Role of estradiol in women smokers' acute HPA axis hormone response to naltrexone

描述（申请人提供）：内源性阿片系统参与尼古丁的急性反应和尼古丁依赖的发展和维持。因此，一种用于戒烟治疗的药物是阿片受体拮抗剂纳洛酮。然而，最近的临床试验检查了纳洛酮在戒烟中的连续治疗效果，结果不一，因此需要进一步研究。与这些临床结果的潜在相关性，内源性阿片系统和尼古丁都对下丘脑-垂体-肾上腺（HPA）轴有作用，主要与应激反应有关的系统。与非吸烟者相比，吸烟者的HPA轴对应激或药理学激活反应严重不足。重要的是，这种HPA轴功能障碍可能在成瘾的维持和复发的可能性中起作用。纳洛酮急性激活HPA轴，以前曾假设，这种HPA轴活性的增加可能会降低一个人治疗镰状细胞瘤的效率，也可能是吸烟。然而，纳洛酮对HPA轴的作用与其减少吸烟行为之间的关系尚未被研究。最后，吸烟者对纳洛酮的反应可能存在重要但未被探索的性别差异。女性吸烟者对男性的纳洛酮在主观、行为和HPA轴激素测量方面具有更高的敏感性，以及在使用纳洛酮的戒烟试验中更好地戒烟。这些明显的性别差异可能与男性和女性之间的雌二醇水平差异有关，雌二醇是人类中主要的雌激素。在女性中，跨月经周期的雌二醇水平波动可能影响可用阿片受体的数量，因此可能影响纳洛酮的疗效。本申请中的研究旨在测试纳洛酮对男性和女性吸烟者的HPA轴和吸烟行为的影响，为了研究雌二醇对女性吸烟者的反应的影响，女性将在月经周期的两个不同阶段进行测试：卵泡早期（月经周期中雌二醇水平最低）和卵泡晚期（雌二醇水平最高）。本研究的结果可能为雌二醇水平的性别差异机制提供证据，并可能对使用纳洛酮戒烟具有指导性的临床意义。

DESCRIPTION (provided by applicant): endogenousopioidsystemisinvolvedinacuteresponsetonicotineandthedevelopmentand maintenanceofnicotinedependence.Accordingly,onedrugbeinginvestigatedforsmokingcessation treatmentisnaltrexone,aopioidreceptorantagonist.However,recentclinicaltrialsexaminingtheefficacyof adjunctivetreatmentwithnaltrexoneinsmokingcessationhaveyieldedmixedresultsand,therefore,further researchisneeded.Ofpotentialrelevancetotheseclinicaloutcomes,boththeendogenousopioidsystemand nicotinehaveactiononthehypothalamicpituitaryadrenal(HPA)axis,asystemthatisprimarilyassociated withresponsetostress.SmokershaveanacutelyunderresponsiveHPAaxistostressorsor pharmacologicalactivationcomparedtononsmokers.Importantly,thisHPAaxisdysfunctionmayplayarole inmaintenanceofaddictionandsusceptibilitytorelapse.NaltrexoneacutelyactivatestheHPAaxisandithas beenpreviouslyhypothesizedthatthisincreaseinHPAaxisactivitymayunderlienaltrexone'sefficacyfor treatmentofalcoholismandpossiblysmoking.However,therelationshipbetweennaltrexone'sactiononthe HPAaxisanditsreductionofsmokingbehaviorhasnotbeeninvestigated.Finally,theremaybeimportant,yet unexploredsexdifferencesinsmokers'responsetonaltrexone.Womensmokershaveshownmoreacute sensitivitytonaltrexonethanmenintermsofsubjective,behavioral,andHPAaxishormonemeasures,aswell asbetterquitratesinsmokingcessationtrialsusingnaltrexone.Thesereportedsexdifferencesmaybe relatedtodifferencesinlevelsofestradiol,thepredominantestrogeninhumans,betweenmenandwomen.In women,fluctuationsinestradiollevelsacrossthemenstrualcyclemayaffecttheamountofavailableopioid receptorsand,therefore,mayaffecttheefficacyofnaltrexone.Thestudiesinthisapplicationaredesignedto testtheeffectsofnaltrexoneontheHPAaxisandsmokingbehaviorinmaleandfemalesmokers,andto examinehowestradiollevelaffectstheseresponsestonaltrexoneinfemalesmokers.Inordertoexaminethe effectofestradiolonresponsetonaltrexone,womenwillbetestedattwodifferentstagesofthemenstrual cycle:theearlyfollicularphase(thelowestlevelofestradioloccurringduringthemenstrualcycle)andthelate follicularphase(thehighestoccurringlevelofestradiol).Theresultsofthisstudywouldpotentiallyprovide evidenceforestradiollevelasamechanismunderlyingsexdifferencesinresponsetonaltrexoneandmay havetranslationalclinicalimplicationsfortheuseofnaltrexoneinsmokingcessation.