CENTRAL NERVOUS SYSTEM REGULATION OF INTESTINAL MOTILITY: ROLE OF ENDOGENOUS OPIOID PEPTIDES (ENDORPHINS, ENKEPHALINS).
AuthorGALLIGAN, JAMES JOSEPH.
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PublisherThe University of Arizona.
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AbstractThe complex interaction between the central nervous system, the enteric nervous system and local and endocrine hormones enables drugs affecting gastrointestinal motility to produce their effects through multiple sites and mechanisms of action. Opiates are one class of drugs which can have dramatic effects on gastrointestinal function and the mechanisms for these actions have been the subject of intense study in recent years. These changes in motility have assumed increased importance following the discovery of several endogenous opioid peptides. In the present studies, centrally-administered morphine was more potent than peripherally-administered morphine at inhibiting intestinal propulsion and gastric emptying in rats. Direct measurement of intestinal motility revealed that the antipropulsive effects of morphine were due to an inhibition of intestinal contractions. The opioid peptide, β-endorphin, and a stabilized enkephalin analog, [D-Ala², Met⁵] enkephalinamide, also inhibited intestinal propulsion only after central administration. These effects were not blocked by a peripherally selective opioid receptor antagonist, diallylnormorphinium. These data indicated that there is an opioid sensitive mechanism in the brain of rats that, when activated, can inhibit intestinal motility. Physiological activation, by electroconvulsive shock or inescapable footshock, or pharamcological activation by kyotorphin (Tyr-Arg) treatment, did not affect gastrointestinal motility but did produce naloxone-reversible analgesia. These data indicate that the opioid mechanisms mediating analgesia and inhibition of intestinal motility are independent and may be a function of different receptor systems. Several opioid receptor selective agonists were used to determine the specific receptors mediating the analgesic and motility effects of centrally-administered opioids. Mu selective agonists produced analgesia and inhibition of intestinal transit, while delta receptor agonists produced analgesia only. Kappa agonists did not produce analgesia or an inhibition of intestinal motility. Mu receptors mediate the analgesic and intestinal motility effects of exogenously administered opioids, while delta receptors can mediate analgesia without altering gut motility. It appears then, that electroconvulsive shock, inescapable footshock and kyotorphin may produce their analgesic effects by releasing enkephalins, which are delta selective agonists. This accounts for the failure of these treatments to alter gastrointestinal motility while still producing the analgesic effects reported here.
Degree ProgramPharmacology and Toxicology