Abstract
We previously reported that U50488H, a κ-selective opioid agonist, stimulates the release of adrenocorticotropin (ACTH) in the ovine fetus via the release of hypothalamic arginine vasopressin and corticotropin releasing factor. In this study we examined the effects of the endogenous κ-preferring opioid peptide, dynorphin A1–13, on fetal ACTH release using the unanesthetized, chronically catheterized fetal lamb model. Fetal plasma samples were collected at timed intervals after fetal administration of dynorphin A1–13 (0.5 mg/kg, i.v.) and subsequently analyzed by radioimmunoassay for immunoreactive-ACTH and immunoreactive-cortisol. Dynorphin A1–13 produced a highly significant and rapid increase in immunoreactive-ACTH (P = .002) and immunoreactive-cortisol (P = .002) with peak levels of 383.3 ± 43.8 pg/ml and 32.8 ± 9.0 ng/ml, respectively, at 15 min after administration. A similar increase in plasma immunoreactive-ACTH was seen after the same dose of dynorphin A1–17 (P = .02) but not dynorphin A2–17. This ACTH response to dynorphin A1–13 was shown to be insensitive to the opioid antagonist, naloxone (12 mg/hr), as well as antagonists of corticotropin releasing factor and arginine vasopressin. These data suggest that dynorphin A1–13 in the ovine fetus may be acting through a mechanism distinct from the κ-opioid system and that the dynorphins may serve as secretagogues of ACTH directly at the anterior pituitary through nonopioid receptors.
Footnotes
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Send reprint requests to: Dr. Hazel H. Szeto, Department of Pharmacology, Cornell University Medical College, 1300 York Ave., New York, NY 10021.
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↵1 This research was supported by Grant DA02475-16. C.C.T. is supported by training Grant from NIDA (DA07274-04).
- Abbreviations:
- HPA
- hypothalamic-pituitary-adrenal
- ACTH
- adrenocorticotropin
- AVP
- arginine vasopressin
- CRF
- corticotropin releasing factor
- ir-ACTH
- immunoreactive adrenocorticotropin
- ir-cortisol
- immunoreactive cortisol
- U50
- 488H, trans-(±)-3,4-dichloro-N-methyl-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide
- icv
- intracerebroventricular
- ANOVA
- analysis of variance
- Received May 20, 1996.
- Accepted September 13, 1996.
- The American Society for Pharmacology and Experimental Therapeutics
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