Suppressed prolactin response to dynorphin A1-13 in methadone-maintained versus control subjects
Suppressed prolactin response to dynorphin A1-13 in methadone-maintained versus control subjects
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DOI：
10.1124/jpet.103.050682
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发表时间：
2003-08-01
影响因子：
3.5
通讯作者：
Kreek, MJ
中科院分区：
文献类型：
--
作者：
Bart, G;Borg, L;Kreek, MJ
强啡肽A(1-13)是强啡肽A(1-17)的缩写序列，是一种主要的kappa-阿片受体喜好多肽。此前，我们发现给正常志愿者注射强啡肽A(1-13)会引起血清催乳素水平的迅速升高，这可能反映了结节漏斗中多巴胺能张力的降低。这项研究是为了确定美沙酮维持治疗患者的漏斗结节多巴胺能张力是否降低。8名无持续药物或酒精滥用或依赖的海洛因依赖者和15名无药物或酒精依赖史的正常志愿者对照组接受强啡肽A(1-13)的静脉注射，剂量分别为120和500 mg/kg。研究在服用美沙酮前一小时开始，以避免预期的催乳素增加，这与美沙酮的血浆峰值水平一致。静脉注射强啡肽A(1-13)后，两组大鼠血清催乳素水平均呈剂量-反应关系增加，20min内达到高峰。在基线或服用安慰剂后，两组之间的催乳素水平没有差异。与对照组相比，服用美沙酮的志愿者对每一剂量强啡肽A(1-13)的催乳素反应显著降低。这些结果表明，在美沙酮维持的受试者中，漏斗结节多巴胺能张力改变。目前尚不清楚多巴胺能张力改变是在阿片成瘾之前存在的，是海洛因成瘾的结果，还是反映了美沙酮的维持。本研究不能确定美沙酮维持治疗的受试者对强啡肽和其他kappa阿片受体配体在中脑边缘-中皮质和黑质纹状体多巴胺能系统中是否也有降低的多巴胺能反应。
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.