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 alpha(2)-adrenergic control of motor and se nsory function of descending colon and rectum. Methods: In 32 healthy volunteers, we assessed compliance, fasting and post prandial tone, and sensations of gas, urgency and pain during phasic disten tions. Each subject received one agent at clinically approved doses: clonid ine (0.05, 0.1, 0.2 or 0.3 mg p.o.); or the alpha(2) 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 ton e, 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, y ohimbine dose-dependently altered the compliance curve, increased tone and sensations of gas, pain and urgency. Drug effects in the colon were more ma rked at low distensions; alpha(2) modulation of rectal sensation was observ ed at all levels of distension. Conclusions: alpha(2)-adrenergic mechanisms modulate colorectal sensations and motility; at doses as low as 0.05 mg, clonidine reduced colorectal sens ation while the tone response to feeding was preserved. These studies provi de insight into the potential use of alpha(2) agents in disease states.