Suppressed prolactin response to dynorphin A1-13 in methadone-maintained versus control subjects

Dynorphin A(1-13), a shortened sequence of the natural peptide dynorphin A(1-17), is a primarily kappa-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 mug/kg and 500 mug/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 kappa-opioid receptor ligands in mesolimbic-mesocortical and nigrostriatal dopaminergic systems cannot be determined from this study.