Morphine actions on supraoptic oxytocin neurones in anaesthetized rats: tolerance after i.c.v. morphine infusion.

Pumford, K. M.; Leng, Gareth; Russell, John A.

doi:10.1113/jphysiol.1991.sp018717

Cited by 54 publications

(35 citation statements)

References 45 publications

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“…Over the course of 5 days of infusion, the milk-ejection reflex returns to normal, even with an increase in the dose of morphine up to 0 83 ,tg min-' (in morphine-naive rats, 1 jug morphine I.C.V. will silence oxytocin neurones; Pumford et al 1991). After 5 days, oxytocin neurones show near-normal spontaneous activity and normal responsiveness to i.v.…”

Section: Morphine Tolerance and Dependence In Magnocellular Oxytocin mentioning

confidence: 99%

Opioid tolerance and dependence in the magnocellular oxytocin system: a physiological mechanism?

Ja¹,

Leng²,

Rj³

1995

Experimental Physiology

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At the neurosecretory terminals in the neural lobe, oxytocin secretion is restrained by co‐secreted endogenous opioids, which act via kappa‐receptors. The co‐secreted opioids include products of pro‐dynorphin (released by both vasopressin and oxytocin terminals) and proenkephalin (released by oxytocin terminals). In morphine‐tolerant rats this opioid mechanism is more effective, but in late pregnancy it is less effective. Opioids also act directly on oxytocin cell bodies, via separate mu‐ and kappa‐receptors, inhibiting excitation by all stimuli tested, and also exert presynaptic and more distal actions on afferent systems. During chronic morphine exposure, tolerance and dependence develop in oxytocin neurones; the former involves reduction in mu‐opioid receptor density, while the latter may involve compensatory upregulation of mechanisms regulating Ca2+ influx. In mid‐pregnancy, the effectiveness of opioid mechanisms in the neural lobe increases, assisting the accumulation of oxytocin stores in advance of parturition, but by the end of pregnancy the effectiveness of these mechanisms is reduced. At this time, a separate endogenous opioid system, acting via mu‐receptors, actively restrains the electrical activity of oxytocin neurones. Release of this endogenous opioid inhibition may contribute to the increase in activity during parturition analogous to that occurring during morphine withdrawal excitation. Central opioid mechanisms retain the ability to control oxytocin neurones during parturition, and can interrupt established parturition by inhibiting oxytocin neurone firing rate in disadvantageous environmental circumstances.

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Section: Morphine Tolerance and Dependence In Magnocellular Oxytocin mentioning

confidence: 99%

Opioid tolerance and dependence in the magnocellular oxytocin system: a physiological mechanism?

Ja¹,

Leng²,

Rj³

1995

Experimental Physiology

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“…The secretion of oxytocin during parturition is under tonic opioid inhibitory restraint since naloxone increases oxytocin secretion and accelerates parturition . Similarly injection of the t-opioid agonist, morphine, interrupts parturition and inhibits oxytocin secretion (Russell et al, 1989a), acting centrally on the firing-rate of oxytocin neurones but not on the posterior pituitary (Wakerley et al, 1983;Coombes & Russell, 1988;Pumford et al, 1991). We have now studied the effects of the K-agonist U50,488 on the time-course of parturition, and on oxytocin secretion during I Author for correspondence.…”

Section: Introductionmentioning

confidence: 99%

Effects of the κ‐opioid agonist U50,488 on parturition in rats

Douglas

Clarke

Macmillan

et al. 1993

British J Pharmacology

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1 The effects of the ic-opioid agonist U50,488 on parturition were studied in the rat. 2 Given directly after the birth of the second pup U50,488 (5 mg or 10 mg kg-', i.p.) delayed the birth of the subsequent 4 pups by ca. 100 min, acting like morphine (10 mg kg-', i.p.). In controls given the vehicle i.p., the birth of the 4 pups after treatment took 45.4 ± 4.6 min. The effects of U50,488 could be prevented by simultaneous naloxone injection (10 mg kg-'). Injection of either U50,488 or morphine at 1 mg kg-', i.v. also significantly delayed parturition. The effects of U50,488 but not of morphine were fully prevented by preinjection with nor-binaltorphimine (0.5 mg kg ', i.v.) showing selective K-opioid receptor-mediated inhibition by U50,488 of established parturition. 3 In rats with an indwelling jugular venous cannula, i.v. injection of U50,488 (5 mg kg-') after the birth of the second pup slowed parturition in a similar way to i.p. injection and significantly reduced blood plasma oxytocin concentration measured by radioimmunoassay compared with vehicle-injected controls. 4 Bolus i.v. injections of oxytocin (4 mu once per 5 min) significantly reduced the delay in parturition caused by i.v. U50,488, but continuous i.v. infusion of oxytocin (4 mu 5 min-') was less effective. 5 Since i.v. oxytocin did not immediately reverse the effects of U50,488 on parturition, direct effects of U50,488 on isometric uterine contractions in vitro were sought. U50,488 inhibited spontaneous or oxytocin-stimulated contractions of uteri from rats within 24 h after parturition in a dose-related manner; the inhibitory effect was not naloxone-reversible. 6 Thus U50,488 inhibited established parturition in the rat in a K-opioid selective manner by reducing oxytocin secretion. The inhibitory effect may well have been potentiated by a direct non-opioid depressant action on contractile activity of the uterus.

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“…Opioids directly inhibit OT secretion in mammals through action in the posterior pituitary and the hypothalamus (21, 22). Opioids not only inhibit OT release from the axon terminal in the posterior pituitary but also suppress the functional activity of OT neurons via opioid action on their cell bodies in the hypothalamus (23,24). The chronic administration of morphine, a prototypical μ-opioid receptor agonist, also influences both the synthesis and secretion of OT (25).…”

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Oxytocin under opioid antagonism leads to supralinear enhancement of social attention

Monte

Piva

Anderson

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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To provide new preclinical evidence toward improving the efficacy of oxytocin (OT) in treating social dysfunction, we tested the benefit of administering OT under simultaneously induced opioid antagonism during dyadic gaze interactions in monkeys. OT coadministered with a μ-opioid receptor antagonist, naloxone, invoked a supralinear enhancement of prolonged and selective social attention, producing a stronger effect than the summed effects of each administered separately. These effects were consistently observed when averaging over entire sessions, as well as specifically following events of particular social importance, including mutual eye contact and mutual reward receipt. Furthermore, attention to various facial regions was differentially modulated depending on social context. Using the Allen Institute's transcriptional atlas, we further established the colocalization of μ-opioid and κ-opioid receptor genes and OT genes at the OT-releasing sites in the human brain. These data across monkeys and humans support a regulatory relationship between the OT and opioid systems and suggest that administering OT under opioid antagonism may boost the therapeutic efficacy of OT for enhancing social cognition.T he efficacy of oxytocin (OT) in improving social abilities is under debate, largely due to frequently observed weak effect sizes and problems with replicability (1-3). Clinical trials of OT in autistic patients are ongoing, yet several studies have produced inconclusive results (4-8), demanding improvements to the efficacy and reliability of OT-based therapeutics. One strategy is to take advantage of existing physiological pathways in the brain that regulate OT activity to combinatorially enhance the oxytocinergic effects on social functions. In this regard, a promising candidate is the opioid system.In addition to the evolutionarily conserved OT system (9), the opioid system has been implicated in regulating social behavior. Excessive opioid activity in the brain has been discussed with respect to the development of early childhood autism (10). Abnormalities in central opioid levels have been observed in some individuals with autism, and clinical trials with predominantly μ-opioid blockers, such as naltrexone or naloxone (NAL), have yielded promising results in ameliorating both social and nonsocial deficits (11). Specifically, μ-opioid receptors have been studied in relation to reward, emotion, and behavior in the social domain (12) and are strongly expressed in reward-related regions of the primate brain (13). In rhesus macaques, carrying the G allele of the μ-opioid receptor gene OPRM1, compared with homozygous C alleles, is associated with stronger maternal attachment in infants (14) and more effective prevention of infant separation in mothers (15). Additionally, opioid agonists, such as morphine, decrease physical contact between social partners, whereas NAL administration increases solicitation for social contact, such as grooming and proximity (16)(17)(18)(19).The physiological relationship between the opi...

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Morphine actions on supraoptic oxytocin neurones in anaesthetized rats: tolerance after i.c.v. morphine infusion.

Cited by 54 publications

References 45 publications

Opioid tolerance and dependence in the magnocellular oxytocin system: a physiological mechanism?

Opioid tolerance and dependence in the magnocellular oxytocin system: a physiological mechanism?

Effects of the κ‐opioid agonist U50,488 on parturition in rats

Oxytocin under opioid antagonism leads to supralinear enhancement of social attention

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