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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 Aug; 8(8):579-85.JN

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

Calogero AE
First Internal Medicine Department, Chair of Andrology, University of Catania Medical School, Italy.
Scaccianoce S
No affiliation info available
Burrello N
No affiliation info available
Nicolai R
No affiliation info available
Muscolo LA
No affiliation info available
Kling MA
No affiliation info available
Angelucci L
No affiliation info available
D'Agata R
No affiliation info available

MeSH

Adrenocorticotropic HormoneAnalysis of VarianceAnimalsBenzomorphansCells, CulturedCorticosteroneCorticotropin-Releasing HormoneHypothalamo-Hypophyseal SystemHypothalamusMaleOrgan Culture TechniquesPituitary GlandPituitary-Adrenal SystemRatsRats, Sprague-DawleyReceptors, Opioid, kappaStimulation, Chemical

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., Angelucci, L., & 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), 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 -
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