Sigma receptor ligands alter concentrations of corticosterone in plasma in the rat

doi:10.1016/0028-3908(91)90046-E

Neuropharmacology

Volume 30, Issue 1, January 1991, Pages 79-87

https://doi.org/10.1016/0028-3908(91)90046-E Get rights and content

Abstract

Both BMY-14802 (alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine-butanol hydrochloride) and gevotroline (WY-47384; 8-fluoro-2,3,4,5-tetrahydro-2-[3-(3-pyridinyl)-propyl]-1H-pyrido[4,3-b]indole hydrochloride) are known to antagonize the psychotomimetic action of N-allyl-normetazocine (NAN; SKF-10047) and exhibit a high affinity for the sigma receptor. Unexpectedly, the putative antagonists BMY-14802 and gevotroline acted like the agonist NAN and increased activity in the hypothalamic-pituitary-adrenal axis to elevate levels of corticosterone in plasma. During the acrophase (peak) of the effects of the circadian rhythm on the hypothalamic-pituitary-adrenal axis, the ED₅₀ was 6.5 mmol/kg for BMY-14802 and 9.6 mmol/kg for gevotroline. The ED₅₀s for BMY-14802 and gevotroline during the low activity phase were 15.8 and 21.2 mmol/kg, respectively. The efficacies during both phases of the circadian rhythm were similar for each drug. Additive effects on the levels of corticosterone in plasma were observed when the animals were pretreated with doses above the respective ED₅₀ values and then subjected to a rotational stress, but a small dose of BMY-14802 (0.5 mg/kg) had the opposite effect and completely inhibited the stress-related increases in corticosterone in plasma. Neither drug, at large doses, altered the increase in levels of corticosterone in plasma generated by the circadian rhythm, but at smaller doses BMY-14802 did lower circadian-related levels of corticosterone. Pretreatment with dexamethasone blocked the gevotroline-related increase in corticosterone in plasma, but not the BMY-14802-related increase. These data suggest that central sigma receptor mechanisms are involved in the regulation of the hypothalamic-pituitary-adrenal axis and that therapeutic agents that affect these receptors may alter the activity in this axis.

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The present study characterized the response of the hypothalamo-pituitary-adrenal axis after the acute administration of enantiometic pairs of drugs that bind to phencyclidine (PCP) and σ receptors. Rats were injected with the enantiomers of 1-(1-phenylcyclohexyl)-3-methylpiperidine (PCMP), $N- allylnormetazocine$ (SKF 10,047), dioxadrol (dexoxadrol and levoxadrol) or pentazocine, and plasma levels of adrenocorticotropin (ACTH) and corticosterone were determined by radioimmunoassay. The effects of the enantiomers of PCMP and dioxadrol showed stereospecificity as both (+)-PCMP and dexoxadrol increased plasma levels of ACTH and corticosterone but (-)-PCMP and levoxadrol had no effect. Whereas (-)-pentazocine produced greater responses than (+)-pentazocine, the two enantiomers of SKF 10,047 did not show stereoselectivity. Although the potency of the enantiomers of PCMP and dioxadrol parallel their affinity for binding to PCP receptors, the potency of the enantiomers of pentazocine did not. These results suggest that although the stimulation of the hypothalamo-pituitary-adrenal axis by PCP and drugs with PCP-like activity might be due to interactions with PCP receptors, the effects of pentazocine also involve interactions at other sites.

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Sigma receptor ligands alter concentrations of corticosterone in plasma in the rat

Abstract

Life Sci.

Neuropharmacology

Pharmac. Biochem. Behav.

Eur. J. Pharmac.

Neuropharmacology

Neuropharmacology

Life Sci.

Ann. Rep. Med. Chem.

Antipsychotic activity of substituted gamma-carbolines

J. med. Chem.

Disorders of the adrenal cortex

The sigma receptor: A novel site implicated in psychosis and antipsychotic drug efficacy

Clin. Neuropharmac.

Effects of ethyl-ketocyclazocine and N-allyl-normetazocine on plasma corticosterone

Pharmacologist

Plasma corticosterone changes in response to central or peripheral administration of kappa and sigma opiate agonists

J. Pharmac. exp. Ther.

Inhibition and facilitation of feedback influences of dexamethasone on adrenocortical responses to either stress in rats with hypothalamic deafferentations and brain lesions

Acta endocrin.

Fluorometric determination of corticosterone and cortisol in 0.02–0.05 milliliters of plasma or sub-milligram samples of adrenal tissue

Endocrinology

Phencyclidine and sigma opiate receptors in brain: Biochemical and autoradiographical differentiation

Eur. J. Pharmac.

Subjective effects of narcotic antagonists cyclazocine and nalorphine on the addiction research center inventory (ACRI)

Psychopharmacologia (Berl.)