Melanocortin 4 receptor mediates neuropathic pain through p38MAPK in spinal cord.
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 p-p38MAPK were located in the same cells.


CONCLUSIONS
The mechanisms of neuropathic pain mediated by MC4R is related to the inhibition of p38MAPK activation. P38MAPK may be a downstream of MC4R.
Department of Anesthesiology, Affiliate Hospital of Qingdao University Medical College, Qingdao, Shandong Province, China.
Haichen
H
Chu
Jiangling
J
Xia
Hongmei
H
Xu
Zhao
Z
Yang
Jie
J
Gao
Shihai
S
Liu
D000704:Analysis of Variance; D000818:Animals; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D006930:Hyperalgesia / Q000188:drug therapy / Q000209:etiology; D007093:Imidazoles / Q000008:administration & dosage; D008297:Male; D017288:Pain Threshold / Q000187:drug effects; D010456:Peptides, Cyclic / Q000008:administration & dosage; D011725:Pyridines / Q000008:administration & dosage; D051381:Rats; D017208:Rats, Wistar; D044105:Receptor, Melanocortin, Type 4 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012585:Sciatica / Q000473:pathology*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases / Q000187:drug effects*
D004791:Enzyme Inhibitors; C116941:HS014 cyclic peptide; D007093:Imidazoles; D010456:Peptides, Cyclic; D011725:Pyridines; D044105:Receptor, Melanocortin, Type 4; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580