Sex-dependent expression and utilization of spinal mu- and kappa-opioid systems

脊髓 mu 和 kappa 阿片系统的性别依赖性表达和利用

• 批准号: 8248791
• 负责人: ALAN R GINTZLER
• 金额: $ 26.92万
• 依托单位: SUNY DOWNSTATE MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8248791
• 关键词: Absence of pain sensation; Adult; Analgesics; Antibodies; Attenuated; Behavioral; Biochemical; Biological; Characteristics; Coupled; Data; Dependency; Dose; Drug Delivery Systems; Dynorphins; Female; Gonadal Steroid Hormones; Knowledge; Male Castration; Measures; Mediating; Mediation; Molecular; Molecular Profiling; Morphine; Nature; Neonatal; Oligonucleotides; Opioid; Opioid Receptor; Outcome; Ovarian; Pain; Pain management; Pathway interactions; Pharmacological Treatment; Physiological; Prevalence; Process; RNA Splicing; Rattus; Receptor Signaling; Recruitment Activity; Regulation; Relapse; Reliance; Role; Spices; Spinal; Spinal Cord; Staging; System; Testing; Validation; Variant; Woman; addiction; attenuation; base; cDNA Arrays; density; drug mechanism; endogenous opioids; endomorphin 2; male; men; novel; opioid withdrawal; public health relevance; research study; response; sex

DESCRIPTION (provided by applicant): Previous studies that defined sex dependency of opioid antinociception were not poised to reveal relevant mechanistic underpinnings and biological substrates. The present application proposes to establish a causal association between sex-dependent pharmacological characteristics of spinal opioid antinociception and (1) the sexual dimorphic nature of spinal opioid receptors and (2) the sex-dependent release of spinal opioids by intrathecal (i.t.) morphine. Hypothesized sexual dimorphic relationships among spinal ?-opioid receptors (MOR), endomorphin 2 (EM2), ?-opioid receptors (KOR) and dynorphin 1-17 (Dyn) are supported by substantial preliminary data, which is undergirded by our previous demonstrations that i.t. morphine elicits predominantly MOR-coupled spinal antinociception in males, whereas in females i.t. morphine recruits a more inclusive integrative system that requires concomitant activity of spinal MOR and KOR. Sexual dimorphic expression levels of spinal MOR splice variants and MOR KOR heterodimers are postulated to be molecular underpinnings of the female phenotypic response to spinal morphine. In parallel with the postulated sexually dimorphic organization of spinal opioid receptors, we hypothesize that the sex-dependent regulation of the release of and analgesic responsiveness to spinal opioids are integral component of sex-dependent spinal opioid antinociception. Specifically, Aim 1 will test the hypothesis that the antinociception produced by i.t. morphine, requires the release of EM2 from the spinal cord of males, but not females. Aim 2 will test the hypothesis that i.t. EM2 elicits greater antinociception in males vs. females, which exacerbates the consequences of the sex-dependent release of spinal EM2 by i.t. morphine. We postulate that this is mediated, at lest in part, by the sex-dependent expression of spinal MOR splice variants. Validation that release of spinal EM2 by i.t. morphine is a prerequisite for the spinal antinociception it produces in males, but not females, would not fully reveal the sex-dependent landscape that underlies spinal morphine antinociception. To do so requires knowledge of the analgesic substrates recruited by i.t. morphine in females. Accordingly, Aim 3 will test the hypothesis that in females, i.t. morphine analgesia is mediated via the release of Dyn, not EM2. Aim 4 will test the hypothesis that the requirement in females for the concomitant activation of spinal MOR and KOR for spinal morphine antinociception to be manifest reflects the presence of significantly higher expression levels of MOR KOR heterodimers in spinal cord of females vs. males. We will pursue these interrelated Aims using a multi-dimensional approach that integrates behavioral, pharmacological, molecular and immuno-based biochemical levels of analyses. These will be used as complementary measures to cross validate findings. Since pain and addiction share common substrates, expected outcomes will reveal novel drug targets that are not only relevant to optimizing pain management in men and women but also to treating opioid withdrawal and relapse in a sex-dependent fashion. PUBLIC HEALTH RELEVANCE: This application will establish sexual dimorphic functional relationships among spinal ?- and ?-opioid receptors and the endogenous opioids endomorphin 2 and dynorphin 1-17. This will provide a rationale framework for understanding the sex divide in pain processing and its differential regulation in men vs. women.. Since pain and addiction share common substrates, expected outcomes will reveal novel drug targets and mechanisms that are not only relevant to the sex-dependent optimization of pain management but also to treating opioid withdrawal and relapse in women as well as men.

描述（由申请人提供）：先前的研究表明，确定阿片类药物抗伤害感受的性依赖性的研究未准备揭示相关的机械基础和生物底物。目前的应用建议建立脊柱阿片类药物抗伤害感受的性依赖性药理学特征与（1）脊柱阿片类受体的性二态性质与（2）通过静脉内（I.T.）吗啡对性依赖性脊柱阿片类药物的性释放。脊柱受体（MOR），内啡肽2（EM2），？ - 阿片受体（KOR）和Dynorphin 1-17（dyn）之间假定的性二态关系，这是由我们先前的先前证明I.T.的实质性初步数据支持的。 ？ ？脊柱MOR剪接变体和MOR kor异二聚体的性二态表达水平被认为是女性表型反应对脊髓吗啡的分子基础。与假定的脊柱阿片类受体的性二态性组织同时，我们假设性别依赖性调节对脊柱阿片类药物的释放和镇痛反应性是性别依赖性脊柱阿片类药物抗脑感染的组成部分。具体而言，AIM 1将检验以下假设：I.T。产生的抗伤害感受。吗啡需要从男性的脊髓中释放出EM2，而不是女性。 AIM 2将检验I.T.的假设EM2引起男性与女性的更大抗伤害感受，这加剧了I.T.脊柱EM2的性别依赖性释放的后果。吗啡。我们假设这是由于脊柱MOR剪接变体的性别依赖性表达而部分介导的。验证I.T.释放脊柱EM2吗啡是其在雄性而非女性中产生的脊柱抗激活的先决条件，不会完全揭示脊柱吗啡抗伤害感受的性别依赖性景观。为此，需要了解I.T.招募的镇痛基底物的知识。女性的吗啡。因此，AIM 3将检验以下假设：在女性中，I.T。吗啡镇痛是通过DYN的释放而不是EM2介导的。 AIM 4将检验以下假设：女性对脊柱MOR和KOR对脊柱吗啡抗伤害感受的同时激活的需求表明，在女性与雄性的脊髓中，MOR KOR异二聚体的表达水平明显较高。我们将使用多维方法来追求这些相互关联的目标，该方法整合了行为，药理，分子和基于免疫化的生化分析水平。这些将用作跨验证发现的补充措施。由于疼痛和成瘾共有共同的底物，因此预期的结果将揭示新的药物靶标，这不仅与优化男性和女性疼痛管理有关，而且还与以性依赖性方式治疗阿片类药物的戒断和复发有关。 公共卫生相关性：此应用将在脊柱之间建立性二态功能关系？ - 和？阿片受体以及内源性阿片类药物内派2和Dynorphin 1-17。这将提供一个理由框架，以理解疼痛处理中的性别鸿沟及其在男性与女性中的不同调节。