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）：先前定义阿片类镇痛作用性别依赖性的研究尚未准备好揭示相关的机制基础和生物底物。本申请提出建立脊髓阿片类药物抗伤害作用的性别依赖性药理学特征与(1)脊髓阿片类药物受体的性别二态性和(2)鞘内(i.t.)吗啡引起的脊髓阿片类药物的性别依赖性释放之间的因果关系。脊髓α-阿片受体（MOR）、内吗啡肽2（EM2）、α-阿片受体（KOR）和强啡肽1-17（Dyn）之间假设的性别二态性关系得到了大量初步数据的支持，这些数据得到了我们之前的论证的支持。吗啡在男性中主要引起 MOR 偶联脊髓镇痛作用，而在女性中则主要引起 MOR 偶联脊髓镇痛作用。吗啡招募了一个更具包容性的整合系统，需要脊髓 MOR 和 KOR 的同时活动。脊髓 MOR 剪接变体和 MOR KOR 异二聚体的性别二态性表达水平被认为是女性对脊髓吗啡表型反应的分子基础。与假定的脊髓阿片受体的性别二态性组织平行，我们假设脊髓阿片类药物的释放和镇痛反应的性别依赖性调节是性别依赖性脊髓阿片类镇痛作用的组成部分。具体来说，目标 1 将检验 i.t. 产生的抗伤害作用这一假设。吗啡需要男性脊髓释放 EM2，但女性不需要。目标 2 将检验以下假设：与女性相比，EM2 在男性中引起更强的镇痛作用，这加剧了 i.t. 脊髓 EM2 性别依赖性释放的后果。吗啡。我们假设这至少部分是由脊髓 ​​MOR 剪接变体的性别依赖性表达介导的。验证 i.t. 释放脊髓 EM2吗啡是其在男性而非女性中产生脊髓镇痛作用的先决条件，因此无法完全揭示脊髓吗啡镇痛作用背后的性别依赖性景观。为此，需要了解 i.t. 招募的镇痛底物。女性使用吗啡。因此，目标 3 将检验以下假设：在女性中，i.t.吗啡镇痛是通过 Dyn 的释放来介导的，而不是 EM2。目标 4 将检验以下假设：女性需要同时激活脊髓 MOR 和 KOR 才能表现出脊髓吗啡抗伤害作用，这反映了女性脊髓中 MOR KOR 异二聚体的表达水平显着高于男性。我们将采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、药理学、分子和基于免疫的生化水平的分析。这些将用作交叉验证研究结果的补充措施。由于疼痛和成瘾具有共同的基础，预期结果将揭示新的药物靶点，这些靶点不仅与优化男性和女性的疼痛管理相关，而且还与以性别依赖性方式治疗阿片类药物戒断和复发有关。 公共健康相关性：本申请将建立脊髓α-和β-阿片受体与内源性阿片类药物内吗啡肽 2 和强啡肽 1-17 之间的性二态功能关系。这将为理解疼痛处理中的性别差异及其男性与女性的差异调节提供一个基本框架。由于疼痛和成瘾具有共同的基础，预期结果将揭示新的药物靶点和机制，这些靶点和机制不仅与性别依赖性疼痛管理的优化相关，而且还与治疗女性和男性的阿片类药物戒断和复发有关。