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The kappa-opioid receptor agonist MR-2034 stimulates the rat hypothalamic-pituitary-adrenal axis: studies in vivo and in vitro.
J Neuroendocrinol 1996; 8(8):579-85JN

Abstract

There is increasing evidence that opiates not only have analgesic properties, but also regulate mechanisms activated during the stress response, such as the hypothalamic-pituitary-adrenal (HPA) axis. Indeed, opioid-containing neurons innervate the paraventricular nucleus and the median eminence, thus modulating inputs to ACTH-controlling neurons. In addition, dynorphin (the endogenous ligand of the kappa-opioid receptor)-like peptides have been found co-localized with corticotrophin-releasing hormone (CRH) and are believed to be co-secreted with it in the hypophyseal portal circulation to modulate ACTH release. In this study, we evaluated the effects of the selective kappa-opioid receptor agonist MR-2034 [(-)-N-(2-tetrahydrofurfuryl)-normetazocine] on the HPA axis in vivo and in vitro. MR-2034 was given intravenously to catheterized, freely moving, male Sprague-Dawley rats and serial blood samples were collected for ACTH and corticosterone (B) measurements. We evaluated also the site of MR-2034 action on the HPA axis in vivo, after the administration of alpha-helical CRH9-41, a CRH receptor antagonist, on hypothalamic CRH, pituitary ACTH, and B release in vitro. MR-2034 increased plasma ACTH and B levels in a dose-related fashion and this effect was antagonized by the selective kappa-opioid receptor antagonist MR-1452. In the presence of alpha-helical CRH9-41, the responses of plasma ACTH and B to MR-2034 were blunted significantly, suggesting that this compound activates the HPA axis through a CRH-dependent mechanism. Accordingly, MR-2034 stimulated hypothalamic CRH release in vitro in a concentration-dependent fashion and this effect was antagonized dose-dependently by MR-1452. However, the stimulatory effect of MR-2034 on plasma ACTH and B in vivo was not completely abolished by alpha-helical CRH9-41, suggesting that an additional, CRH-independent, mechanism was involved. Indeed, MR-2034 was able to stimulate basal ACTH output in a dose-dependent manner and this effect was antagonized by MR-1452 in vitro. On the other hand, MR-2034 did not have any effect on B release from adrenocortical cells or adrenal quarters in vitro. These results show that the benzomorphan MR-2034 stimulates the HPA axis in the rat by acting at the hypothalamic and the pituitary level. We hypothesize that endogenous kappa-opioid peptides not only act at the pituitary level to increase ACTH output, but may also act at the hypothalamic level to increase CRH release through an autocrine and/or ultrashort positive feedback mechanism.

Authors+Show Affiliations

First Internal Medicine Department, Chair of Andrology, University of Catania Medical School, Italy.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

8866244

Citation

Calogero, A E., et al. "The Kappa-opioid Receptor Agonist MR-2034 Stimulates the Rat Hypothalamic-pituitary-adrenal Axis: Studies in Vivo and in Vitro." Journal of Neuroendocrinology, vol. 8, no. 8, 1996, pp. 579-85.
Calogero AE, Scaccianoce S, Burrello N, et al. The kappa-opioid receptor agonist MR-2034 stimulates the rat hypothalamic-pituitary-adrenal axis: studies in vivo and in vitro. J Neuroendocrinol. 1996;8(8):579-85.
Calogero, A. E., Scaccianoce, S., Burrello, N., Nicolai, R., Muscolo, L. A., Kling, M. A., ... D'Agata, R. (1996). The kappa-opioid receptor agonist MR-2034 stimulates the rat hypothalamic-pituitary-adrenal axis: studies in vivo and in vitro. Journal of Neuroendocrinology, 8(8), pp. 579-85.
Calogero AE, et al. The Kappa-opioid Receptor Agonist MR-2034 Stimulates the Rat Hypothalamic-pituitary-adrenal Axis: Studies in Vivo and in Vitro. J Neuroendocrinol. 1996;8(8):579-85. PubMed PMID: 8866244.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The kappa-opioid receptor agonist MR-2034 stimulates the rat hypothalamic-pituitary-adrenal axis: studies in vivo and in vitro. AU - Calogero,A E, AU - Scaccianoce,S, AU - Burrello,N, AU - Nicolai,R, AU - Muscolo,L A, AU - Kling,M A, AU - Angelucci,L, AU - D'Agata,R, PY - 1996/8/1/pubmed PY - 1996/8/1/medline PY - 1996/8/1/entrez SP - 579 EP - 85 JF - Journal of neuroendocrinology JO - J. Neuroendocrinol. VL - 8 IS - 8 N2 - There is increasing evidence that opiates not only have analgesic properties, but also regulate mechanisms activated during the stress response, such as the hypothalamic-pituitary-adrenal (HPA) axis. Indeed, opioid-containing neurons innervate the paraventricular nucleus and the median eminence, thus modulating inputs to ACTH-controlling neurons. In addition, dynorphin (the endogenous ligand of the kappa-opioid receptor)-like peptides have been found co-localized with corticotrophin-releasing hormone (CRH) and are believed to be co-secreted with it in the hypophyseal portal circulation to modulate ACTH release. In this study, we evaluated the effects of the selective kappa-opioid receptor agonist MR-2034 [(-)-N-(2-tetrahydrofurfuryl)-normetazocine] on the HPA axis in vivo and in vitro. MR-2034 was given intravenously to catheterized, freely moving, male Sprague-Dawley rats and serial blood samples were collected for ACTH and corticosterone (B) measurements. We evaluated also the site of MR-2034 action on the HPA axis in vivo, after the administration of alpha-helical CRH9-41, a CRH receptor antagonist, on hypothalamic CRH, pituitary ACTH, and B release in vitro. MR-2034 increased plasma ACTH and B levels in a dose-related fashion and this effect was antagonized by the selective kappa-opioid receptor antagonist MR-1452. In the presence of alpha-helical CRH9-41, the responses of plasma ACTH and B to MR-2034 were blunted significantly, suggesting that this compound activates the HPA axis through a CRH-dependent mechanism. Accordingly, MR-2034 stimulated hypothalamic CRH release in vitro in a concentration-dependent fashion and this effect was antagonized dose-dependently by MR-1452. However, the stimulatory effect of MR-2034 on plasma ACTH and B in vivo was not completely abolished by alpha-helical CRH9-41, suggesting that an additional, CRH-independent, mechanism was involved. Indeed, MR-2034 was able to stimulate basal ACTH output in a dose-dependent manner and this effect was antagonized by MR-1452 in vitro. On the other hand, MR-2034 did not have any effect on B release from adrenocortical cells or adrenal quarters in vitro. These results show that the benzomorphan MR-2034 stimulates the HPA axis in the rat by acting at the hypothalamic and the pituitary level. We hypothesize that endogenous kappa-opioid peptides not only act at the pituitary level to increase ACTH output, but may also act at the hypothalamic level to increase CRH release through an autocrine and/or ultrashort positive feedback mechanism. SN - 0953-8194 UR - https://www.unboundmedicine.com/medline/citation/8866244/The_kappa_opioid_receptor_agonist_MR_2034_stimulates_the_rat_hypothalamic_pituitary_adrenal_axis:_studies_in_vivo_and_in_vitro_ DB - PRIME DP - Unbound Medicine ER -