Original ArticlesEffects of mu, kappa, and delta opioid receptor agonists and antagonists on rat hypothalamic noradrenergic neurotransmission
Introduction
A multiplicity of neurotransmitter systems regulate the release of gonadotrophin-releasing hormone (GnRH) from their neurons in the hypothalamus, which in turn control luteinising hormone (LH) secretion from the anterior pituitary. An example of such a neurotransmitter system is that secreting the endogenous opioid peptides (EOPs), which have a profound inhibitory influence on LH release [15]. It has been reported that a reduction in the activity of these peptides in the hypothalamus is permissive [19] and amplifies the anticipated LH surge in estrogen-treated ovariectomised (ovx) rats [23]. Opioid peptidergic neurons and fibres have been identified in the hypothalamus and in other brain areas 20, 25. Different classes of opioid receptor types (μ, κ and δ) exist in the hypothalamus and other brain areas 8, 22, 30 and administration of opioid agonists inhibits the preovulatory LH surge and therefore, ovulation 4, 10, 15.
Conversely, administration of an opioid antagonist, naloxone, overcomes the tonic inhibitory effects of the EOPs on GnRH release and enhances the secretion of LH 2, 6. This inhibitory opioidergic action, however, is thought to be indirect and mediated by central noradrenergic neurons, because naloxone-induced LH release can be prevented by prior administration of α-adrenergic blockers and dopamine-β-hydroxylase inhibitors [16]. Noradrenaline (NA) is believed to play an important role in the central regulation of LH release 3, 14. Noradrenergic projections have been shown to make synaptic contacts with the GnRH neurons in the medial preoptic area (MPOA), median eminence (ME), arcuate nucleus (ARN) and other hypothalamic areas 7, 18, 32.
Modulatory effects of different opioid receptor agonists on the central noradrenergic neurotransmission have been reported 4, 17. Immunocytochemical studies have illustrated a degree of overlap in the distribution of opioid peptidergic perikarya and NA neurons and terminals [17]. Moreover, noradrenergic terminals within the brain possess μ-, κ- and δ-opioid receptors 5, 11, 26. Activation of μ- and δ-opioid receptor types inhibits [9] and naloxone stimulates [27] NA release within the hypothalamus.
The present study was undertaken to determine 1) the modulating effects of specific μ-, κ- and δ-opioid receptor agonists and antagonists on hypothalamic noradrenergic neurotransmission and on LH release and 2) the interrelationship between the opioid peptidergic and aminergic systems in the control of GnRH activity in the ovx and steroid-primed rats.
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Animals
Adult female Sprague-Dawley rats (Harlan, UK Ltd., Oxon, UK) weighing 240–280 g were maintained under controlled temperature (21 ± 1°C) and light conditions (lights on from 07.00 h–19.00 h). Food and water were provided ad lib. The animals were ovx under halothane anaesthesia and then allowed to recover for a period of 10–21 days. Forty-eight h prior to experimentation the rats were injected subcutaneously (s.c.) with 17 β-oestradiol (5 μg/0.2 ml olive oil). Progesterone (0.5 mg/0.2 ml olive
Effects of various opioid agonists and antagonists on hypothalamic NA and DHPG concentrations
Figure 1a–d shows NA levels in the MPOA, SCN, ME and ARN. The DHPG (NA metabolite) results are summarised in Table 1. Diamorphine, the μ-agonist, significantly reduced the concentrations of NA and DHPG in the four hypothalamic regions examined. Administration of U-69593 or DPDPE resulted in significant decreases in the levels of NA and DHPG in all four hypothalamic areas.
When naloxone was coadministered with diamorphine, the inhibitory effects of the μ-agonist on NA concentrations in all the
Discussion
Administration of diamorphine decreased concentrations of both NA and DHPG in all four hypothalamic areas studied. Naloxone antagonised the effects of μ-agonist on NA concentrations in the hypothalamus, but had no effect on its metabolite. These results are consistent with previous reports suggesting that opioids inhibit NA release and/or turnover via μ-opioidergic receptors located at the noradrenergic nerve terminals 11, 26. Morphine decreases noradrenergic activity in the MPOA and ME of ovx
Acknowledgements
Bayram Yilmaz is grateful to Firat University in Turkey for financial support. The authors would like to thank to the following institutions for the gifts of the drugs employed in the experiments: Boehringer Ingelheim Ltd. (Heidelberg, Germany) for MR1452, the Upjohn Company (Kalamazoo, Michigan, USA) for U-69593 and the National Institute on Drug Abuse (Rockville, MD, USA) for DPDPE.
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