Modification of Morphine Withdrawal by Drugs interacting with Humoral Mechanisms: Some Contradictions and their Interpretation

I The opiate antagonist naloxone, injected or topically applied to the cerebral cortex, had no significant effect on the spontaneous output of cortical acetylcholine (ACh) in rats. 2 Morphine (2.5 mg/kg) administered intravenously inhibited the release of cortical ACh. A subsequent injection of naloxone rapidly reversed morphine-induced inhibition, and produced a sustained increase in the release of ACh. Topical application of naloxone solutions, after morphine, produced a slow and weak reversal of its inhibitory action. 3 Destruction of the medial thalamus abolished both the inhibitory effects of morphine on the cortical ACh release, and its antagonism by naloxone administered after the agonist. 4 Injection of naloxone in a low dose (0.1 mg/kg) increased the release of cortical ACh provoked by electrical stimulation of either the medial thalamus or the reticular formation in normal rats. In the morphine-dependent rat, naloxone also facilitated the evoked release and its action was greater than in control animals. The facilitatory effect of naloxone on the cortical release evoked by stimulation of the medial thalamus was greater than its effect on the release evoked by stimulation of the reticular formation in both normal and morphine-dependent rats. Naltrexone, a narcotic antagonist, also facilitated the electrically stimulated release of cortical ACh. 6 It is suggested that (a) morphine and naloxone act at a subcortical site, probably the medial thalamus, to modify the cortical ACh release and that (b) naloxone may facilitate the electricallyinduced release of ACh in the CNS by antagonizing the effect of the endogenous morphine-like factor, enkephalin.

Section: Introductionsupporting

confidence: 72%

Morphine–naloxone Interaction in the Central Cholinergic System: The Influence of Subcortical Lesioning and Electrical Stimulation

Jhamandas

Sutak

1976

“…showed a similar result (unpublished observations). Furthermore, the doses of nalorphine and naloxone that in our experiments produced an increase in the release of brain ACh in the dependent rats, corresponded very closely to those which precipitated the abstinence syndrome in morphine-dependent rats (Kerr & Pozuelo, 1971;Collier, Francis & Schneider, 1972). It therefore appears likely that an increased release of brain ACh occurs during precipitated narcotic abstinence in the rat and possibly in other species.…”

Section: Discussionmentioning

confidence: 49%

Modification of Brain Acetylcholine Release by Morphine and Its Antagonists in Normal and Morphine‐dependent Rats

Jhamandas

Sutak

1974

The spontaneous release of acetylcholine (ACh) from the cerebral cortex of control and morphine-dependent rats was investigated. The rate of resting output of ACh in morphine-dependent animals was lower than that in the control animals. 2 Administration of naloxone and nalorphine to morphine-dependent rats was followed by a significant rise in the release of cortical ACh. In control rats no such increase in the release of ACh occurred after similar injections of narcotic antagonists. 3 Injections of morphine produced a consistent decrease in the rate of spontaneous release of cortical ACh in the control rats, but similar injections in the dependent rats did not produce a decrease in the rate of cortical ACh release. 4 The relevance of these results with regard to development of the narcotic abstinence syndrome is discussed.

“…However, some neurones did not show this desensitization to morphine excitation and none showed it to morphine-induced inhibition. Although the time scale for this effect is shorter than that normally considered for the development of morphine tolerance, we would like to suggest, in view of the fact that tolerance to morphine has been found to develop rapidly after a single injection in man (Martin & Fraser, 1961) and animals (Collier, Francis & Schneider, 1972), that desensitization to microiontophoretic morphine may be regarded as a form of 'acute tolerance' and may reflect, at the level of the single neurone, the phenomenon which occurs Table 2 Interactions of iontophoretically applied morphine with effects of excitatory and inhibitory agents. Thus, although morphine has complex effects when applied microiontophoretically to brain stem neurones, particularly in relation to effects of neurotransmitters, the fact that it has a powerful excitatory action on many neurones, and that this effect shows 'tolerance' with repeated applications, is probably worthy of further investigation, particularly with specific antagonists.…”

Section: Discussionmentioning

confidence: 99%

Morphine and Neurotransmitter Substances: Microiontophoretic Study in the Rat Brain Stem

Bradley¹,

Dray

1974

The effects of microiontophoretically applied morphine and its interactions with the effects of microiontophoretic applications of either acetylcholine, (–)‐noradrenaline or 5‐hydroxytryptamine have been studied on single neurones in the brain stem of rats anaesthetized with urethane. Morphine excited or inhibited most neurones tested and the effects, especially excitation, were often extremely powerful. However, the time course of the excitatory and inhibitory effects were somewhat different. Desensitization to the excitation produced by morphine was seen after repeated or prolonged applications and it is suggested that this phenomenon may be related to the tolerance which develops after chronic administration of morphine. No desensitization was observed to inhibition of neuronal activity by morphine. Morphine usually reduced the excitation of neurones by acetylcholine, noradrenaline or 5‐hydroxytryptamine but sometimes potentiated the effect, although not always on the same neurones. Inhibition of neuronal activity by these compounds was never modified by morphine and neither were the effects of glutamate or D,L‐homocysteic acid when used as control agonists. The in vitro release of morphine from six micropipettes was determined and the transport number was calculated to be 0.051 (s.d. 0.021). The implications of these observations in explaining the pharmacological actions of morphine are discussed.