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The Kappa‐Opioid Receptor Agonist MR‐2034 Stimulates the Rat Hypothalamic‐Pituitary‐Adrenal Axis: Studies in vivo and in vitro [Note 1. Presented in the form of an abstract at the ...]
Author(s) -
Calogero A. E.,
Scaccianoce S.,
Burrello N.,
Nicolai R.,
Muscolo L. A. A.,
Kling M. A.,
Angelucci L.,
D'Agata R.
Publication year - 1996
Publication title -
journal of neuroendocrinology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.062
H-Index - 116
eISSN - 1365-2826
pISSN - 0953-8194
DOI - 10.1111/j.1365-2826.1996.tb00691.x
Subject(s) - medicine , endocrinology , chemistry , agonist , corticotropin releasing hormone , κ opioid receptor , opioid , median eminence , receptor , opioid receptor , hypothalamus , dynorphin , in vivo , hypothalamic–pituitary–adrenal axis , corticosterone , opioid peptide , hormone , biology , microbiology and biotechnology
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 κ ‐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 α ‐helical CRH 9–41 , 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 κ ‐opioid receptor antagonist MR‐1452. In the presence of α ‐helical CRH 9–41 , 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 α ‐helical CRH 9–41 , 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 .