Suppression of small intestinal motility and morphine withdrawal diarrhoea by clonidine: peripheral site of action

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Abstract
The effects of systemic administration of morphine (4.0 mg kg‐1) and clonidine (‐2.5–10.0 μg kg‐1), as well as the peripherally active α2‐adrenoceptor agonist oxymetazoline (2.8–11.2 μg kg‐1), were studied on the migrating myo‐electric complexes (MMCs) of the small intestine in conscious, naive rats. Furthermore, the effects of naloxone (1.0 mgkg‐l) and the peripherally acting opioid antagonist, methylbromide naloxone (1.0–2.0 mg kg‐1) were studied on the MMCs in morphine‐dependent animals. Similar doses of clonidine or oxymetazoline inhibited the MMCs of the small intestine, which suggests a peripheral site of action of clonidine. Since naloxone (1.0 mg kg‐1) did not antagonize the effect of clonidine, and yohimbine (1.0 mg kg‐1) failed to antagonize the effect of morphine on the MMC, the inhibitory effects on intestinal motility of clonidine and morphine are mediated through different receptors. Morphine‐dependent rats showed a prolonged interval between activity fronts and decreased propagation velocity of the activity fronts. Both naloxone (1.0 mg kg‐1) and methylbromide naloxone (1.0–2.0 mg kg‐1) induced intense spiking activity and profuse diarrhoea. Clonidine (5.0–10.0 μg kg‐1) as well as oxymetazoline (5.6–11.0 μg kg‐1) given prior to naloxone prevented the intense spiking as well as the concomitant diarrhoea. We conclude that the potent inhibition of small intestinal myoelectric activity by α2‐adrenoceptor agonists is mainly executed via peripheral mechanisms. This effect may contribute to their beneficial action in morphine withdrawal diarrhoea, and partly underlie a general antidiarrhoeal action. Thus, peripherally acting α2‐adrenoceptor agonists, lacking side effects of clonidine such as sedation and hypotension, may prove interesting tools in the treatment of diarrhoea.