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

Abstract

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.

Action of Enkephalin Analogues and Morphine on Brain Acetylcholine Release: Differential Reversal by Naloxone and an Opiate Pentapeptide

“…Experiments were performed on Sprague-Dawley rats (250 to 300 g) lightly anaesthetized with a mixture of pentobarbitone and urethane (Jhamandas & Sutak, 1976). The spontaneous release of cortical ACh, in the presence of neostigmine (50 mg/ml) and atropine (0.8 mg/ml), was measured by the cup technique.…”

“…The reversal of morphine (Jhamandas & Sutak, 1976), methadone and levorphanol (Jhamandas, Hron & Sutak, 1975) by naloxone is always complete and it is associated with a large overshoot. In contrast, the reversal of Met-enkephalin by naloxone at similar doses is often incomplete and it is not associated with an overshoot phenomenon (Jhamandas et al, 1977).…”

The Effect of Naloxone on Opioid‐induced Inhibition and Facilitation of Acetylcholine Release in Brain Slices

“…In fact, Vasko & Domino (1976) showed that morphine at a low dose (1 mg/kg s.c.) increased locomotor activity and, concomitantly, increased ACh utilization in the thalamus. Moreover, Jhamandas & Sutak (1976) found that naloxone, either alone or after morphine, facilitated the increase of cortical ACh release caused by medial thalamus stimulation. Morphine and enkephalins did not modify resting ACh release in any area tested (Szerb, 1974;Vizi et al, 1977).…”

“…This effect which is prevented by naloxone (Jhamandas, Phillis & Pinsky, 1971;Jhamandas, Hron & Sutak, 1975;Beani, Siniscalchi & Sarto, 1979;Domino, 1979;Jhamandas & Sutak, 1980), may be due to an action on subcortical sites, since it is abolished by lesions of the medial thalamus or septum (Jhamandas & Sutak, 1976;Pepeu, Garau, Mulas & Marconcini-Pepeu, 1975).…”

“…Recently Wood & Stotland (1980) showed that p-opiate agonists and enkephalins reduce ACh turnover rate in the hippocampus and parietal cortex, but not in the striatum. On the other hand, some workers have demonstrated increased ACh utilization and release in certain structures (Vasko & Domino, 1976;Jhamandas & Sutak, 1976). …”