Suppression of small intestinal motility and morphine withdrawal diarrhoea by clonidine: peripheral site of action.
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)
Thollander
M
M
Department of Pharmacology, Karolinska Institute, Stockholm, Sweden.
Hellström
P M
PM
Svensson
T H
TH
D000818:Animals; D003000:Clonidine / Q000008:administration & dosage*; D003967:Diarrhea / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D005769:Gastrointestinal Motility / Q000187:drug effects*; D007421:Intestine, Small / Q000187:drug effects*; D008297:Male; D009020:Morphine / Q000008:administration & dosage; D009021:Morphine Dependence / Q000150:complications* / Q000503:physiopathology; D009270:Naloxone / Q000008:administration & dosage; D010109:Oxymetazoline / Q000008:administration & dosage; D051381:Rats; D011919:Rats, Inbred Strains; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy* / Q000503:physiopathology
D009270:Naloxone; D009020:Morphine; D010109:Oxymetazoline; D003000:Clonidine