Effects of opioids on the ACh-induced contraction of the toad rectus

The inhibitory effect of morphine, nalorphine, oxymorphone, naloxone, naltrexone, N-methylnaloxone, levorphanol, levallophan, dextrorphan, dextrallophan, levo-methadone, dextro-methadone, pethidine, leu-enkephalin and U-50 488 on the acetylcholine (ACh)-induced contraction of the toad rectus was investigated. The dose-response curves obtained in the absence and presence of increasing concentrations (0.1-3.2 or 10-320 mumol/l) of each opioid were subjected to three types of inhibition model discrimination, namely competitive, noncompetitive and uncompetitive. The results show that the opioids, except morphine, nalorphine and levorphanol, inhibit the ACh-induced contraction by multiple modes of action. Except for the morphinans, the opioids inhibit competitively indicating that they are able to compete with ACh for cholinergic receptors at the nicotinic site. The opioids also inhibit noncompetitively (except oxymorphone and N-methylnaloxone) and uncompetitively (except oxymorphone) indicating the possible existence of separate opioid binding sites and the combination of the opioids with the ACh receptor complex, respectively. The effect of morphine and levorphanol on the ACh-induced contraction varies with the concentration of the two opioids. At concentrations below 80 mumol/l both opioids tend to inhibit the contraction while at concentrations of 80 mumol/l and above there is no apparent effect. Nalorphine has no effect on the contraction at the concentrations (10-320 mumol/l) employed in the study. An apparent structure-activity relationship between the phenanthrenes and the various binding sites is noticeable; so also is the difference in the activity between the dextro and levo-isomers of levorphanol and levallorphan indicating that the receptors exhibit stereospecificity.