Melanocortin 4 Receptor Mediates Neuropathic Pain Through p38MAPK in Spinal Cord

Abstract

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...

MC4R Is Involved in Neuropathic Pain by Regulating JNK Signaling Pathway After Chronic Constriction Injury

“…Therefore, the expressions of MC4R and related proteins in the JNK signaling pathway were examined in order to figure out the underlying molecular mechanisms. Similar to previous researches (Chu et al, 2012b; Jiang et al, 2019), data in the current study also showed that MC4R level was significantly induced with CCI surgery, but decreased by HS and SP treatments after CCI surgery, both on mRNA level and protein level. More recently, there has been interest in the c-Jun-related bZIP transcription factor, ATF3, and its function in neurons.…”

“…Besides neurons, astrocytes were also reported to express the MC4R (Selkirk et al, 2007). In recent decades, it has been discovered that an intraplantar injection of MC4R antagonists could weaken chronic constriction injury (CCI)-induced allodynia and hyperalgesia, thereby this research suggested that MC4R might exert an important role in the formation and transduction of neuropathic pain (Starowicz et al, 2004; Chu et al, 2012b). However, the detailed mechanism through which MC4R regulates the process of neuropathic pain is still elusive.…”

“…Intrathecal lidocaine could reverse tactile allodynia following CCI through attenuation of p-p38 MAPK in the activated microglia (Gu et al, 2008). Additionally, by using p38 MAPK inhibitor, researchers found that MC4R induced hyperalgesia and allodynia after CCI by the activation of p38 MAPK in dorsal root ganglion (DRG) (Chu et al, 2012b, c). c-Jun N-terminal kinase (JNK) is another branched signaling pathway of MAPK that can be triggered by various stress stimuli and leads to the upregulation of proinflammatory mediators (Liu et al, 2017; Yu et al, 2018).…”

Midbrain microglia mediate a specific immunosuppressive response under inflammatory conditions

“…In PD, chronic inflammation concurs with dopaminergic neurodegeneration in the SNc and it is likely to influence disease progression [45, 46]. The genetic association of PD with the human leukocyte antigen that encodes part of the MHC-II complex, and with the TNFα, IL6, and IL1 receptor genes, supports the involvement of the immune system and offers new targets to develop novel therapies [47–50]. In vivo imaging studies of microglial activation in PD show an early, widespread activation that remains stable over the course of the disease, without correlating with [ 18 F]-dopa uptake in the putamen (equivalent to the caudate/putamen in rodents) [51].…”

Genetics of Common Antipsychotic-Induced Adverse Effects

“…MC4-R has also been implicated in molecular pathways regulating sexual arousal, inflammatory response, pain modulation, and blood pressure [83,84,85,86]. MC4-R is widely distributed throughout the brain, though it primarily regulates metabolic pathways from within hypothalamic and brain stem nuclei [82,87].…”