic pain are associated with microglial activation in the spinal cord. We have investigated the characteristics of spinal microglial activation in three distinct models of peripheral neuropathic pain in the rat: spared nerve injury (SNI), chronic constriction injury, and spinal nerve ligation. In all models, dense clusters of cells immunoreactive for the microglial marker CD11b formed in the ipsilateral dorsal horn 7 days after injury. Microglial expression of ionised calcium binding adapter molecule 1 (Iba1) increased by up to 40% and phosphorylation of p38 mitogen-activated protein kinase, a marker of microglial activity, by 45%. Expression of the lysosomal ED1-antigen indicated phagocytic activity of the cells. Unlike the peripheral nerve lesions, rhizotomy produced only a weak microglial reaction within the spinal gray matter but a strong activation of microglia and phagocytes in the dorsal funiculus at lumbar and thoracic spinal cord levels. This suggests that although degeneration of central terminals is sufficient to elicit microglial activation, it does not account for the inflammatory response in the dorsal horn after peripheral nerve injury. Early intrathecal treatment with low-dose methotrexate, beginning at the time of injury, decreased microglial activation, reduced p38 phosphorylation, and attenuated pain-like behavior after SNI. In contrast, systemic or intrathecal delivery of the glucocorticoid dexamethasone did not inhibit the activation of microglia or reduce pain-like behavior. We confirm that microglial activation is crucial for the development of pain after nerve injury, and demonstrates that suppression of this cellular immune response is a promising approach for preventing neuropathic pain.
Pain 2008 Aug 15
PMID:Low-dose methotrexate reduces peripheral nerve injury-evoked spinal microglial activation and neuropathic pain behavior in rats. 1821 68

Microglia in the spinal cord may play an important role in the development and maintenance of neuropathic pain. A metabotropic ATP receptor, P2Y(12), has been shown to be expressed in spinal microglia constitutively and be involved in chemotaxis. Activation of p38 mitogen-activated protein kinase (MAPK) occurs in spinal microglia after nerve injury and may be related to the production of cytokines and other mediators, resulting in neuropathic pain. However, it remains unknown whether any type of P2Y receptor in microglia is involved in the activation of p38 MAPK and the pain behaviors after nerve injury. Using the partial sciatic nerve ligation (PSNL) model in the rat, we found that P2Y(12) mRNA and protein increased in the spinal cord and peaked at 3 d after PSNL. Double labeling studies revealed that cells expressing increased P2Y(12) mRNA and protein after nerve injury were exclusively microglia. Both pharmacological blockades by intrathecal administration of P2Y(12) antagonist and antisense knockdown of P2Y(12) expression suppressed the development of pain behaviors and the phosphorylation of p38 MAPK in spinal microglia after PSNL. The intrathecal infusion of the P2Y(12) agonist 2-(methythio) adenosine 5'-diphosphate trisodium salt into naive rats mimicked the nerve injury-induced activation of p38 in microglia and elevated pain behaviors. These data suggest a new mechanism of neuropathic pain, in which the increased P2Y(12) works as a gateway of the following events in microglia after nerve injury. Activation of this receptor by released ATP or the hydrolyzed products activate p38 MAPK pathway and may play a crucial role in the generation of neuropathic pain.
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PMID:P2Y12 receptor upregulation in activated microglia is a gateway of p38 signaling and neuropathic pain. 1833 20

The sensory neuron-specific sodium channel Na(v)1.8 and p38 mitogen-activated protein kinase are potential therapeutic targets within nociceptive dorsal root ganglion (DRG) neurons in inflammatory, and possibly neuropathic, pain. Na(v)1.8 channels within nociceptive DRG neurons contribute most of the inward current underlying the depolarizing phase of action potentials. Nerve injury and inflammation of peripheral tissues cause p38 activation in DRG neurons, a process that may contribute to nociceptive neuron hyperexcitability, which is associated with pain. However, how substrates of activated p38 contribute to DRG neuron hyperexcitability is currently not well understood. We report here, for the first time, that Na(v)1.8 and p38 are colocalized in DRG neurons, that Na(v)1.8 within DRG neurons is a substrate for p38, and that direct phosphorylation of the Na(v)1.8 channel by p38 regulates its function in these neurons. We show that direct phosphorylation of Na(v)1.8 at two p38 phospho-acceptor serine residues on the L1 loop (S551 and S556) causes an increase in Na(v)1.8 current density that is not accompanied by changes in gating properties of the channel. Our study suggests a mechanism by which activated p38 contributes to inflammatory, and possibly neuropathic, pain through a p38-mediated increase of Na(v)1.8 current density.
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PMID:Phosphorylation of sodium channel Na(v)1.8 by p38 mitogen-activated protein kinase increases current density in dorsal root ganglion neurons. 1835 22

Toll-like receptors (TLRs) play an essential role in innate immune responses and in the initiation of adaptive immune responses. Microglia, the resident innate immune cells in the CNS, express TLRs. In this study, we show that TLR3 is crucial for spinal cord glial activation and tactile allodynia after peripheral nerve injury. Intrathecal administration of TLR3 antisense oligodeoxynucleotide suppressed nerve injury-induced tactile allodynia, and decreased the phosphorylation of p38 mitogen-activated protein kinase, but not extracellular signal-regulated protein kinases 1/2, in spinal glial cells. Antisense knockdown of TLR3 also attenuated the activation of spinal microglia, but not astrocytes, caused by nerve injury. Furthermore, down-regulation of TLR3 inhibited nerve injury-induced up-regulation of spinal pro-inflammatory cytokines, such as interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha. Conversely, intrathecal injection of the TLR3 agonist polyinosine-polycytidylic acid induced behavioral, morphological, and biochemical changes similar to those observed after nerve injury. Indeed, TLR3-deficient mice did not develop tactile allodynia after nerve injury or polyinosine-polycytidylic acid injection. Our results indicate that TLR3 has a substantial role in the activation of spinal glial cells and the development of tactile allodynia after nerve injury. Thus, blocking TLR3 in the spinal glial cells might provide a fruitful strategy for treating neuropathic pain.
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PMID:Toll-like receptor 3 contributes to spinal glial activation and tactile allodynia after nerve injury. 2260 98

The activation of glial cells in the CNS has been suggested to be involved in abnormal pain sensation after peripheral nerve injury. Previous studies demonstrated phosphorylation of p38 mitogen-activated protein kinase (MAPK) in spinal cord glial cells after peripheral nerve injury, and such phosphorylation has been suggested to be involved in the development of neuropathic pain. The aim of this study was to examine the dorsal column nuclei for phosphorylation of p38 MAPK following peripheral nerve injury and to explore a possibility of its contribution to neuropathic pain. Immunohistochemical labeling for phosphorylated p38 (p-p38) MAPK was performed in histological sections of the rat spinal cord and medulla oblongata after the fifth lumbar (L5) spinal nerve ligation (SNL). The number of p-p38 MAPK-immunoreactive (IR) cells was significantly increased in the L5 dorsal horn and the gracile nucleus ipsilateral to the injury at days 3-21 after SNL. Double immunofluorescence labeling with cell-specific markers revealed that p-p38 MAPK-IR cells co-expressed OX-42, suggesting their microglial identity. Increased immunofluorescence labeling for OX-42 indicated that microglial cells were activated by SNL in the L5 dorsal horn and the gracile nucleus ipsilateral to the injury. Continuous infusion of a p38 MAPK inhibitor into the cisterna magna for 14 days beginning on the day of SNL suppressed the development of tactile allodynia, but not thermal hyperalgesia induced by nerve injury. These results demonstrate that SNL activates p38 MAPK pathway in microglia in the gracile nucleus as well as in the spinal cord dorsal horn. Activation of p38 MAPK in medullary microglia may contribute to the pathogenesis of neuropathic pain.
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PMID:Activation of microglia and p38 mitogen-activated protein kinase in the dorsal column nucleus contributes to tactile allodynia following peripheral nerve injury. 1844 Jul 13

Several lines of evidence have shown that in some brain regions brain-derived neurotrophic factor (BDNF) is important for long-term potentiation (LTP), a synaptic model of memory storage. In the present work we evaluate the role of BDNF in LTP of C-fiber evoked field potentials in spinal dorsal horn, a synaptic model of pain memory. We found that spinal application of BDNF-induced LTP of C-fiber evoked field potentials with a long latency, lasting for >8 h, and the effect was blocked by either tyrosine kinase inhibitor (K252a) or BNDF scavenger (TrkB-Fc). The potentiation produced by BDNF was occluded by late-phase LTP (L-LTP) but not by early-phase LTP (E-LTP) induced by electrical stimulation. Pretreatment of K252a or TrkB-Fc selectively blocked spinal L-LTP induced by low-frequency stimulation (LFS) but not E-LTP. BDNF-induced LTP was completely abolished by the protein synthesis inhibitor (anisomycin), by N-methyl-D-aspartate (NMDA) receptor blocker (MK-801), by extracellular signal-regulated protein kinase (ERK) inhibitor (PD98059) or by p38 mitogen-activated protein kinase (MAPK) inhibitor (SB203580) but not by c-Jun N-terminal kinase (JNK) inhibitor (SP600125). Nuclear factor-kappaB (NF-kappaB) inhibitor (PDTC) also suppressed spinal BDNF-LTP. The results suggest that BDNF play a crucial role in protein synthesis-dependent L-LTP in spinal dorsal horn via activation of ERK, p38 MAPK and NF-kappaB signal pathways.
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PMID:BDNF induces late-phase LTP of C-fiber evoked field potentials in rat spinal dorsal horn. 1856 12

Spinal proinflammatory cytokines are powerful pain-enhancing signals that contribute to pain following peripheral nerve injury (neuropathic pain). Recently, one proinflammatory cytokine, interleukin-1, was also implicated in the loss of analgesia upon repeated morphine exposure (tolerance). In contrast to prior literature, we demonstrate that the action of several spinal proinflammatory cytokines oppose systemic and intrathecal opioid analgesia, causing reduced pain suppression. In vitro morphine exposure of lumbar dorsal spinal cord caused significant increases in proinflammatory cytokine and chemokine release. Opposition of analgesia by proinflammatory cytokines is rapid, occurring < or =5 min after intrathecal (perispinal) opioid administration. We document that opposition of analgesia by proinflammatory cytokines cannot be accounted for by an alteration in spinal morphine concentrations. The acute anti-analgesic effects of proinflammatory cytokines occur in a p38 mitogen-activated protein kinase and nitric oxide dependent fashion. Chronic intrathecal morphine or methadone significantly increased spinal glial activation (toll-like receptor 4 mRNA and protein) and the expression of multiple chemokines and cytokines, combined with development of analgesic tolerance and pain enhancement (hyperalgesia, allodynia). Statistical analysis demonstrated that a cluster of cytokines and chemokines was linked with pain-related behavioral changes. Moreover, blockade of spinal proinflammatory cytokines during a stringent morphine regimen previously associated with altered neuronal function also attenuated enhanced pain, supportive that proinflammatory cytokines are importantly involved in tolerance induced by such regimens. These data implicate multiple opioid-induced spinal proinflammatory cytokines in opposing both acute and chronic opioid analgesia, and provide a novel mechanism for the opposition of acute opioid analgesia.
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PMID:Proinflammatory cytokines oppose opioid-induced acute and chronic analgesia. 1859 65

P38alpha is a protein kinase that regulates the expression of inflammatory cytokines, suggesting a role in the pathogenesis of diseases such as rheumatoid arthritis (RA) or systemic lupus erythematosus. Here, we describe the preclinical pharmacology of pamapimod, a novel p38 mitogen-activated protein kinase inhibitor. Pamapimod inhibited p38alpha and p38beta enzymatic activity, with IC(50) values of 0.014 +/- 0.002 and 0.48 +/- 0.04 microM, respectively. There was no activity against p38delta or p38gamma isoforms. When profiled across 350 kinases, pamapimod bound only to four kinases in addition to p38. Cellular potency was assessed using phosphorylation of heat shock protein-27 and c-Jun as selective readouts for p38 and c-Jun NH(2)-terminal kinase (JNK), respectively. Pamapimod inhibited p38 (IC(50), 0.06 microM), but inhibition of JNK was not detected. Pamapimod also inhibited lipopolysaccharide (LPS)-stimulated tumor necrosis factor (TNF) alpha production by monocytes, interleukin (IL)-1beta production in human whole blood, and spontaneous TNFalpha production by synovial explants from RA patients. LPS- and TNFalpha-stimulated production of TNFalpha and IL-6 in rodents also was inhibited by pamapimod. In murine collagen-induced arthritis, pamapimod reduced clinical signs of inflammation and bone loss at 50 mg/kg or greater. In a rat model of hyperalgesia, pamapimod increased tolerance to pressure in a dose-dependent manner, suggesting an important role of p38 in pain associated with inflammation. Finally, an analog of pamapimod that has equivalent potency and selectivity inhibited renal disease in lupus-prone MRL/lpr mice. Our study demonstrates that pamapimod is a potent, selective inhibitor of p38alpha with the ability to inhibit the signs and symptoms of RA and other autoimmune diseases.
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PMID:Pamapimod, a novel p38 mitogen-activated protein kinase inhibitor: preclinical analysis of efficacy and selectivity. 1877 65

Activation of p38 mitogen-activated protein kinase (MAPK) in the spinal cord has been implicated in the development and maintenance of pain states. In this study, we tested whether p38 MAPK is involved in the response to first-degree burn of the hind paw. This injury induces central sensitization leading to tactile allodynia and is mediated by activation of Ca(2+) permeable AMPA/kainate receptors through PKC and PKA. We demonstrate that p38 MAPK is rapidly and robustly activated in the superficial spinal dorsal horn after mild thermal injury to the hind paw. Activated p38 MAPK was localized primarily to microglia and to a lesser extent in oligodendrocytes and lamina II neurons. Astrocytes were not involved in the p38 MAPK response. Intrathecal pretreatment of pharmacological inhibitors of p38 MAPK (SB203580, SD-282) dose-dependently blocked development of tactile allodynia, a characteristic of the first-degree burn model. The effects of the inhibitors on tactile allodynia were lost when they were administered after injury. These studies identify p38 MAPK as a major mediator of tactile allodynia, most likely activated downstream of AMPA/kainate receptors.
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PMID:Spinal p38 mitogen-activated protein kinase mediates allodynia induced by first-degree burn in the rat. 1885 36

A cardinal feature of inflammation is heightened pain sensitivity at the site of the inflamed tissue. This results from the local release by immune and injured cells of nociceptor sensitizers, including prostaglandin E(2), bradykinin, and nerve growth factor, that reduce the threshold and increase the excitability of the peripheral terminals of nociceptors so that they now respond to innocuous stimuli: the phenomenon of peripheral sensitization. We show here that the proinflammatory cytokine interleukin-1beta (IL-1beta), in addition to producing inflammation and inducing synthesis of several nociceptor sensitizers, also rapidly and directly activates nociceptors to generate action potentials and induce pain hypersensitivity. IL-1beta acts in a p38 mitogen-activated protein kinase (p38 MAP kinase)-dependent manner, to increase the excitability of nociceptors by relieving resting slow inactivation of tetrodotoxin-resistant voltage-gated sodium channels and also enhances persistent TTX-resistant current near threshold. By acting as an IL-1beta sensor, nociceptors can directly signal the presence of ongoing tissue inflammation.
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PMID:Nociceptors are interleukin-1beta sensors. 1910 89


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