An opioid receptor independent mechanism underlies motility dysfunction and visceral hyperalgesia in opioid-induced bowel dysfunction

Background and Aims: Constipation and abdominal pain are commonly encountered in opioid-induced bowel dysfunction (OBD). The underlying mechanisms are incompletely understood, and treatments are not satisfactory. As OBD patients often have fecal retention, we aimed to determine whether fecal retention plays a pathogenic role in the development of constipation and abdominal pain in OBD, and if so to investigate the mechanisms. Methods: A rodent model of OBD was established by daily morphine treatment at 10 mg/kg for 7 days. Bowel movements, colonic muscle contractility, visceromotor response to colorectal distention, and cell excitability of colon-projecting dorsal root ganglion neurons were determined in rats fed in normal pellet food, or in clear liquid diet. Results: Morphine treatment (Mor) reduced fecal outputs starting on day 1, and caused fecal retention afterwards. Compared to controls, Mor rats demonstrated suppressed muscle contractility, increased neuronal excitability and visceral hypersensitivity. Expression of cyclooxygenase-2 (COX-2) and nerve growth factor (NGF) was up-regulated in smooth muscle of the distended colon in Mor rats. However, prevention of fecal retention by feeding rats with clear liquid diet blocked up-regulation of COX-2 and NGF, restored muscle contractility, and attenuated visceral hypersensitivity in Mor rats. Moreover, inhibition of COX-2 improved smooth muscle function and fecal outputs, whereas anti-NGF antibody administration attenuated visceral hypersensitivity in Mor rats. Conclusions: Morphine-induced fecal retention is an independent pathogenic factor for motility dysfunction and visceral hypersensitivity in OBD rats. Liquid diet may have therapeutic potential for OBD by preventing fecal retention-induced mechano-transcription of COX-2 and NGF.