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Central Endogenous Opioid Inhibition of Supraoptic Oxytocin Neurons in Pregnant Rats

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Central Endogenous Opioid Inhibition of Supraoptic Oxytocin Neurons in Pregnant Rats The Journal of Neuroscience, July 1995, 15(7): 5049-5057 Central Endogenous Opioid Inhibition of Supraoptic Oxytocin Neurons in Pregnant Rats A. J. Douglas,’ I. Neumann,2,a H. K. M. Meeren, 3,b G. Leng,4 L. E. Johnstone,’ G. Munro,i,C and J. A. Russell1 ‘Department of Physiology, University Medical School, Teviot Place, Edinburgh, EH8 9AG, United Kingdom, 2Department of Medical Physiology, University of Calgary, Alberta, Canada, 3Department of Physiology, University of Leiden, 2300 RC Leiden, The Netherlands, and 4Department of Neurobiology, The Babraham Institute, Babraham, Cambridge, CB2 4AT, United Kingdom Naloxone increases oxytocin secretion in pregnant rats, trophysiology, oxytocin release into the SOfWfrom den- suggesting restraint by endogenous opioicls but we have drites, oxytocin secretion, microdialysis, cholecystokinin] previously reported that oxytocin nerve terminals in the neural lobe become desensitized to opioid actions in late During pregnancy, in preparation for parturition, the oxytocin pregnancy. Therefore, we sought evidence for opioid inhi- content of the rat neural lobe increasesprogressively (for ex- bition on oxytocin cell bodies and their inputs at this time. ample, Douglas et al., 1993b), and the accumulated excess is In conscious 21 d pregnant rats naloxone increased the secretedduring parturition itself to stimulate uterine contractility number of neurons expressing Fos (an indicator of neu- and fetal expulsion. The increasein neural lobe oxytocin is not ronal activity) in the supraoptic nucleus (SON) but had no conspicuouslya result of increasedsynthesis since there is little effect on 16 d pregnant or virgin rats. Release of oxytocin change in hypothalamic oxytocin mRNA (Brooks, 1992; Doug- within the SON, measured by microdialysis in conscious las and Russell, 1994), but at least in part appearsto be a con- rats, was also increased by naloxone in late pregnancy but sequenceof an active restraint of secretion.We have shown that not before. Nor-binaltorphimine, a specific K- opioid antag- endogenousopioids inhibit oxytocin neurons in late pregnancy onist, did not increase Fos or affect oxytocin release within since injection of the opioid antagonistnaloxone into conscious the SON in any group. In anesthetized rats the firing rate late pregnant rats rapidly increasesoxytocin secretion(Hartman of SON neurons was recorded and oxytocin neurons iden- et al., 1986; Douglas et al., 1993b). Opioids may restrain oxy- tified by an excitatory response to intravenous cholecys- tocin secretion either by p- or K-opioid mechanismsacting on tokinin. Naloxone potentiated the cholecystokinin-induced the oxytocin cell body in the hypothalamus (Pumford et al., firing rate response on day 21 of pregnancy but not in 16 1993) or by preterminal K-mediatedinhibition at the neural lobe d pregnant or virgin rats. Blood sampling in anesthetized (Zhao et al., 1988; Russell et al., 1993). Oxytocin neurons are rats showed that naloxone also increased the oxytocin se- highly susceptibleto inhibition by either p.- or K-agonists,which cretory response to cholecystokinin in late pregnant rats. thus suppressthe milk-ejection reflex (Clarke and Wright, 1984), We conclude that in late pregnancy, after day 16, endog- oxytocin secretion, and Fos expressionin supraoptic magnocel- enous opioids inhibit oxytocin neurons either directly, on lular neurons in parturition (Russell et al., 1989; Douglas and their cell bodies, or presynaptically on inputs. These en- Russell, 1993; Douglas et al., 1993a; Luckman et al., 1993). dogenous opioids do not act through K- opioid receptors In virgin rats inhibition of oxytocin secretion by endogenous since nor-binaltorphimine was ineffective, but may act via opioids appearsto be via receptors on oxytocin nerve terminals p-opioid receptors. Thus, the opioids restrain premature in the neural lobe, since naloxone increasesplasma oxytocin oxytocin secretion until parturition when there is a high concentration without increasing oxytocin neuron firing rate demand for it. (Leng et al., 1992). In early- to mid-pregnancy secretionof en- [Key words: enciogenous opioids, pregnancy, Fos, elec- dogenousopioids, such as extended enkephalinsor dynorphins colocalized with oxytocin (Leng et al., 1994), in the neural lobe may locally inhibit oxytocin secretion and induce downregula- Received Oct. 26, 1994; revised Feb. 13, 1995; accepted Feb. 16, 1995. tion of K-opioid receptor binding sites (Sumner et al., 1992). This work was supported by an Agriculture and Food Research Council However, by the end of pregnancy oxytocin nerve terminals in Linked Research Group Grant and the IBRO/British Council. I.N. was sup- ported by a Human Frontier Science Programme (Strasbourg). L.E.J. and G.M. the neural lobe appear to be desensitizedto opioid actions and were supported by AFRC Research Studentships. H.K.M.M. was an Erasmus naloxone is relatively ineffective at this time in potentiating oxy- exchange student from the Department of Physiology, University of L&den, tocin secretion from the isolated neural lobe (Douglas et al., The Netherlands. We thank Prof. R. Landgraf (Munich) for RIA of oxytocin in dialysates and Mrs. K. Grant and Mrs. Cl. Grant (Edinburgh) for their assis- 1993b). Thus, from this mismatch at the end of pregnancy be- tance with histology. tween enhancedactivity of systemically administerednaloxone Correspondence should be addressed to Dr. A. J. Douglas, Department of and declining efficiency of naloxone at the neural lobe level, we Physiology, University Medical School, Teviot Place, Edinburgh, EH8 9AG. UK. have speculatedthat at the end of pregnancy a secondendoge- “Present address: Max Planck Institute of Psychiatry, Clinical Institute, Mu- nous opioid mechanismacts more centrally on the oxytocin neu- nich, Germany. “Present address: Katholicke University, Nijmegen, The Netherlands. rons in the hypothalamus. ‘Present address: Oregon Regional Primate Center, Beaverton, OR. We now report studiestesting the hypothesis that there is a Copyright 0 1995 Society for Neuroscience 0270.6474/95/155049-09$05.00/O central component of endogenousopioid inhibition of oxytocin 5050 Douglas et al. + Central Opioid Inhibition of Oxytocin in Pregnancy neurons in late pregnancy. We have performed parallel experi- tally with its U-shaped tip within the right SON (1.1 mm caudal to ments to seek endogenous opioid restraint in pregnancy of the bregma, 1.8 mm lateral to the midline, and 9.3 mm below the surface of the skull; see Paxinos and Watson, 1982). The probes were secured expression of Fos protein (a sign of neuronal activation) in the in place with stainless steel screws and dental cement and the rats were supraoptic nucleus (SON) and oxytocin release within the SON. housed singly after recovery from surgery. In addition we have sought endogenous opioid restraint of inputs On the day of the experiment the inflow tube of the implanted probe to oxytocin neurons in pregnancy by measuring the effects of was connected to an infusion pump via 20.gauge tubing long enough to allow the rat free mobility. Themicrodiaiysis probes-were-perfused naloxone on stimulus evoked oxytocin neuron firing rate and with aCSF at 3.9 iJ/min for at least 30 min before samoling. Conscious stimulated oxytocin secretion. virgin rats and rats on days 10, 18, and 21 of pregnant; ea:h had three Some of the data have previously been reported in abstract consecutive 30 min samples collected; before starting the second per- form (Douglas et al., 1993, 1994a,b). fusion period either vehicle (0.9% saline, 0.5 ml/kg, II = 6, 6, 8, 7, respectively) or naloxone (5 mg/kg, n = 7, 7, 8, 9, respectively) was Materials and Methods injected subcutaneously. Another group of 21 d pregnant rats was in- jected subcutaneously with norBNI(1 mg/kg, IZ = 6). After completion Experiment 1. The effect of opioid antagonistson SON neuron of each experiment, direct osmotic stimulation (with 1 M NaCl aCSF Fos expressionin pregnancy over one 30 min period) via the microdialysis probe was used to verify Female Sprague-Dawley, age-matched rats were given food and water both the placement of the probe ante mortem and the ability of the ad libitum and housed according to standard conditions in Edinburgh nucleus to respond to a local osmotic stimulus. Only data from rats (Douglas et al., 1993b). Rats were mated overnight with sexually expe- which showed an increase in oxytocin release in the SON in response rienced males and pregnancy was confirmed by the presence of a vaginal to this test were included in the results (Neumann et al., 1993b). Rats plug of semen which had been shed into the mating cage the following were killed by an overdose of pentobarbitone, their brains were removed morning (day 0 of pregnancy). In the initial study we sought evidence and fixed in formaldehyde, and placement of the probe was verified for opioid inhibition on day 21 of pregnancy using naloxone. (1) Con- histologically in 60 pm Vibratome serial frontal sections. Dialysates scious 21 d pregnant rats were injected-intraperitoneally (i.p.) with either were lyophilized and their oxytocin content measured without extraction by a sensitive and specific radioimmunoassay (Neumann et al., 1993b). vehicle (0.9% saline, 0.5 ml/kg.-. n = 6) or naloxone (5 m&n. 10 ma/ml. tz = 6) and virgin rats (n = 6) were injected with naloxone,\ “Y, all between‘2 The minimal detection limit was 0.1 pg/sample and the intra- and in- 10.30 and 11.45 hr. Two virgin females were injected with 1.5 M NaCl terassay coefficients of variation were between 7 and 10% and 9 and (4 ml/kg, i.p.) as positive controls for Fos expression (Giovannelli et al., 13%, respectively. The in vitro relative recovery of the probe tested 1992; Hamamura et al., 1992). (2) Subsequently we partly repeated the with ‘*‘I-oxytocin dissolved in aCSF and at 37°C was 1.7 -C 0.2% experiment, and also tested naloxone in animals on day 16 of pregnancy (Neumann et al., 1993a,b). and included virgin and 21 d pregnant groups to test for specific K-opioid effects.
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