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.

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Colon distention induces persistent visceral hypersensitivity by mechanotranscription of pain mediators in colonic smooth muscle cells

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00328.2014 ◽

2015 ◽

Vol 308 (5) ◽

pp. G434-G441 ◽

Cited By ~ 10

Author(s):

You-Min Lin ◽

Yu Fu ◽

Chester C. Wu ◽

Guang-Yin Xu ◽

Li-Yen Huang ◽

...

Keyword(s):

Smooth Muscle ◽

Abdominal Pain ◽

Smooth Muscle Cells ◽

Mechanical Stress ◽

Muscle Cells ◽

Visceral Hypersensitivity ◽

Time Dependent ◽

Rat Colon ◽

Dependent Manner ◽

Cox 2

Abdominal pain and distention are major complaints in irritable bowel syndrome. Abdominal distention is mainly attributed to intraluminal retention of gas or solid contents, which may cause mechanical stress to the gut wall. Visceral hypersensitivity (VHS) may account for abdominal pain. We sought to determine whether tonic colon distention causes persistent VHS and if so whether mechanical stress-induced expression (mechanotranscription) of pain mediators in colonic smooth muscle cells (SMCs) plays a role in VHS. Human colonic SMCs were isolated and stretched in vitro to investigate whether mechanical stress upregulates expression of the pain mediator cyclooxygenase-2 (COX-2). Rat colon was distended with a 5-cm-long balloon, and gene expression of COX-2, visceromotor response (VMR), and sensory neuron excitability were determined. Static stretch of colonic SMCs induced marked expression of COX-2 mRNA and protein in a force- and time-dependent manner. Subnoxious tonic distention of the distal colon at ∼30–40 mmHg for 20 or 40 min induced COX-2 expression and PGE2 production in colonic smooth muscle, but not in the mucosa layer. Lumen distention also increased VMR in a force- and time-dependent manner. The increase of VMR persisted for at least 3 days. Patch-clamp experiments showed that the excitability of colon projecting sensory neurons in the dorsal root ganglia was markedly augmented, 24 h after lumen distention. Administration of COX-2 inhibitor NS-398 partially but significantly attenuated distention-induced VHS. In conclusion, tonic lumen distention upregulates expression of COX-2 in colonic SMC, and COX-2 contributes to persistent VHS.

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