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

Abstract

The effects of systemic administration of morphine (4.0 mg kg-1) and clonidine (2.5-10.0 micrograms kg-1), as well as the peripherally active alpha 2-adrenoceptor agonist oxymetazoline (2.8-11.2 micrograms 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 mg kg-1) 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 micrograms kg-1) as well as oxymetazoline (5.6-11.2 micrograms 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 alpha 2-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.(ABSTRACT TRUNCATED AT 250 WORDS)