Activation of p38 Mitogen-activated Protein Kinase in Spinal Microglia Contributes to Incision-induced Mechanical Allodynia

Wen, Yeong-Ray; Suter, Marc R; Ji, Ru-Rong; Yeh, Geng Chang; Wu, Yen Sheng; Wang, Kuo Ching; Kohno, Tatsuro; Sun, Wei‐Zen; Wang, Chia–Chuan

doi:10.1097/aln.0b013e318190bc16

Cited by 124 publications

(113 citation statements)

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“…The activation of microglia in the postoperative pain model are reported in previous studies. Marked upregulation of p38 phosphorylation was observed in spinal microglia as early as 1 h after plantar incision and IT administration of a p38 inhibitor attenuated incision-induced mechanical allodynia, while in contrast, no upregulation of the microglial surface marker OX-42 was observed in the spinal cord until 3 days after incision [10]. Ito et al have also demonstrated microglial activation with OX-42 3days after plantar incision without inhibitory effects of minocycline on mechanical hypersensitivity [8].…”

Section: Discussionmentioning

confidence: 88%

“…One study demonstrates a bone cancer pain increases BDNF production in the spinal cord from activated microglia [6] while another study shows no hyperactive microglia with the cancer pain [7]. In postoperative pain model, BDNF overexpression was observed in both DRG neurons and spinal cord nerve terminals [3], although activation of microglia in spinal cord and subsequent BDNF production with surgical incision are obscure especially in the early post-incision period [8][9][10]. Thus, the role of microglia and BDNF are seem to be different in neuropathic, cancer and postoperative pain.…”

Section: Introductionmentioning

confidence: 99%

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Early Postoperative Nociceptive Threshold and Production of Brain-Derived Neurotrophic Factor Induced by Plantar Incision Are Not Influenced with Minocycline in a Rat: Role of Spinal Microglia

et al. 2016

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Background: Brain-derived neurotrophic factor (BDNF) from spinal microglia is crucial for aberrant nociceptive signaling in several pathological pain conditions, including postoperative pain. We assess the contribution of spinal microglial activation and associated BDNF overexpression to the early post-incisional nociceptive threshold. Methods: Male Sprague-Dawley rats were implanted with an intrathecal catheter. A postoperative pain model was established by plantar incision. Thermal and mechanical nociceptive responses were assessed by infrared radiant heat and von Frey filaments before and after plantar incision. Rats were injected intrathecally the microglial activation inhibitor minocycline before incision, 24 h after incision, or both. Other groups were subjected to the same treatments and the L4-L5 spinal cord segment removed for immunohistochemical analysis of microglia activation and BNDF expression. Results: Plantar incision reduced both thermal latency and mechanical threshold, indicating thermal hypersensitivity and mechanical allodynia. Minocycline temporally reduced thermal withdrawal latency but had no effect on mechanical withdrawal threshold, spinal microglial activity, or dorsal horn BDNF overexpression during the early post-incision period. Conclusion: These results suggest that spinal microglia does not contribute substantially to post-incisional nociceptive threshold. The BDNF overexpression response that may contribute to postoperative hyperalgesia and allodynia is likely derived from other sources.

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Section: Discussionmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Early Postoperative Nociceptive Threshold and Production of Brain-Derived Neurotrophic Factor Induced by Plantar Incision Are Not Influenced with Minocycline in a Rat: Role of Spinal Microglia

et al. 2016

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“…Recently MC4R was found in dorsal root ganglia (DRG) where nerve injury can affect its expression 3 , but the underlying mechanisms are still unclear. P38MAPK was improved to play an important role in the development and maintenance of nerve injury, inflammation and incision pain [4][5][6][7][8][9] . Intrathecal inhibitor of p38 has been shown to attenuate neuropathic pain in different ABSTRACT: Background: neuropathic pain is characterised by spontaneous ongoing or shooting pain and evoked amplified pain responses after noxious or non-noxious stimuli.…”

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confidence: 99%

Melanocortin 4 Receptor Mediates Neuropathic Pain Through p38MAPK in Spinal Cord

Xia

et al. 2012

Can. J. Neurol. Sci.

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458Peripheral nerve injury often results in neuropathic pain associated with hyperalgesia and allodynia 1 . Several lines of evidence suggest that melanocortin 4 receptor (MC4R) plays an important role in the initiation of neuropathic pain. MC4R is activated after nerve injury. Intraplantar injection of MC4 receptor antagonists can abolish chronic constriction injury (CCI)-induced allodynia and hyperalgesia 2 . It suggests that MC4R is involved in the transduction of neuropathic pain. Recently MC4R was found in dorsal root ganglia (DRG) where nerve injury can affect its expression 3 , but the underlying mechanisms are still unclear. P38MAPK was improved to play an important role in the development and maintenance of nerve injury, inflammation and incision pain [4][5][6][7][8][9] . Intrathecal inhibitor of p38 has been shown to attenuate neuropathic pain in different ABSTRACT: Background: neuropathic pain is characterised by spontaneous ongoing or shooting pain and evoked amplified pain responses after noxious or non-noxious stimuli. neuropathic pain develops as a result of lesions or disease affecting the somatosensory nervous system either in the periphery or centrally. Melanocortin 4 receptor (MC4R) plays an important role in the initiation of neuropathic pain but the underlying mechanisms are still unclear. Methods: Adult male Wistar rats were given chronic constriction injury (CCI) or sham operations. Part of CCI rats were intrathecally treated with HS014 (MC4R antagonist) or Sb203580 (p38MAPK inhibitor). on the third, seventh and fourteenth day, the thermal threshold of operated paws was tested. In addition, the MC4R or phosphorylated p38MAPK (p-p38MAPK) levels of lumbar spinal cord were tested with eLISA（enzyme-linked immunosorbent assay), western blot and immunohistochemistry. Results: Here we demonstrate that (1) both HS014 and Sb203580 reduced CCI reduced hyperalgesia (2) p-p38MAPK was increased after CCI with a time course parallel to that of the MC4R change, (3) The p38 activation was prevented by blocking MC4R with an antagonist HS014, but MC4R-IR was not prevented by Sb203580. (4) MC4R and pp38MAPK were located in the same cells. Conclusion: The mechanisms of neuropathic pain mediated by MC4R is related to the inhibition of p38MAPK activation.P38MAPK may be a downstream of MC4R. RÉSUMÉ: Médiation de la douleur neuropathique par le récepteur de la mélanocortine 4 par l'entremise de p38MAPK dans la moelle épinière. Contexte : La douleur neuropathique est caractérisée par une douleur spontanée persistante ou lancinante et des réponses douloureuses amplifiées évoquées suite à des stimuli, qu'ils soient nocifs ou non. La douleur neuropathique apparaît suite à des lésions ou à une maladie qui touche le système nerveux somatosensitif périphérique ou central. Le récepteur de la mélanocortine 4 (MC4R) joue un rôle important dans la genèse de la douleur neuropathique. Les mécanismes sous-jacents demeurent cependant mal connus. Méthode : Des rats Wistar mâles adultes ont subi une lésion par constriction chroni...

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“…Small neurons respond to thermal, mechanical and chemical nociceptive stimulations whereas large neurons transmit touch and proprioceptive sensations. (26) Akt, MAPK, c-Jun or c-Fos did not co-localize with NF-200 in large DRG neurons. It is possible that aqueous extract of H. erinaceus could trigger the expression of protein kinases and early genes that regulate nociceptive function and inflammation associated with nerve recovering.…”

Section: Discussionmentioning

confidence: 92%

Hericium erinaceus (Bull.: Fr.) Pers., a medicinal mushroom, activates peripheral nerve regeneration

Wong

Kanagasabapathy

Naidu

et al. 2014

Chin. J. Integr. Med.

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Activation of p38 Mitogen-activated Protein Kinase in Spinal Microglia Contributes to Incision-induced Mechanical Allodynia

Abstract: Plantar incision-induced mechanical allodynia can be prevented by the p38 inhibitor. Our results suggest that p38 activation in spinal microglia play a role in incision-induced mechanical allodynia in rats. Therefore, p38 inhibition may be useful in treating postsurgical pain.

Cited by 124 publications

References 56 publications

Early Postoperative Nociceptive Threshold and Production of Brain-Derived Neurotrophic Factor Induced by Plantar Incision Are Not Influenced with Minocycline in a Rat: Role of Spinal Microglia

Early Postoperative Nociceptive Threshold and Production of Brain-Derived Neurotrophic Factor Induced by Plantar Incision Are Not Influenced with Minocycline in a Rat: Role of Spinal Microglia

Melanocortin 4 Receptor Mediates Neuropathic Pain Through p38MAPK in Spinal Cord

Hericium erinaceus (Bull.: Fr.) Pers., a medicinal mushroom, activates peripheral nerve regeneration

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