Melatonin reduces median nerve injury‐induced mechanical hypersensitivity via inhibition of microglial p38 mitogen‐activated protein kinase activation in rat cuneate nucleus

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 SB203580, 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.

3D melatonin nerve scaffold reduces oxidative stress and inflammation and increases autophagy in peripheral nerve regeneration

“…Melatonin treatment could efficiently reduce neuroma formation in peripheral nerve transection injury . Melatonin also decreased median nerve injury via downregulating MAPK signaling . The melatonin application in severe nerve defect injury was not reported before, which required long‐term regeneration.…”

m-Trifluoromethyl-diphenyl diselenide, a multi-target selenium compound, prevented mechanical allodynia and depressive-like behavior in a mouse comorbid pain and depression model

“…Phosphorylated p38 (p-p38) MAPK, the active form of p38 MAPK, is highly expressed in hyperactive microglia in the central nervous system (CNS) after peripheral nerve injury and is essential for activation of microglia (Tsuda et al, 2004). In addition, it has been reported that p38 MAPK activation is strongly implicated in neuropathic pain state (Chiang et al, 2013). Possible upstream mechanisms causing p38 MAPK activation in the CNS after peripheral nerve injury could involve direct activation by pro-inflammatory cytokines or increase of glutamate release from primary afferents as a result of an immediate injury discharge or altered ectopic activity (Ji and Suter, 2007).…”

Erythropoietin reduces nerve demyelination, neuropathic pain behavior and microglial MAPKs activation through erythropoietin receptors on Schwann cells in a rat model of peripheral neuropathy

“…Therefore, we have developed an experimental model of chronic constriction injury (CCI) on the median nerve to induce neuropathic pain in forelimbs of rats based on procedures proposed by Bennett and Xie (). In our model, phosphorylation of MAPKs and activation of microglia were observed in the cuneate nucleus (CN) (Chiang, Huang, & Tsai, ; Huang & Tsai, ; Huang et al, ; Lin, Yeh, Chen, Chou, & Tsai, ). Phosphorylated MAPKs are selectively expressed in hyperactive microglia of the CN after median nerve CCI and is prerequisite for the ensuing microglial activation (Chiang, Huang, & Tsai, ; Huang & Tsai, ; Huang et al, ).…”

“…In our model, phosphorylation of MAPKs and activation of microglia were observed in the cuneate nucleus (CN) (Chiang, Huang, & Tsai, ; Huang & Tsai, ; Huang et al, ; Lin, Yeh, Chen, Chou, & Tsai, ). Phosphorylated MAPKs are selectively expressed in hyperactive microglia of the CN after median nerve CCI and is prerequisite for the ensuing microglial activation (Chiang, Huang, & Tsai, ; Huang & Tsai, ; Huang et al, ). The CN subsequently transmits this tactile hypersensitivity information to the thalamus; thus, the CN may modulate ascending neuropathic pain signaling to the thalamus (Day, Lue, Sun, Shieh, & Wen, ; Tsai et al, ).…”

“…The CN subsequently transmits this tactile hypersensitivity information to the thalamus; thus, the CN may modulate ascending neuropathic pain signaling to the thalamus (Day, Lue, Sun, Shieh, & Wen, ; Tsai et al, ). Further, it was observed that a microinjection of MAPK inhibitors into the CN alleviates median nerve injury‐induced tactile allodynia (Chiang, Huang, & Tsai, ; Huang & Tsai, ; Huang et al, ).…”