Towards identifying optimal doses for alpha‐2 adrenergic modulation of colonic and rectal motor and sensory function

Rationale: Visceral sensation and motility are important in functional gut disorders and are partly controlled by adrenergic innervation. Objectives: To characterize the α2-adrenergic control of motor and sensory function of descending colon and rectum. Methods: In 32 healthy volunteers, we assessed compliance, fasting and postprandial tone, and sensations of gas, urgency and pain during phasic distentions. Each subject received one agent at clinically approved doses: clonidine (0.05, 0.1, 0.2 or 0.3 mg p.o.); or the α2 antagonist yohimbine (0.0125 mg, 0.05 mg, 0.125 mg or 0.2 mg intravenously and infusion over 2.5 h). Results: Clonidine increased colonic and rectal compliance, and reduced tone, pain, gas sensation and rectal urgency. Clonidine showed large pairwise differences in sensation and motility between 0.05 and 0.1 mg doses, which did not interfere with the colon’s motor response to feeding. Conversely, yohimbine dose-dependently altered the compliance curve, increased tone and sensations of gas, pain and urgency. Drug effects in the colon were more marked at low distensions; α2 modulation of rectal sensation was observed at all levels of distension. Conclusions: α2-adrenergic mechanisms modulate colorectal sensations and motility; at doses as low as 0.05 mg, clonidine reduced colorectal sensation while the tone response to feeding was preserved. These studies provide insight into the potential use of α2 agents in disease states.