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Melatonin reduces median nerve injury‐induced mechanical hypersensitivity via inhibition of microglial p38 mitogen‐activated protein kinase activation in rat cuneate nucleus
Author(s) -
Chiang Rayleigh PingYing,
Huang ChunTa,
Tsai YiJu
Publication year - 2013
Publication title -
journal of pineal research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.881
H-Index - 131
eISSN - 1600-079X
pISSN - 0742-3098
DOI - 10.1111/jpi.12029
Subject(s) - melatonin , mapk/erk pathway , p38 mitogen activated protein kinases , endocrinology , microglia , protein kinase a , medicine , cuneate nucleus , pharmacology , chemistry , kinase , inflammation , central nervous system , biochemistry
Abstract In this study, we examined the relationships between p38 mitogen‐activated protein kinase ( MAPK ) activation in the cuneate nucleus ( CN ) and behavioral hypersensitivity after chronic constriction injury ( CCI ) of the median nerve. We further investigated effects of melatonin administration and pinealectomy on p38 MAPK activation and development of hypersensitivity. Using immunohistochemistry and immunoblotting, low levels of phosphorylated p38 (p‐p38) MAPK were detected in CN of normal rats. As early as 1 day after CCI , p‐p38 MAPK levels in the ipsilateral CN were significantly increased (1.4 ± 0.2‐fold, P < 0.05), which reached a maximum at 7 days (5.1 ± 0.4‐fold, P < 0.001). Double immunofluorescence labeling with cell‐specific markers showed that p‐p38 MAPK immunoreactive cells co‐expressed OX ‐42, a microglia activation maker, suggesting the expression of p‐p38 MAPK in microglia. Microinjection of SB 203580, a p38 MAPK inhibitor, into the CN 1 day after CCI attenuated injury‐induced behavioral hypersensitivity in a dose‐dependent manner. Furthermore, animals received melatonin treatment at daily doses of 37.5, 75, 150, or 300 mg/kg from 30 min before until 3 days after CCI . Melatonin treatment dose‐dependently attenuated p‐p38 MAPK levels, release of pro‐inflammatory cytokines, and behavioral hypersensitivity following CCI ; conversely, pinealectomy that resulted in a reduction in endogenous melatonin levels exacerbated these effects. In conclusion, median nerve injury‐induced microglial p38 MAPK activation in the CN modulated development of behavioral hypersensitivity. Melatonin supplementation eased neuropathic pain via inhibition of p38 MAPK signaling pathway; contrarily, reducing endogenous blood melatonin levels by pinealectomy promoted phosphorylation of p38 MAPK and made rats more vulnerable to nerve injury‐induced neuropathic pain.