Effects of dexmedetomidine on P2X4Rs, p38-MAPK and BDNF in spinal microglia in rats with spared nerve injury

Microglia in the spinal cord is evidenced to play a crucial role in neuropathic pain. Spinal P2X4 receptors (P2X4R5), which are mainly expressed in microglia, have been investigated for their roles in neuropathic pain. Dexmedetomidine (DEX), a highly selective agonist of alpha(2)-adrenergic receptors, is clinically applied to sedation and analgesia. Despite the proposed mechanisms underlying DEX-induced analgesia, the possible interactions between DEX and P2X4R5 at a molecular level have not been elucidated. We designated the spared nerve injury (SNI) to establish the neuropathic pain model. Mechanical paw withdrawal threshold (MWT) was measured to evaluate the sensitivity of neuropathic pain in rats. MWT was significantly decreased in SNI rats versus control rats. Expressions of spinal P2X4R5, phosphorylated p38-mitogen-activated protein kinase (p-p38-MAPK) and brain-derived neurotrophic factor (BDNF) were upregulated in SNI rats. Immunofluorescence assay indicated higher densities of microglia and P2X4R5, which appeared yellow in colour, suggesting they were co-labelled. Intraperitoneal injections of DEX 40 mu g/kg for 14 consecutive days markedly reversed the SNI-induced decline of MWT; the activation of microglia was markedly inhibited; in addition, the protein expressions of P2X4Rs, p-p38-MAPK and BDNF were significantly downregulated. Thus, DEX could attenuate the neuropathic pain in SNI rats, of which the mechanism might be related to the down-expressed P2X4R5, p-p38 and BDNF in microglia of spinal dorsal horn. (C) 2014 Elsevier B.V. All rights reserved.