The role of noradrenaline (NA) in the behavioural and pharmacological effects of morphine was evaluated in rats. Animals received specific injections of 6-hydroxydopamine (6-OHDA) into the dorsal noradrenergic bundle (DB) resulting in selective depletion of telencephalic NA levels and increased levels of noradrenaline in the spinal cord and cerebellum. Employing changes in the hypoactive phase of morphine-induced locomotor activity as an index of tolerance development, it was observed that injection of 6-OHDA into the dorsal noradrenergic bundle resulted in a slower rate and a lesser degree of tolerance development to morphine. The effect of the DB-6-0HDA lesion on physical dependence was assessed by measuring naltrexone-induced withdrawal in lesioned and control animals who had received chronic morphine treatment. Results indicate that although NA is important in tolerance development, it does not mediate a dominant role in withdrawal, although behavioural evidence suggesting a secondary or modulatory role is presented. The interaction of amphetamine and morphine with the dopamine (DA) system was also assessed by studying the behavioural effects of amphetamine in animals following either acute or chronic morphine treatment. It was observed that amphetamine potentiated the spontaneous locomotor hyperactivity following both acute and chronic morphine treatment. The DB-6-OHDA lesion did not affect the locomotor potentiation of amphetamine in morphine pre-treated animals, and the hypothesis that another transmitter system mediates this effect, specifically DA, is discussed. / Medicine, Faculty of / Graduate

The acute administration of an analgesic dose (1mg/kg) of morphine sulfate to conscious and hydrated rats produced a pronounced antidiuretic response. This was accompanied by an increase in urine osmolality and a decrease in free water clearance in the normal and Brattleboro rats heterozygous for the diabetes insipidus trait. The response was comparable to that of an exogenous dose of vasopressin. Antidiuresis was also observed in the homozygous D.I. rats. Since these rats are incapable of synthesizing vasopressin, the antidiuresis must be mediated by other mechanism(s). When arterial blood pressure was monitored, it was found that the mean arterial pressure decreased sharply immediately after the morphine injection in all animals. This can account for the antidiuresis in the homozygous D.I. rats. In the normal and heterozygous D.I. animals, it is quite possible that both morphine-mediated release of vasopressin and hypotension are responsible for the decrease in urinary flow. In addition, hypotension per se may act as a stimulus for vasopressin release. To study the chronic effects of morphine, rats were rendered tolerant and physically dependent by two means: multiple injections and pellet implantation of morphine sulfate. In contrast to the antidiuretic effects of acute morphine administration, chronic treatment resulted in polyuria. Using a vasopressin radioimmunoassay (RIA), it was found that rats implanted with a morphine pellet for 3 days had a significantly lower neurohypophyseal store of vasopressin (744.3 ± 27.9 ng, n=6) as compared to the placebo pellet implanted controls (1024. 1 ± 66.0 ng, n=6). This depletion was replenished as the animals developed tolerance to the drug.. abrupt withdrawal of the drug from physically dependent animals also produced a significant depletion of the neurohypophyseal vasopressin stores - from 902.4 ± 37.0 ng (n=6) to 638. 3 ± 36.0 ng (n=6). In contrast to rats implanted with morphine pellets, no significant changes in the neurohypophyseal vasopressin stores were observed in those injected daily with morphine for 2 weeks. Withdrawal from the drug in these animals also did not produce any detectable changes in the vasopressin stores. A withdrawal symptom, reduction in body weight, monitored after 24 hr of abstinence suggested that the degree of physical dependence in these animals is very light. ³H-naloxone binding performed on whole brain homogenate of rats injected with morphine for 2 weeks revealed no significant changes in the number of binding sites (q). The affinity constant (Kd) was augmented from a control value of 5.33 nM to 22.37 nM in the morphine-injected rats. The changes in g and Kd suggested the presence of morphine in the whole brain homogenates. Moreover, the Kd was restored to the control value in animals withdrawn from the drug for 24 hr. Vasopressin or oxytocin iid not have any direct effect on the ³H-naloxone binding. Thus, it is unlikely that the facilitation of morphine tolerance by the neurohypophyseal peptides is mediated by their direct action on the opiate receptor. / Medicine, Faculty of / Cellular and Physiological Sciences, Department of / Graduate