Effect of sodium valproate on naloxone-stimulated ACTH and cortisol release in humans.
1. Gamma-aminobutyric acid (GABA) and endogenous opioids each inhibit hypothalamic CRH secretion. In humans, the opioid antagonist, naloxone, stimulates the release of CRH, and so of ACTH and cortisol, while alprazolam, an indirect GABAA agonist, blocks naloxone-induced ACTH and cortisol secretion. Sodium valproate (SV) inhibits ACTH release in response to CRH, metyrapone and substance P. We hypothesized that, if this action is GABAA-mediated, SV should also inhibit naloxone-stimulated ACTH release. 2. We studied five healthy volunteers in randomized, double-blind, placebo-controlled afternoon studies with SV 400 mg, given 180 min before i.v. naloxone 125 micrograms/kg bodyweight. Plasma concentrations of ACTH, cortisol and SV were measured at intervals during the experiments. 3. SV had no effect on the mean integrated ACTH and cortisol responses to naloxone; ACTH: 165 +/- 21 versus 284 +/- 40 pmol.min per L, P = 0.08; cortisol: 10.5 +/- 1.9 versus 12.8 +/- 1.2 nmol.min per L-3, P = 0.14, placebo/nal versus SV/nal respectively. Basal ACTH and cortisol levels were also not significantly altered by SV (P > 0.30). Mean SV levels were not significantly different between SV/nal and SV/placebo studies (P > 0.50). 4. In conclusion, SV had no effect on naloxone-induced ACTH and cortisol release in normal humans at the dose and plasma drug concentrations studied. This contrasts with the potent inhibitory effect of alprazolam, and suggests that the effect of SV on the human hypothalamic-pituitary-adrenal axis may not be through a GABAA-mediated mechanism. Alternatively, higher plasma SV levels or more sustained exposure to SV may be necessary to inhibit hypothalamic secretion of CRH.
Torpy
D J
DJ
Department of Medicine, University of Queensland, Greenslopes Hospital, Brisbane, Australia.
Grice
J E
JE
Hockings
G I
GI
Crosbie
G V
GV
Walters
M M
MM
Jackson
R V
RV
D000324:Adrenocorticotropic Hormone / Q000097:blood*; D000328:Adult; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D018682:GABA Agents / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D006854:Hydrocortisone / Q000097:blood*; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D009270:Naloxone / Q000008:administration & dosage / Q000494:pharmacology*; D009292:Narcotic Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D014635:Valproic Acid / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*
D018682:GABA Agents; D009292:Narcotic Antagonists; D009270:Naloxone; D014635:Valproic Acid; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D006854:Hydrocortisone