Hypothalamic opioid mechanisms controlling oxytocin neurones during parturition

Bicknell, R.J.; Leng, Gareth; Russell, John A.; Dyer, R. G.; Mansfield, S.; Zhao, Baoliang

doi:10.1016/0361-9230(88)90086-x

Cited by 61 publications

(36 citation statements)

References 29 publications

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“…The supralinear effects of OTNAL may be due to simultaneous engagement of feedforward endogenous OT release from neurons with OT receptors (46), as well as the removal of opioid-mediated inhibition of OT release in OT neurons (27), resulting in overall higher endogenous OT levels that reach a threshold needed for social functions. Observational studies in patients with autism have shown that administration of an opioid antagonist could decrease self-injurious behavior, stereotypies, hyperactivity, and withdrawal, although increasing verbal production, social communication, proximity seeking, and eye contact (47)(48)(49)(50).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, during parturition, endogenous opioids control the release of OT both into blood and the brain in a tightly coordinated manner (26). Enhancing opioidergic tone with morphine severely delays the course of parturition, accompanied by a reduced level of circulating OT, whereas attenuating opioidergic tone with NAL acutely increases the speed of parturition by greatly elevating OT levels, reversing this delay (27)(28)(29). Similarly, the inhibition of OT secretion from neural tissues by morphine underlies the mechanism by which morphine disrupts milk ejection in lactation (30,31).…”

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confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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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“…Thus during sustained endogenous opioid action, oxytocin neurones would be first inhibited, then become tolerant and resume normal activity, and finally increase activity on cessation of opioid action. Such a sequence has been postulated to take place during pregnancy, in preparation for parturition (Bicknell, Leng, Russell, Dyer, Mansfield & Zhao, 1988b;Leng & Russell, 1989).…”

Section: Discussionmentioning

confidence: 99%

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

Pumford

Leng

Russell

1991

The Journal of Physiology

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SUMMARY1. The effects of acute i.v. administration of morphine on putative oxytocin neurones of the supraoptic nucleus were studied in urethane-anaesthetized female rats which had been exposed to i.c.v. infusion of morphine (up to 50 ag h-') or vehicle for 5 days.2. In vehicle-infused rats, i.v. morphine inhibited the spontaneous activity of six out of seven putative oxytocin neurones. Increasing doses of morphine were given, from 1 ,ag kg-' to 5 mg kg-'. The median cumulative threshold dose to produce significant inhibition was 20 ,ug kg-' (seven cells in six rats); six out of seven cells were inhibited at 161 1ag kg-1. The highest doses tested inhibited by -90% (excluding one unaffected cell). Inhibition was fully reversed by i.v. naloxone without overshoot, indicating a lack of acute dependence.3. Injection of morphine i.c.V. inhibited firing at doses that were ineffective by i.v. injection and the effects of i.c.V. morphine were reversed by i.v. naloxone.4. Acute morphine (500 jug kg-' i.v.) reduced the plasma concentration of oxytocin, measured after 15 min by specific radioimmunoassay, by 34% (n = 14).5. In lactating rats i.c.V. injection of morphine (1-2 ,ug) inhibited the activity of supraoptic neurones identified as oxytocinergic by their responses to suckling.6. In seventeen rats infused with i.c.V. morphine the initial firing rate of twentyeight spontaneously active, non-phasic neurones was significantly less, by 24 %, than thirty-four similar cells in control rats, indicating incomplete tolerance to I.C.V. morphine. Morphine (up to 161 ,ug kg-' given i.v.) inhibited none of nine active nonphasic neurones (P < 0'01 compared to control rats), but at higher doses inhibited four of nine cells; the overall median threshold cumulative dose (1660 jag kg-') was significantly greater than in vehicle-infused controls, indicating tolerance to i.v. morphine. In contrast with control rats, some cells (5/9) were modestly excited by low doses of morphine. Naloxone (5 mg kg-' i.v.) produced withdrawal excitation: the firing rate of putative oxytocin neurones increased to -260 % of the pre-i.v. morphine value, indicating dependence in mechanisms regulating the firing rate of these neurones.t To whom correspondence should be sent. MS 8865K. M. PUMFORD. G. LENG AND J. A. R.UTSSELL 7. In morphine-infused rats, the basal firing rate of nineteen phasically active, putative vasopressin supraoptic neurones was not different in nineteen phasic cells in controls (6-4 + 0-7 vs. 4 2 + 0 6 Hz).8. Thus morphine potently inhibits the firing of magnocellular oxytocin neurones in the female rat, inhibiting oxytocin secretion. Morphine tolerance and dependence develop during i.c.V. infusion of morphine for 5 days. Similar tolerance to and dependence upon endogenous opioids during pregnancy may be important in the preparation of oxytocin neurones for parturition.

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“…This suggests a role for these neuropeptides in the mediation of inflammatory nocioception, and/or the early pathophysiology of experimental arthritis. We have examined whether increased endogenous opioid inhibition of oxytocin neurones in pregnancy (Bicknell et al 1988) alters sensitivity to the potent central inhibitory actions of p-agonists on oxytocin secretion. Urethaneanaesthetized (1.25 g kg-l) Sprague-Dawley rats were given increasing I.V.…”

Section: ±3mentioning

confidence: 99%

“…Considering the reduced plasma [Na'] in pregnancy, and the reduced stimulatory (hyperosmotic) effect of urethane, we conclude that the threshold for hypernatraemic stimulation of oxytocin secretion is not reduced in pregnancy. Morphine inhibited stimulated oxytocin secretion, with increased sensitivity in 16-day pregnant rats, coinciding with the start of inhibitory endogenous opioid tone on oxytocin secretion (Bicknell et al 1988 We have therefore investigated the effects of intracerebroventricular (I.C.V.) injections of a GABA-A receptor agonist, muscimol (Sigma), and an antagonist, bicuculline methiodide (Sigma), on the milk ejection reflex in the rat.…”

Section: ±3mentioning

confidence: 99%

Proceedings of the Physiological Society, 14‐15 February 1992, Bristol Meeting: Communications

1992

The Journal of Physiology

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Brown adipose tissue (BAT) possesses atypical f3-adrenoceptors (fi3) which stimulate energy expenditure by increasing lipogenesis and thermogenesis. Holloway et al. (1991) reported that ICI D7114 selectively stimulates these atypical k3-receptors, increasing BAT oxygen consumption and thermogenesis.We have previously reported that CBA/Ca obese diabetic mice exhibit reduced lipogenesis compared to normal littermates (Al-Qatari et al. 1991) .In vivo lipogenesis rates were estimated by measuring the incorporation of 3H into fatty acids extracted from adipose tissue following I.P. injection of 3H20 (Mercer & Trayhurn, 1983). D7114 was administered either chronically in the food (dose equivalent to 3 mg (kg body weight)-l day-' for 3 weeks) or acutely (5 mg kg-' I.P.) 1 hour prior to 3H20 injection. Insulin (1 IU kg-' I.P.) was injected 15 minutes before 3H20. Mitochrondrial activity was monitored by measuring the specific activity of cytochrome oxidase.Acute D7114 significantly increased basal BAT lipogenesis rates from 63.7 ± 0.6 to 109.9 ± 16.9 jug atoms H incorporated h-' (g fat-free tissue weight)-l (means ± S.E.M., n = 10-13; P < 0.03, t test). Chronic treatment with D7114 also increased BAT lipogenesis by 61 % above controls. In contrast, insulinstimulated BAT lipogenesis was lower following acute D7114: 60.0 ± 7.0 compared with 119.9 ± 20.2 (n = 9-14) in controls. Basal and insulin-stimulated lipogenesis in white adipose tissue (epididymal fat pads) was unaltered by either acute or chronic D7114. Chronic D7114 treatment significantly increased cytochrome c oxidase activity (P < 0.01, t test): 22.5 ± 2.3 compared with 13.1 ± 1.3,umol cyto c min-' in controls. Acute D7114 had no effect on cytochrome c oxidase activity.These results demonstrate that D7114 is effective in increasing basal rates of BAT lipogenesis in obese diabetic mice and that chronic dosing increases mitochondrial activity, thus increasing energy expenditure.We are grateful to ICI Pharmaceuticals for supplies of D7114.

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Hypothalamic opioid mechanisms controlling oxytocin neurones during parturition

Cited by 61 publications

References 29 publications

Oxytocin under opioid antagonism leads to supralinear enhancement of social attention

Oxytocin under opioid antagonism leads to supralinear enhancement of social attention

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

Proceedings of the Physiological Society, 14‐15 February 1992, Bristol Meeting: Communications

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