Adaptation of a neuron to normorphine and clonidine.

65 The decreased sensitivity to clonidine would appear to be an important and reversible sign of withdrawal in the guinea-pig ileum. Such interactions between opiate receptors and a-adren-ergic receptors do not appear to occur in the mouse vas deferens (Gillan et al., 1979). However, vasa deferentia from rats treated chronically with clonidine showed lower sensitivity to the inhibitory effects of /%endorphin and adenosine, as well as to those of clonidine (Ishii et al., 1982). In man, clonidine ameliorated certain aspects of the opiate withdrawal syndrome (Gold et al., 1978). It is possible that cooperation between the effects of administered clonidine and the residual opiate in centrally situated neurons may be the basis of this effect. Similarly, changes in a common presynaptic post-recognition pathway may be related to the observation that, after chronic treatment of rats with clonidine, tolerance to the analgesic effect of clonidine is accompanied by cross-tolerance to morphine (Paalzow, 1978). Alternatively, in this latter instance, a common pathway mediating the analgesic effects of the compounds may be postsynaptic. In ileum from morphine-treated guinea pigs, a contraction of the longitudinal muscle seen in response to naloxone is due, at least in part, to the release of acetylcholine from post-ganglionic neurones, and has been suggested to be related to the occurrence However, the magnitude of the nalozone-induced contraction was the same in ileum treated with morphine in vitro under various regimes and in ileum from pellet-implanted animals. In contrast, the degree of depression of the response to clonidine varied, being most marked in tissues from pellet-implanted animals and barely detectable in tissues incubated with morphine (1. 6 ~ ~) for 3h at 37OC (Kosterlitz et af., 1981). It would therefore appear that the two phenomena are not related in a simple way. Continued treatment of a mammal with opiate induces tolerance and dependence. Tolerance is characterized by a diminished response to opiates, and dependence by (i) a heightened response to selective opiate antagonists and (ii) a behavioural disturbance on withdrawal (the withdrawal syndrome). The relationship between opiate-tolerance and-dependence is obscursd by the fact that tolerance cannot be measured without giving drug, and dependence without withdrawing it (Collier, 1973). Some part of opiate-tolerance appears, however, to be closely associated with dependence (Wuster, 1982); and so we can speak of opiate-dependence and associated tolerance. Opiate-dependence and associated tolerance was first observed in man and later reproduced in laboratory animals. More recently the …