The influence of opioid substances on the secretion in vivo and in vitro of corticosterone, corticotrophin (ACTH) and corticotrophin releasing factor (CRF) in the rat was studied. Rats given a single injection of morphine exhibited a marked hypersecretion of ACTH and an exaggeration of the hypothalamo-pituitary-adrenocortical (HPA) response to stress. In contrast, animals rendered tolerant to morphine failed to release ACTH or corticosterone in response either to a subsequent injection of the opiate or to stress. The development of the inhibitory effect paralleled the development of tolerance to the analgesic actions of the drug. The production of ACTH by pituitary segments removed from control animals was not affected by the addition of opioid substances to the incubation medium. However, morphine, met-enkephalin and leu-enkephalin stimulated the secretion of CRF by hypothalami and their effects were competitively antagonized by naloxone. The secretory activity of hypothalami removed from rats treated acutely with morphine was enhanced. In contrast hypothalami from morphine-tolerant rats failed to secrete CRF in response to morphine, met-enkephalin, acetylcholine or 5-hydroxytryptamine. Neither the density nor the affinity of 3H-naloxone binding sites in the hypothalamus was influenced by the morphine treatment. The results suggest the opioid peptides and their receptors play a major role in the regulation of HPA function.
The effects of selective agonists and antagonists of opioid receptors on the secretion of corticotrophin releasing factor (CRF) by isolated rat hypothalami in vitro were studied. Morphine (10–8–10–6M) and the µ-opioid receptor agonists, FK33–824CH (10–8–10–6M) and Tyr-D-Ala-Gly-MePhe-NH(CH2)2OH (10–8–10–6M), caused dose-related increases in the release of CRF from isolated hypothalami. The K-opioid receptor agonist, U50,488 (10–8–10–6M), was also weakly active in this respect but the δ-opioid receptor agonist, (D-Pen2, D-Pen5)-enkephalin (2 × 10–10–2 × 10–7M), was not. The stimulatory actions of morphine and Tyr-D-Ala-Gly-MePhe-NH(CH2)2OH on CRF release were antagonized by naloxone (10–8M) and by the µ/δ-opioid receptor antagonist, β-funaltrexamine (β-FNA, 10–9M), but not by the µ/δ-opioid receptor antagonist, ICI-154129 (5 × 10–6M). The effects of U50,488 on CRF release were unaffected by either β-FNA or ICI-154129 but were antagonized by high doses of naloxone (10–6M). The results suggest that both µ- and K-opioid receptors are involved in the stimulation of CRF secretion but that δ-opioid receptors are not important in this respect.
The influences of morphine and naloxone on hypothalamo-pituitary-adrenocortical (HPA) function were studied in the rat to investigate further the role of opioidergic mechanisms in the control of the secretion of corticotrophin and its hypothalamic releasing factor (CRF). Morphine not only caused rises in hypothalamic CRF content and plasma ACTH concentration but also potentiated the HPA response to stress. Its effects were antagonized by naloxone which, when given alone, did not influence basal plasma concentrations of ACTH and corticosterone but which inhibited, in a dose-dependent manner, the release of both of these hormones which normally occurs in response to stress. Naloxone also attenuated the exaggeration in stress-induced HPA activity but did not affect the increases in plasma ACTH concentration which followed adrenalectomy. The findings suggest that opioidergic mechanisms may be involved in the regulation of the HPA response to stress.
The effects of morphine and naloxone on hypothalamo-pituitary-adrenocortical (HPA) activity and blood pressure were studied in rats in which adrenergic transmission had been impaired pharmacologically. The αi-adrenoceptor antagonist, prazosin and the tyrosine hydroxylase inhibitor, α-methyl-para-tyrosine (α-MPT), increased the hypothalamic corticotrophin releasing factor (CRF) content and the plasma corticotrophin (ACTH) concentration and exaggerated the HPA response to stress. In addition, the spontaneous secretion of CRF by hypothalami in vitro was increased by α-MPT-treatment. Morphine enhanced the basal and stress-induced activity of the HPA system in vivo. It also stimulated the secretion of CRF by hypothalami in vitro. Naloxone did not affect resting HPA activity but reduced markedly the stress-induced release of corticotrophin. The effects of morphine and naloxone on the HPA axis, in vivo, were reduced by pretreatment with α-MPT and prazosin, respectively. The HPA responses could not be correlated with the changes in blood pressure which the drugs caused. The results suggest that opioid substances stimulate HPA activity by depressing the activity of the adrenergic pathways which inhibit the secretion of CRF.
Johnston, A.L., E. Koenig-Berard, T.A. Cooper, and S.E. File: Comparison of the effects of clonidine, rilmenidine, and guanfacine in the holeboard and elevated plusmaze. Drug Dev. Res. 15:405-414, 1988.The effects of clonidine, rilmenidine, and guanfacine were studied in the holeboard and elevated-plus maze tests in rats. In the holeboard test, clonidine had a profound effect on locomotor activity, significantly (P < 0.05) reducing this measure at all but one of the doses tested (0.005-0.25 mg/kg). In contrast, rilmenidine and guanfacine only markedly affected locomotor activity at 2.5 mg/kg or higher. The ED50's for locomotor activity were as follows: clonidine, 0.024 mg/kg; rilmenidine, 1.92 mgikg; and guanfacine, 1.65 mgikg. All three compounds also caused significant decreases in the number of head dips and time spent head-dipping. The effects of clonidine (0.005-0.25 mg/kg) and rilmenidine (0.25-1 0 mgikg) on the number of head-dips were significant (P < 0.01) at all doses and were dose dependent. The actions of guanfacine were similar, with all doses (0.1 25-5 mg/kg) differing significantly (P < 0.05) from the controls, except 1 mgikg. However, the time spent head-dipping was only decreased significantly (P < 0. (as judged by reductions in locomotor activity in the holeboard), with clonidine being much more potent on this measure. Guanfacine differed from the other two compounds in its apparent anxiogenic-like effects in the plus maze.
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