The Role of Neurokinin 1 Receptors in the Maintenance of Visceral Hyperalgesia Induced by Repeated Stress in Rats

Background & Aims: The neurokinin 1 receptors (NK1Rs) and substance P (SP) have been implicated in the stress and/or pain pathways involved in chronic pain conditions. Here we examined the participation of NK1Rs in sustained visceral hyperalgesia observed in rats exposed to chronic psychological stress. Methods: Male Wistar rats were exposed to daily 1-hour water avoidance stress (WA) or sham WA for 10 consecutive days. We tested intraperitoneal or intrathecal injection of the NK1R antagonist SR140333 on the visceromotor reflex to colorectal distention in both groups at day 11. Real-time reverse-transcription polymerase chain reaction, Western blot, and immunohistochemistry were used to assess the expression of NK1Rs and/or SP in samples of colon, spinal cord, and dorsal root ganglia. Results: Both intraperitoneal and intrathecal SR140333 injection diminished the enhanced visceromotor reflex to colorectal distention at day 11 in stressed rats but did not affect the response in control animals. Real-time polymerase chain reaction and Western blotting demonstrated stress-induced up-regulation of spinal NK1Rs. Immunohistochemistry showed an increased number of NK1R-expressing neurons in the laminae I of the dorsal horn in stressed rats. The expression of NK1Rs was decreased in colon from stressed rats compared with control. The expression of SP gene precursor in dorsal root ganglia was unchanged in stressed rats compared with controls. Conclusions: Stress-induced increased NK1R expression on spinal neurons and the inhibitory effect of intrathecal NK1R antagonist on visceral hyperalgesia support the key contribution of spinal NK1Rs in the molecular pathways involved in the maintenance of visceral hyperalgesia observed after chronic WA.