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

Alterations in the intracellular signal transduction pathway in primary afferents may contribute to pain hypersensitivity. We demonstrated that very rapid phosphorylation of p38 mitogen-activated protein kinase occurred in dorsal root ganglion (DRG) neurons that were participating in the transmission of noxious signals. Capsaicin injection induced phosphorylated-p38 (p-p38) in small-to-medium diameter sensory neurons with a peak at 2 min after capsaicin injection. Furthermore, we examined the p-p38 labeling in the DRG after noxious thermal stimuli and found a stimulus intensity-dependent increase in labeled cell size and the number of activated neurons. Most of these p-p38-immunoreactive (IR) neurons were small- and medium-sized neurons, which coexpressed transient receptor potential ion channel TRPV1 and phosphorylated-extracellular signal-regulated protein kinase. Intrathecal administration of the p38 inhibitor, FR167653, reversed the thermal hyperalgesia produced by the capsaicin injection. Inhibition of p38 activation was confirmed by the decrease in the number of p-p38-IR neurons in the DRG following capsaicin injection. Taken together, these findings suggest that the activation of p38 pathways in primary afferents by noxious stimulation in vivo may be, at least in part, correlated with functional activity, and further, involved in the development of thermal hyperalgesia.
Pain 2005 Jan
PMID:Activation of p38 MAPK in primary afferent neurons by noxious stimulation and its involvement in the development of thermal hyperalgesia. 1562 64

Neuropathic pain is a common and severely disabling state that affects millions of people worldwide. Such pain can be experienced after nerve injury or as part of diseases that affect peripheral nerve function, such as diabetes and AIDS; it can also be a component of pain in other conditions, such as cancer. Following peripheral nerve injury, microglia in the spinal cord become activated. Recent evidence indicates that activated microglia are key cellular intermediaries in the pathogenesis of nerve injury-induced pain hypersensitivity because P2X(4) purinoceptors and p38 mitogen-activated protein kinase, which are present in activated microglia, are required molecular mediators. It is important to establish how these molecules are activated in spinal microglia following nerve injury and how they cause signaling to neurons in the dorsal horn pain transmission network. Answers to these questions could lead to new strategies that assist in the diagnosis and management of neuropathic pain--strategies not previously anticipated by a neuron-centric view of pain plasticity in the dorsal horn.
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PMID:Neuropathic pain and spinal microglia: a big problem from molecules in "small" glia. 1566 33

Antagonist studies show that spinal p38 mitogen-activated protein kinase plays a crucial role in spinal sensitization. However, there are two p38 isoforms found in spinal cord and the relative contribution of these two to hyperalgesia is not known. Here we demonstrate that the isoforms are distinctly expressed in spinal dorsal horn: p38alpha in neurons and p38beta in microglia. In lieu of isoform selective inhibitors, we examined the functional role of these two individual isoforms in nociception by using intrathecal isoform-specific antisense oligonucleotides to selectively block the expression of the respective isoform. In these rats, down-regulation of spinal p38beta, but not p38alpha, prevented nocifensive flinching evoked by intraplantar injection of formalin and hyperalgesia induced by activation of spinal neurokinin-1 receptors through intrathecal injection of substance P. Both intraplantar formalin and intrathecal substance P produced an increase in spinal p38 phosphorylation and this phosphorylation (activation) was prevented when spinal p38beta, but not p38alpha, was down-regulated. Thus, spinal p38beta, probably in microglia, plays a significant role in spinal nociceptive processing and represents a potential target for pain therapy.
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PMID:Spinal p38beta isoform mediates tissue injury-induced hyperalgesia and spinal sensitization. 1574 68

Microglia play an important role as immune cells in the central nervous system (CNS). Microglia are activated in threatened physiological homeostasis, including CNS trauma, apoptosis, ischemia, inflammation, and infection. Activated microglia show a stereotypic, progressive series of changes in morphology, gene expression, function, and number and produce and release various chemical mediators, including proinflammatory cytokines that can produce immunological actions and can also act on neurons to alter their function. Recently, a great deal of attention is focusing on the relation between activated microglia through adenosine 5'-triphosphate (ATP) receptors and neuropathic pain. Neuropathic pain is often a consequence of nerve injury through surgery, bone compression, diabetes, or infection. This type of pain can be so severe that even light touching can be intensely painful and it is generally resistant to currently available treatments. There is abundant evidence that extracellular ATP and microglia have an important role in neuropathic pain. The expression of P2X4 receptor, a subtype of ATP receptors, is enhanced in spinal microglia after peripheral nerve injury model, and blocking pharmacologically and suppressing molecularly P2X4 receptors produce a reduction of the neuropathic pain. Several cytokines such as interleukin-1beta (IL-1beta), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) in the dorsal horn are increased after nerve lesion and have been implicated in contributing to nerve-injury pain, presumably by altering synaptic transmission in the CNS, including the spinal cord. Nerve injury also leads to persistent activation of p38 mitogen-activated protein kinase (MAPK) in microglia. An inhibitor of this enzyme reverses mechanical allodynia following spinal nerve ligation (SNL). ATP is able to activate MAPK, leading to the release of bioactive substances, including cytokines, from microglia. Thus, diffusible factors released from activated microglia by the stimulation of purinergic receptors may have an important role in the development of neuropathic pain. Understanding the key roles of ATP receptors, including P2X4 receptors, in the microglia may lead to new strategies for the management of neuropathic pain.
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PMID:The function of microglia through purinergic receptors: neuropathic pain and cytokine release. 1616 95

The present study aimed to investigate the role of spinal p38 mitogen-activated protein kinase (p38 MAPK) activation in chronic constriction injury (CCI) of the sciatic nerve induced neuropathic pain. CCI model was produced by loosely ligating the left sciatic nerve proximal to the sciatica's trifurcation with 4-0 silk thread in male Sprague-Dawley rat. SB203580, a specific inhibitor of the p38 MAPK, was intrathecally administered on day 5 post-CCI. Thermal and mechanical nociceptive thresholds were assessed with the paw withdrawal lantency (PWL) to radiant heat and the paw withdrawal threshold (PWT) to von Frey filaments respectively. The protein levels of the phosphorylated p38 MAPK (p-p38 MAPK) and phosphorylated cAMP response element binding protein (pCREB) were assessed by Western blot analysis. The results showed that CCI significantly increased the expressions of cytosolic and nuclear p-p38 MAPK in the spinal cord. Intrathecal administration of SB203580 dose-dependently reversed the established mechanical allodynia and thermal hyperalgesia induced by CCI. Correlated with behavior results, SB203580 dose-dependently inhibited the CCI-induced increase of the expressions of cytosolic and nuclear p-p38 MAPK and nuclear pCREB in the spinal cord. Taken together, these findings suggest that the activation of p38 MAPK pathway contributes to the development of neuropathic pain induced by CCI, and that the function of p-p38 MAPK may partly be accomplished via the CREB-dependent gene expression.
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PMID:Activation of p38 mitogen-activated protein kinase in spinal cord contributes to chronic constriction injury-induced neuropathic pain. 1622 Jan 91

Activation of p38 mitogen-activated protein kinase (p38) in spinal microglia is implicated in spinal nociceptive processing. Minocycline, a tetracycline derivative, displays selective inhibition of microglial activation, a function that is distinct from its antibiotic activity. In the present study we examined antinociceptive effects of intrathecal (IT) administration of minocycline in experimental models of inflammation-evoked hyperalgesia in addition to the effect of minocycline on stimulation-induced activation of p38 in spinal microglia. Intrathecal minocycline produced a dose-dependent reduction of formalin-evoked second-phase flinching behaviour in rats, and prevented thermal hyperalgesia induced by carrageenan injection into the paw. In contrast, systemic delivery (intraperitoneally) of minocycline inhibited the first but not the second phase of formalin-induced flinching, and it had no effect on carrageenan-induced hyperalgesia. Centrally mediated hyperalgesia induced by IT delivery of N-methyl-d-aspartate was completely blocked by IT minocycline. An increase in phosphorylation (activation) of p38 (P-p38) was observed in the dorsal spinal cord after carrageenan paw injection, assessed by both Western blotting and immunohistochemistry. The increased P-p38 immunoreactivity was seen primarily in microglia but also in a small population of neurons. Minocycline, at the IT dose that blocked carrageenan-induced hyperalgesia, also attenuated the increased P-p38 in microglia. In addition, minocycline suppressed lipopolysaccharide-evoked P-p38 in cultured spinal microglial cells. Taken together, these findings show that minocycline given IT produces a potent and consistent antinociception in models of tissue injury and inflammation-evoked pain, and they provide strong support for the idea that this effect is mediated by direct inhibition of spinal microglia and subsequent activation of p38 in these cells.
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PMID:Intrathecal minocycline attenuates peripheral inflammation-induced hyperalgesia by inhibiting p38 MAPK in spinal microglia. 1630 86

Tumor necrosis factor-alpha (TNFalpha) is a proinflammatory cytokine involved in the development and maintenance of inflammatory and neuropathic pain conditions. TNFalpha can have long-lasting effects by regulating the expression of a variety of inflammatory mediators, including other cytokines and TNFalpha itself. However, the speed with which TNFalpha induces tactile and thermal hypersensitivity suggests that transcriptional regulation cannot fully account for its sensitizing effects, and some recent findings suggest that TNFalpha may act directly on primary afferent neurons to induce pain hypersensitivity. In the present study, we show that peripheral administration of TNFalpha induces thermal hypersensitivity in wild-type mice but not in transient receptor potential vanilloid receptor TRPV1(-/-) mice. In contrast, TNFalpha produced equivalent mechanical hypersensitivity in TRPV1(-/-) mice and wild-type littermates, suggesting a role for TRPV1 in TNFalpha-induced thermal, but not mechanical, hypersensitivity. Because tetrodotoxin (TTX)-resistant Na+ channels are a critical site of modulation underlying mechanical hypersensitivity in inflammatory and neuropathic pain conditions, we tested the effects of TNFalpha on these channels in isolated mouse dorsal root ganglion (DRG) neurons. We report that acute application of TNFalpha rapidly enhances TTX-resistant Na+ currents in isolated DRG neurons. This potentiation of TTX-resistant currents by TNFalpha is dramatically reduced in DRG neurons from TNF receptor 1 (TNFR1) knock-out mice and is blocked by the p38 mitogen-activated protein kinase inhibitor SB202190 [4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)1H-imidazole]. Mechanical hypersensitivity induced by peripherally applied TNFalpha is also significantly reduced by SB202190. These results suggest that TNFalpha may induce acute peripheral mechanical sensitization by acting directly on TNFR1 in primary afferent neurons, resulting in p38-dependent modulation of TTX-resistant Na+ channels.
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PMID:Acute p38-mediated modulation of tetrodotoxin-resistant sodium channels in mouse sensory neurons by tumor necrosis factor-alpha. 1639 94

Glial activation is known to contribute to pain hypersensitivity following spinal sensory nerve injury. In this study, we investigated mechanisms by which glial cell activation in medullary dorsal horn (MDH) would contribute to tactile hypersensitivity following inferior alveolar nerve and mental nerve transection (IAMNT). Activation of microglia and astrocytes was monitored at 2 h, 1, 3, 7, 14, 28, and 60 days using immunohistochemical analysis with OX-42 and GFAP antibodies, respectively. Tactile hypersensitivity was significantly increased at 1 day, and this lasted for 28 days after IAMNT. Microglial activation, primarily observed in the superficial laminae of MDH, was initiated at 1 day, maximal at 3 days, and maintained until 14 days after IAMNT. Astrocytic activation was delayed compared to that of microglia, being more profound at 7 and 14 days than at 3 days after IAMNT. Both tactile hypersensitivity and glial activation appeared to gradually reduce and then return to the basal level by 60 days after IAMNT. There was no significant loss of trigeminal ganglion neurons by 28 days following IAMNT, suggesting that degenerative changes in central terminals of primary afferents might not contribute to glial activation. Minocycline, an inhibitor of microglial activation, reduced microglial activation, inhibited p38 mitogen-activated protein kinase (MAPK) activation in microglia, and significantly attenuated the development of pain hypersensitivity in this model. These results suggest that glial activation in MDH plays an important role in the development of neuropathic pain and activation of p38 MAPK in hyperactive microglia contributes to pain hypersensitivity in IAMNT model.
Pain 2006 Apr
PMID:Activation of glia and microglial p38 MAPK in medullary dorsal horn contributes to tactile hypersensitivity following trigeminal sensory nerve injury. 1649 5

Optimal management of neuropathic pain is a major clinical challenge. We investigated the involvement of c-Jun N-terminal kinase (JNK) in neuropathic pain produced by spinal nerve ligation (SNL) (L5). SNL induced a slow (>3 d) and persistent (>21 d) activation of JNK, in particular JNK1, in GFAP-expressing astrocytes in the spinal cord. In contrast, p38 mitogen-activated protein kinase activation was found in spinal microglia after SNL, which had fallen to near basal level by 21 d. Intrathecal infusion of a JNK peptide inhibitor, D-JNKI-1, did not affect normal pain responses but potently prevented and reversed SNL-induced mechanical allodynia, a major symptom of neuropathic pain. Intrathecal D-JNKI-1 also suppressed SNL-induced phosphorylation of the JNK substrate, c-Jun, in spinal astrocytes. However, SNL-induced upregulation of GFAP was not attenuated by spinal D-JNKI-1 infusion. Furthermore, SNL induced a rapid (<12 h) but transient activation of JNK in the L5 (injured) but not L4 (intact) DRG. JNK activation in the DRG was mainly found in small-sized C-fiber neurons. Infusion of D-JNKI-1 into the L5 DRG prevented but did not reverse SNL-induced mechanical allodynia. Finally, intrathecal administration of an astroglial toxin, l-alpha-aminoadipate, reversed mechanical allodynia. Our data suggest that JNK activation in the DRG and spinal cord play distinct roles in regulating the development and maintenance of neuropathic pain, respectively, and that spinal astrocytes contribute importantly to the persistence of mechanical allodynia. Targeting the JNK pathway in spinal astroglia may present a new and efficient way to treat neuropathic pain symptoms.
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PMID:A peptide c-Jun N-terminal kinase (JNK) inhibitor blocks mechanical allodynia after spinal nerve ligation: respective roles of JNK activation in primary sensory neurons and spinal astrocytes for neuropathic pain development and maintenance. 1657 63

Hypersensitivity to mechanical stimulation is a well documented symptom of neuropathic pain, for which there is currently no effective therapy. Src-family kinases (SFKs) are involved in proliferation and differentiation and in neuronal plasticity, including long-term potentiation, learning, and memory. Here we show that activation of SFKs induced in spinal cord microglia is crucial for mechanical hypersensitivity after peripheral nerve injury. Nerve injury induced a striking increase in SFK phosphorylation in the ipsilateral dorsal horn, and SFKs were activated in hyperactive microglia but not in neurons or astrocytes. Intrathecal administration of the Src-family tyrosine kinase inhibitor 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2) suppressed nerve injury-induced mechanical hypersensitivity but not heat and cold hypersensitivity. Furthermore, PP2 reversed the activation of extracellular signal-regulated protein kinase (ERK), but not p38 mitogen-activated protein kinase, in spinal microglia. In contrast, there was no change in SFK phosphorylation in primary sensory neurons, and PP2 did not decrease the induction of transient receptor potential ion channel TRPV1 and TRPA1 in sensory neurons. Together, these results demonstrate that SFK activation in spinal microglia contributes to the development of mechanical hypersensitivity through the ERK pathway. Therefore, preventing the activation of the Src/ERK signaling cascade in microglia might provide a fruitful strategy for treating neuropathic pain.
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PMID:Activation of Src-family kinases in spinal microglia contributes to mechanical hypersensitivity after nerve injury. 1692 56


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