Different Opioid Mechanisms Are Involved in the Modulation of ACTH and Gonadotrophin Release in Man

Abstract

Both the pituitary-adrenal axis and the pituitary-gonadal axis are under the tonic inhibitory control of endogenous opioid peptides in man. However, the precise opioid receptor involved in the modulation of these hormones remains unknown. The effect of a dose of intravenous naloxone on serum levels of luteinising hormone (LH), follicle-stimulating hormone (FSH) and plasma cortisol was therefore investigated in ten normal subjects. In the male subjects, naloxone at a dose of 25 µg/kg caused a significant increase in serum LH and FSH; no increase in response was seen at the two higher doses (100 µg/kg and 250 µg/kg). The lowest dose (6 µg/kg) caused no change in serum LH and FSH. In the female subjects, tested in the early follicular phase of their cycles, no dose of naloxone significantly increased circulating gonadotrophins. In both male and female subjects, naloxone only stimulated a rise in serum cortisol at the highest dose (250 µg/kg). A second study in six normal subjects demonstrated that the rise in cortisol with the highest dose of naloxone was secondary to a rise in plasma ACTH. It is concluded that the opioid receptor(s) controlling gonadotrophin release in man are naloxone-sensitive, and are probably epsilon-receptors; the naloxone insensitivity of the pituitary-adrenal axis suggests that these responses are modulated by kappa- or delta-receptors.

The Effects of Endogenous Opioids and Cortisol on Thyrotropin and Prolactin Secretion in Patients with Addison’s Disease1

“…In normal subjects, the infusion of naloxone elevates plasma ACTH and cortisol but only if given in high doses, above 10 -15 mg (1,3,32,36,39,40). In agreement with these data, we found that the infusion of approximately 9 mg naloxone, over 6 1 ⁄2 h, had no effect on plasma ACTH levels during normocortisolism.…”

“…Several explanations may account for this discrepancy: exogenous opiates may show pharmacological and not physiological effects; and apparently, some opiates have agonist activity, as well as antagonist activity (13). Furthermore, opiates differ in their relative affinity for different receptor subtypes (13,32), and the in vivo function of endogenous opioids may involve receptors that are relatively insensitive to naloxone (3,9,13,(33)(34)(35). Naloxone is a competitive inhibitor of opiate receptors; but in low doses, it has the highest affinity for -and ⑀-receptors, whereas relatively large doses are required to block the ␦-and -receptors (3,33).…”

“…Furthermore, opiates differ in their relative affinity for different receptor subtypes (13,32), and the in vivo function of endogenous opioids may involve receptors that are relatively insensitive to naloxone (3,9,13,(33)(34)(35). Naloxone is a competitive inhibitor of opiate receptors; but in low doses, it has the highest affinity for -and ⑀-receptors, whereas relatively large doses are required to block the ␦-and -receptors (3,33). We have used a constant infusion of medium doses of naloxone without bolus injection to obtain a successive blockade of the opioid receptors.…”

Secondary Adrenocortical Insufficiency as a Result of Chronic Fentanyl Treatment: A Case Report

“…In fact, opioids are well known to be a cause of hypogonadotropic hypogonadism [5]. Similar results has been observed in methadone addicts, where previous studies observed decreased plasma cortisol levels as well as an absence of Adrenocorticotrophin Hormone (ACTH) response to CASE REPORT ity swelling with pitting edema, and vinous red striaes on abdomen for one month.…”

Endocrine Consequences of Long-Term Intrathecal Administration of Opioids

“…The restraint on LH release is predominantly mediated through central inhibition of hypothalamic GnRH secretion (18). Taking into account the receptor subtypes, PRL is preferentially activated by ⑀-receptors, TSH by -receptors, and ACTH probably by ␦-or -receptors, whereas the inhibitory control of LH involves ⑀-receptors (19,20). The receptors involved in GH stimulation remain unclear.…”