<p>Central post-stroke pain (CPSP) is a type of neuropathic pain for which the mechanisms and relevant drug pathways remain unknown. Previously, we have demonstrated that bilateral carotid artery occlusion (BCAO) induced CPSP model mice showed mechanical hypersensitivity, and the intracerebral (i.c.v.) injection of nicotine suppress this phenomenon. However, the detailed mechanisms of it are not fully understood. Recently, nicotine regulates the neuronal activity of orexin in the lateral hypothalamus (LH). In this study, we evaluated the mechanism underlying the antinociceptive effect of nicotine. Male ddY mice were subjected to 30 min of BCAO. Mechanical hypersensitivity was assessed by von Frey test. BCAO mice showed hypersensitivity against mechanical stimuli at 3 days after BCAO operation. The i.c.v. injection of nicotine (20 nmol) suppressed BCAO-induced mechanical hypersensitivity. After nicotine injection, the number of c-fos, a neuronal activity marker, increased in the LH and the locus coeruleus (LC) in Sham and BCAO mice. These increments were colocalized in orexin A positive cells in the LH or tyrosine hydroxylase positive cells in the LC. Nicotine-induced antinociception was inhibited by the intrathecal pretreatment of yohimbine, a a2 adrenergic receptor antagonist. These results indicate that nicotine may suppress BCAO-induced mechanical hypersensitivity through activation of the descending pain control system via facilitating orexin-A/orexin receptor 1 receptor signaling.</p>