Suppressed Prolactin Response to Dynorphin A_1–13 in Methadone-Maintained Versus Control Subjects

Abstract

Dynorphin A 1-13 , a shortened sequence of the natural peptide dynorphin A [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17] , is a primarily -opioid receptor-preferring peptide. Previously, we showed that dynorphin A 1-13 administered to normal volunteers causes a prompt dose-dependent elevation in serum prolactin that may reflect a reduction in tuberoinfundibular dopaminergic tone. This study was conducted to determine whether tuberoinfundibular dopaminergic tone is reduced in methadone-maintained patients. Eight former heroin addicts on stable-dose methadone maintenance with no ongoing drug or alcohol abuse or dependence and 15 normal volunteer controls with no history of drug or alcohol dependence received dynorphin A 1-13 intravenously at doses of 120 g/kg and 500 g/kg. Studies began one hour before methadone dosing to avoid the expected increase in prolactin that coincides with peak plasma levels of methadone. After intravenous dynorphin A 1-13 , a dose-response increase in serum prolactin, which peaked within 20 min, was observed in both groups. There was no difference in prolactin between the two groups at baseline or following a placebo. The prolactin response to each dose of dynorphin A 1-13 was significantly lower in the methadone-maintained volunteers compared with the controls. These results suggest that tuberoinfundibular dopaminergic tone is altered in methadone-maintained subjects. It is unknown whether altered dopaminergic tone existed before opiate addiction, is a result of heroin addiction, or is reflective of methadone maintenance. Whether methadone-maintained subjects also have decreased dopaminergic response to dynorphin and other -opioid receptor ligands in mesolimbic-mesocortical and nigrostriatal dopaminergic systems cannot be determined from this study.

Nalmefene Induced Elevation in Serum Prolactin in Normal Human Volunteers: Partial Kappa Opioid Agonist Activity?

“…Despite development of tolerance to many of the effects of chronically administered methadone, we have shown that serum prolactin levels increase for 2-4 h following each daily dose in methadone maintained subjects (Kreek, 1978;Bart et al, 2003). In humans, the natural sequence kappaopioid receptor ligand dynorphin A(1-13) and also synthetic kappa agonists increase serum prolactin (Ur et al, 1997;Kreek et al, 1999;Bart et al, 2003), although the effects following chronic dosing are unknown.…”

Sexual Dysfunction as a Side Effect of Hyperprolactinemia in Methadone Maintenance Therapy

“…Some literature research conclude that many of the hypothalamic and anterior pituitary hormones are adversely affected in heroin misuses and methadone maintained patients (1). But, one of the most seriously endocrine abnormalities in opiate users and methadone maintenance patients is hyperprolactinemia and sexual dysfunction as a side-effects of opioid induced hyperprolactinemia (2). Prolactin is synthesized and secretion by lacto trope cells in adenophypophysis (anterior pituitary gland).…”

Effects of nalbuphine on anterior pituitary and adrenal hormones and subjective responses in male cocaine abusers

“…Both mu and kappa opioid agonists stimulate prolactin release (Bart et al, 2003;Ellingboe et al, 1980;Kreek, 1978;Kreek et al, 1999), so it is likely that the nalbuphine-induced increases in serum prolactin levels observed in the present study involve interactions with both kappa and mu opioid receptors. The most likely mechanism for the effects of opioids on hormone release relates to TIDA, which consists of neurons with cell bodies in the arcuate and periventricular nuclei of the hypothalamus and axons that project into the median eminence of the hypothalamus.…”

“…Serum prolactin levels increased after administration of kappa opioid receptor-selective agonists dynorphin A 1-13 (Bart et al, 2003;Kreek et al, 1999) and spiradoline (Ur et al, 1997) in normal healthy volunteers. Increases in serum prolactin levels have been observed after administration of a variety of mu opioid-selective agonists, including oxycodone (Saarialho-Kere et al, 1989), meptazinol (Kay et al, 1985), morphine (Delitala et al, 1983), dermorphin (Degli Uberti et al, 1983) in normal healthy volunteers.…”

“…Increases in serum prolactin levels have been observed after administration of a variety of mu opioid-selective agonists, including oxycodone (Saarialho-Kere et al, 1989), meptazinol (Kay et al, 1985), morphine (Delitala et al, 1983), dermorphin (Degli Uberti et al, 1983) in normal healthy volunteers. Heroin and methadone also stimulate prolactin release in opioid-dependent men (Bart et al, 2003;Ellingboe et al, 1980;Kreek, 1978). Furthermore, mixed action mu-kappa opioids such as buprenorphine and nalmefene also increase serum prolactin levels in humans (Bart et al, 2005;Rolandi et al, 1983).…”