Chronic intracerebroventricular morphine and lactation in rats: dependence and tolerance in relation to oxytocin neurones.

Abstract

SUMMARY1. Acutely, opioids inhibit oxytocin secretion. To study the responses of oxytocin neurones during chronic opioid exposure, forty-five lactating rats were infused continuously from a subcutaneous osmotically driven mini-pump via a lateral cerebral ventricle with morphine sulphate solution from day 2 post-partum for 5-7 days; the infusion rate was increased 2-or 2-5-fold each 40 h from 10 ,ug/h initially up to 50 ,ug/h; controls were infused with vehicle (1 ,u/h, twenty-eight rats) or were untreated (eight rats).2. Maternal behaviour was disrupted in 27 % of the morphine-treated rats; in rats that remained maternal morphine did not affect body weight or water intake but increased rectal temperature by 0-82 + 0-14 'C (mean+S.E.M.) across the first 4 days.3. Weight gain of the litters of maternal morphine-treated rats was reduced by 32 % during 7 days, predominantly in the first day of treatment when milk transfer was also reduced. Observation of pup behaviour during suckling showed decreased frequency of milk ejections on only the second day of morphine treatment. Plasma concentration of prolactin after 6 days was similar in maternal morphine-treated and control rats, but reduced by 90 % in non-maternal morphine-treated rats, indicating normal control of prolactin secretion by suckling in morphine-treated rats.4. Oxytocin and vasopressin contents, measured by radioimmunoassay, in the supraoptic and paraventricular nuclei and in the neurohypophysis were similar between fourteen maternal morphine-treated, twelve vehicle-treated and eight untreated lactating rats; thus exposure to morphine did not involve increased production and storage of oxytocin.5. Distribution of L3H]morphine infused intracerebroventricularly into six virgin female rats for 6 days was measured by scintillation counting of tissue extracts. Morphine concentration in the hypothalamus and neurohypophysis was 2-7 and 12 8 jug/g, respectively, and in blood plasma 0 75 ,ug/g. Tolerance was not due to failure of morphine infusion. In addition, naloxone (5 mg/kg s.c.) provoked typical withdrawal reactions ('wet dog' shakes, defaecation, burrowing) in lactating rats infused with morphine for 5 days.6. Pups were suckled onto seven maternal morphine-infused and five vehicle-V. C. RA YNER AND OTHERS infused rats anaesthetized with urethane for recording of intramammary and arterial blood pressures after treatment for 5 days. The incidence and pattern of milk ejections, and mammary gland sensitivity to oxytocin were similar in the two groups. Tolerance to the inhibition of suckling-induced oxytocin secretion by intracerebroventricular (i.c.v.) morphine did not extend to acute intravenous morphine (2-5 or 5 mg/kg).7. In fourteen out of fifteen morphine-infused rats under urethane anaesthesia, intravenous naloxone HCl (5 mg/kg) quickly provoked a large, fluctuating increase in intramammary pressure lasting 41-5+ 15 min (mean±+S.D.); this excitation of presumptive oxytocin secretion was independent of suckling and was not seen in twelve vehicle-infused ra...

Oxytocin under opioid antagonism leads to supralinear enhancement of social attention

“…Our analysis of human brain tissue indicates the colocalization of μ-opioid and κ-opioid receptor genes, but not δ-opioid receptor genes, and OT genes at the OT-releasing sites in the brain, including the SO, PVH, and LHT, but not in other cortical and subcortical regions. Based on NAL's much higher affinity for μ-type than for κ-type (greater than eightfold) and δ-type (>60-fold) receptors (45), the supralinear results of OTNAL here are likely driven most strongly by the OTsecreting cells expressing the μ-opioid receptor subtypes, as suggested from posterior pituitary as well as lactation and parturition studies (30,31). This finding is consistent with the notion that OTNAL is amplifying the known OT effects on social attention associated with systemic OT manipulations, in which the functional specificity is likely to be localized to OT-sensitive brain regions following an enhancement of the oxytonergic tone of the brain.…”

“…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).Exploiting the regulatory relationship between the opioid and OT systems in the brain, we tested here whether administering OT …”

The physiological costs of reproduction in small mammals

“…Projections from this area terminate in the paraventricular nucleus (PVN), where the magnocellular cells synthesize oxytocin. Rayner et al (1988) showed that intracerebroventricular (ICV) administration of morphine inhibits oxytocin production in the PVN. Thus, elevated endogenous opioids under hyperthermia might directly reduce oxytocin secretion.…”

Local opioid inhibition and morphine dependence of supraoptic nucleus oxytocin neurones in the rat in vivo

“…The cannula was attached via polythene tubing to a subcutaneous osmotic minipump (Alzet 2001; Charles River Ltd, Margate, Kent, UK). The pump and tubing contained morphine dissolved in sterile pyrogen-free water to deliver increasing doses over 5 days (10 and 20 ìg h¢ for 40 h each and 50 ìg h¢ for the remaining 40 h at 1 ìl h¢; Rayner, Robinson & Russell, 1988). Following surgery animals were housed individually with free access to food and water.…”