Elsevier

Brain Research

Volume 839, Issue 1, 21 August 1999, Pages 173-179
Brain Research

Research report
Opioid and cannabinoid receptor-mediated regulation of the increase in adrenocorticotropin hormone and corticosterone plasma concentrations induced by central administration of Δ9-tetrahydrocannabinol in rats

https://doi.org/10.1016/S0006-8993(99)01756-4Get rights and content

Abstract

The purpose of this study was to investigate the cannabinoid and opioid mediated regulation on the effects of central Δ9-tetrahydrocannabinol (Δ9-THC) administration on hypothalamus–pituitary–adrenal (HPA) axis activity in the male rat. Intracerebroventricular (i.c.v.) administration of Δ9-THC (25, 50, 100 μg/rat) markedly increased plasma adrenocorticotropin hormone (ACTH) and corticosterone concentrations. Time course effect studies revealed that both hormones secretion peaked at 60 min after Δ9-THC i.c.v. administration (50 μg/rat), decreased gradually and returned to baseline levels by 480 min. The i.c.v. administration of the specific cannabinoid receptor antagonist SR-141716A (3 μg/rat) significantly attenuated the increase of both hormones secretion induced by Δ9-THC (50 μg/rat). Nevertheless, higher doses (12.5 and 50 μg/rat) of this compound increased both ACTH and corticosterone plasma concentrations. Subcutaneous (s.c.) administration with the opiate receptor antagonist naloxone (0.3 mg/kg) was without effect but significantly diminished the increase of both hormones secretion induced by Δ9-THC (50 μg/rat). Taken together, these results indicate that opiate and cannabinoid receptors are involved in the activation of the HPA axis induced by Δ9-THC. Furthermore, the increase of ACTH and corticosterone secretion after the administration of higher doses of SR-141716A than those required to block such activation, suggests that endogenous cannabinoids are tonically inhibiting the release of both hormones or that this agonist-like activity may be part of an uncharacterized action of this compound not mediated by cannabinoid receptors.

Introduction

Δ9-Tetrahydrocannabinol (Δ9-THC), the major psychoactive compound of marihuana, produces a variety of behavioral and pharmacological effects, including antinociception, anxiety-like behavior, hypothermia, depression of motor activity, inhibition of intestinal motility and alterations in the secretion of pituitary hormones [6].

A number of reports indicates that acute administration of Δ9-THC, the endogenous cannabinoid ligand anandamide [5]or cannabinoid synthetic receptor agonists such as [3-(1,1,-dimethylheptyl)-(−)11-hydroxy Δ8-THC], HU-210, stimulates the hypothalamus–pituitary–adrenal (HPA) axis as reflected by elevations in corticosterone or adrenocorticotropin hormone (ACTH) plasma levels in rat 6, 12, 16, 19, 25, 26, 27, 29, 31. However, due to the lack of specific cannabinoid receptor antagonists, there have been few attempts to identify whether the stimulatory effects of the cannabinoid receptor agonists on HPA axis secretion are mediated through central cannabinoid receptors. The recent development of the selective cannabinoid receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole carboxamide, SR-141716A [24]now allows an unequivocal examination of the role played by cannabinoid receptors in modulating the secretion of ACTH and corticosterone.

In recent years, our laboratory and others have shown that some of the pharmacological effects produced by acute or chronic administration with cannabinoids appear to involve an interaction between the opioid and the cannabinoid neuronal systems [for review, see Ref. [15]]. Indeed, Δ9-THC and anandamide modulate the expression of physical signs of opioid dependence [28], antinociception induced by THC is blocked by previous μ- or κ-opioid receptor antagonists [30]or selective antibodies against the endogenous κ ligand dynorphin 21, 22, and inhibition of opioid degrading enzymes potentiate Δ9-THC induced antinociception [23]. These results suggest that administration of Δ9-THC may increase the release of endogenous opioids. Recently, it has been shown that administration of CP-55,940, a selective cannabinoid receptor agonist, produces a significant release of dynorphin B in the spinal cord concurrent with the production of antinociception [20]. Furthermore, our group has reported that subchronic or chronic administration with Δ9-THC or cannabinoid receptor agonists apparently increase proopiomelanocortin gene expression in the arcuate nucleus of the hypothalamus 3, 4, prodynorphin and proenkephalin gene expression in the spinal cord [3]and proenkephalin gene expression in various forebrain and hypothalamic regions of the rat [14].

Considering that some of the actions of cannabinoids may be, at least in part, mediated by increasing the release of endogenous opioids and that opiate agonists stimulate the secretion of ACTH and corticosterone secretion in rat (for review, see Ref. [18]), it was of interest to examine the contribution of cannabinoid and opioid receptors in the Δ9-THC-induced increase of pituitary–adrenal–axis hormones. To this aim, the effects of intracerebroventricular (i.c.v.) administration of Δ9-THC on ACTH and corticosterone plasma concentrations were examined on vehicle-, SR-141716A- or naloxone-pretreated male rats.

Section snippets

Animals

Male Sprague–Dawley rats weighing 200–250 g were obtained from Harlan Interfauna Ibérica (San Feliú de Codines, Barcelona, Spain), maintained in a temperature- (23±11°C) and light- (lights on between 08:00 and 20:00 h) controlled environment and provided food (Panlab) and tap water ad libitum. All the experiments included in this study were performed following the highest standards of humane animal care, monitoring health care and minimizing pain and suffering, in accordance with National and

Results

As shown in Fig. 1A and B, i.c.v. administration of Δ9-THC (25–100 μg/rat) 30 min before decapitation increased plasma ACTH and corticosterone concentrations in the rat. The maximal effect was found with the 100 μg dose which significantly increased plasma ACTH (six-fold) and corticosterone (four-fold) concentrations. The potent stimulatory action of Δ9-THC on the secretion of ACTH and corticosterone was revealed again when the time course effects were determined. A single i.c.v. injection of Δ9

Discussion

The results of the present study further demonstrate that central administration of Δ9-THC produces a potent increase in the plasma concentrations of ACTH and corticosterone and provides evidence that such activation is mediated by both cannabinoid and opioid receptors.

The magnitude of the increase of ACTH and corticosterone induced by Δ9-THC was similar to that reported previously [29]. However, in that study, a 25-μg dose of Δ9-THC was without effect on HPA axis hormones secretion, whereas in

Acknowledgements

J. Corchero is a Predoctoral Fellow supported by the “Comunidad Autonoma de Madrid” and J. Manzanares is a Senior Fellow supported by the Spanish Ministry of Education.

References (31)

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