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

描述（由申请人提供）：内源性阿片类药物系统涉及对尼古丁的反应以及尼古丁依赖的发展和维持。因此,onedrugbeinginvestigatedforsmokingcessation treatmentisnaltrexone aopioidreceptorantagonist。然而，最近的临床试验研究了纳曲酮辅助治疗在戒烟中的效果，结果好坏参半，因此需要进一步的研究。与这些临床结果潜在相关的是，内源性阿片系统和尼古丁都对下丘脑-垂体-肾上腺（HPA）轴起作用，这是一个主要与应激反应相关的系统。SmokershaveanacutelyunderresponsiveHPAaxistostressorsor pharmacologicalactivationcomparedtononsmokers。重要的是,thisHPAaxisdysfunctionmayplayarole inmaintenanceofaddictionandsusceptibilitytorelapse。纳曲酮实际上激活了hpais，之前有人假设，这种hpais活性的增加可能会削弱纳曲酮治疗酒精中毒（可能是吸烟）的功效。然而,therelationshipbetweennaltrexone 'sactiononthe HPAaxisanditsreductionofsmokingbehaviorhasnotbeeninvestigated。最后,theremaybeimportant,然而unexploredsexdifferencesinsmokers 'responsetonaltrexone。在主观、行为和hpaa激素测量中，女性吸烟者对纳曲酮的敏感性比男性高，在服用纳曲酮的戒烟试验中，女性吸烟者的戒烟率也比男性高。Thesereportedsexdifferencesmaybe relatedtodifferencesinlevelsofestradiol、thepredominantestrogeninhumans betweenmenandwomen。在女性中，月经周期内雌激素水平的波动可能会影响可用类睾酮受体的数量，因此可能会影响纳曲酮的疗效。本应用程序的研究旨在测试男性和女性吸烟者对hpais和吸烟行为的影响，并检查传统水平如何影响女性吸烟者对hpais和吸烟行为的反应。为了检验雌二醇对曲酮的反应效果，女性将在月经周期的两个不同阶段进行测试：卵泡期早期（在月经周期中雌二醇水平最低）和卵泡期晚期（雌二醇水平最高）。本研究的结果可能会提供证据，证明传统水平作为一种机制，在对丙烯酮的反应中存在性别差异，并可能对在戒烟中使用丙烯酮具有翻译临床意义。

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.