CONTRACTILE EFFECT OF MORPHINE AND RELATED OPIOID ALKALOIDS, β‐ENDORPHIN AND METHIONINE ENKEPHALIN ON THE ISOLATED COLON FROM LONG EVANS RATS

Abstract

1 Morphine and related synthetic surrogates as well as β-endorphin and methionine enkephalin caused a contractile response of the longitudinal musculature of the terminal colon of Long Evans rats. 2 The muscular contraction caused by the narcotic analgesics exhibited stereospecificity, with levorphanol being about 50 times more potent than dextrorphan and (−)-methadone 4 times more potent than (+)-methadone. In addition, the rank order in potency of a homologous series of N-alkyl substituted norketobemidones demonstrated that the activity of these compounds in eliciting contractile responses corresponded to that for analgesic efficacy in the rat and also correlated to the ability of these derivatives to inhibit the muscular twitch evoked by electrical stimulation of the guinea-pig ileum. 3 Naloxone blocked the contractile response of the opiates following competitive kinetics; the naloxone pA₂ values for morphine, etorphine, levorphanol and methadone were very close, in spite of the marked differences in potency of these agents. 4 The contractile effect of morphine on the rat colon was abolished by incubation of the tissues with tetrodotoxin 2.0 × 10⁻⁷ M or by decreasing the external Ca²⁺ level 100 fold. Increasing the external Ca²⁺ concentration caused an apparent non-competitive antagonism of the response to morphine. 5 Pretreatment of the tissues with hexamethonium 8.3 × 10⁻⁵ M caused a modest antagonism of the morphine effect while atropine 5.8 × 10⁻⁷M did not significantly modify the morphine contractile effect. In contrast, methysergide 10⁻⁵ M caused a 10 fold increase in the morphine EC₅₀. 6 Colons from rats rendered tolerant-dependent on morphine were markedly less sensitive to the contractile effects of morphine than those from placebo-treated controls. Tolerance to morphine was also accompanied by an increased sensitivity to the contractile effects of 5-hydroxytryptamine (5-HT). 7 A marked increase in the spontaneous muscular activity of segments of the terminal colon of rats chronically treated with morphine was found to occur upon removal of the residual morphine in the tissues by repetitive washings. The spontaneous activity was arrested by applications of morphine, suggesting that physical dependence can be demonstrated in vitro in this particular preparation. 8 It is concluded that the opiate-induced contractile response is mediated via stereospecific, naloxone-sensitive, opiate receptors and that the muscular response involves the activation of a 5-HT neurone in the nerve terminals of the colon.