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Title: A study of opiate actions on oxytocin neurones
Author: Liddington, Kathryn Mary
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1990
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The thesis describes investigations of the interactions between opiate drugs and oxytocin (OT) neurones in the hypothalamic supraoptic nucleus (SON) of the female albino rat. Both acute and chronic opiate effects were examined, acting at the μ-, k-subtypes of opiate receptor using whole animal and in vitro techniques. The tolerance which develops to the chronic intracerebroventricular (icv) infusion of morphine was quantified in terms of firing rate of identified OT neurones in vivo. We contrasted the attenuation of acute morphine induced inhibition of firing rate, presumably through the μ-type opiate receptor, with the acute effects of the selective k-type receptor agonist, U50,488H. There was no cross-tolerance between morphine and U50,488H. In both cases naloxone, the broad spectrum opiate antagonist evoked a reversal of opiate inhibition of activity with overshoot, indicating withdrawal excitation due to dependence. The density of k-receptors in the SON was assessed by autoradiography after chronic icv infusion of morphine, to see if the manifestations of tolerance in terms of neuronal activity might be reflected in a change in receptor density in the SON. Highly selective ligands for the μ- and δ-subtypes of opiate receptor were used to saturate binding to these two receptor subtypes, thus allowing measurement of k-receptor density by displacement of a high affinity radio-labelled ligand with the equivalent unlabelled ligand. Tolerance to morphine did not produce a measurable change in the density of k-opiate receptors in the SON. The roles of two post-receptor systems in the cell response to opiates were investigated. Using icv pertussis toxin (PT) to inactivate the regulatory GTP-binding proteins (G-proteins) susceptible to it, Gi and Go, we tested the potency of morphine to inhibit the electrical activity of identified OT neurones of the SON, in vivo. Morphine inhibited firing rate less potently after PT but U50,488H remained as potent as in the icv vehicle-injected group. The G-proteins Gi or Go are involved therefore in post-receptor transduction in these cells or in cells projecting to the SON which might mediate the acute affects of morphine. Adenylate cyclase (AC) activity measured in vitro as cAMP content of isolated SON was assessed in SON taken from morphine-naive and chronic morphine-infused rats. Whereas vasoactive intestinal peptide (VIP) was able to powerfully stimulate AC, incubation in vitro with morphine did not affect tissue content of cAMP and treatment of SON derived from chronic morphine-infused rats with naloxone did not result in any change in tissue cAMP content. cAMP appears to play no part in post-receptor events following the activation of the opiate receptor in OT neurones of the SON. Finally we investigated the contribution of the region anterior and ventral to the third ventrical (the AV3V region) to the full expression of the withdrawal hyperexcitation of OT neurones and resultant massive and sustained release of OT into the systemic circulation. In chronic morphine-infused rats, we studied plasma OT concentration, assayed before and at intervals after an electrolytic lesion of the AV3V region which left the SON and paraventricular nucleus intact. The withdrawal response was diminished but was still evident in AV3V-lesioned rats. So only part of the withdrawal response to naloxone is mediated outside the SON in the AV3V region. This suggests that SON OT neurones themselves may develop morphine dependence.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available