Gender and Sex Hormones and Opioid Analgesia

性别和性激素以及阿片类镇痛

• 批准号: 6861796
• 负责人: JON DAVID LEVINE
• 金额: $ 54.63万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-09-30 至 2007-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6861796
• 关键词: African American; Asian Americans; Hispanic Americans; alpha adrenergic agent; alpha adrenergic receptor; analgesia; analgesics; caucasian American; clonidine; dosage; drug interactions; female; gender difference; haloperidol; human subject; male; naloxone; opiate alkaloid; oral facial pain; pain threshold; patient oriented research; pentazocine; postoperative state; racial /ethnic difference; young adult human (21-34)

Despite considerable research on gender differences in pain sensitivity, sex differences in pain modulation by opioid analgesics in humans have only recently been examined. We showed, in postoperative dental patients, that k (kappa)-partial agonist opioids produce significantly greater analgesia in females than in males. This finding was observed with three different opioid analgesics that are k-partial agonists: pentazocine, nalbuphine and butorphanol. In dose response studies performed during the current grant period, we further demonstrated that the greater analgesic potency in females for k- partial agonists may be at least partly due to the existence of a naloxone-sensitive anti-analgesia mechanism that predominates in males. Whereas due to this anti-analgesia a k-opioid (nalbuphine) produced greater pain than placebo in males, the addition of naloxone resulted in a markedly enhanced and prolonged analgesia in both genders. Recent evidence in animal models suggests that k-partial agonists may inhibit analgesia by their action at naloxone-sensitive s (sigma)-receptors, which could explain the anti-analgesic effects of k-opioid partial agonists. In previous experiments, we found that combining k- partial agonists with the alpha2-adrenergic agent, clonidine also enhances analgesia. The proposed experiments will identify the mechanism of the anti- analgesic action of the k-partial agonists. They will also determine optimal doses for the specific k-partial agonist (nalbuphine, butorphanol, pentazocine) naloxone combinations in other clinical settings, including repeated use in hospitalized post-surgical patients and patients with neuropathic pain. We will also explore gender and ethnic differences in analgesic responses resulting from k-opioids combined with the adjuvants known to interact with other neurotransmitter systems/mechanisms involved in pain modulation, that is, agents that act at a2- adrenergic receptors, and s-receptors. Finally, we will further characterize the opioid contribution to placebo analgesia. These studies will provide much-needed knowledge of gender differences in responses to opioid analgesics and should lead to gender- specific recommendations for more effective, better targeted pain therapy.

尽管对疼痛敏感性的性别差异进行了大量研究，但最近才对人类阿片类镇痛药调节疼痛的性别差异进行了研究。 我们在术后牙科患者中发现，k (kappa)-部分激动剂阿片类药物对女性的镇痛作用明显强于男性。 这一发现是通过三种不同的 k-部分激动剂阿片类镇痛药观察到的：喷他佐辛、纳布啡和布托啡诺。 在当前资助期间进行的剂量反应研究中，我们进一步证明，k-部分激动剂对女性具有更大的镇痛效力，这可能至少部分归因于男性中占主导地位的纳洛酮敏感抗镇痛机制的存在。 由于这种抗镇痛作用，k-阿片类药物（纳布啡）在男性中比安慰剂产生更大的疼痛，而纳洛酮的添加导致男女的镇痛效果显着增强和延长。 最近的动物模型证据表明，k-部分激动剂可能通过作用于纳洛酮敏感的 s (sigma)-受体来抑制镇痛，这可以解释 k-阿片类部分激动剂的抗镇痛作用。 在之前的实验中，我们发现将k-部分激动剂与α2-肾上腺素能药物可乐定联合使用也能增强镇痛作用。所提出的实验将确定k-部分激动剂的抗镇痛作用的机制。 他们还将确定特定 k-部分激动剂（纳布啡、布托啡诺、喷他佐辛）纳洛酮组合在其他临床环境中的最佳剂量，包括在住院术后患者和神经性疼痛患者中重复使用。 我们还将探讨 k-阿片类药物与已知与参与疼痛调节的其他神经递质系统/机制（即作用于 α2- 肾上腺素能受体和 s-受体的药物）相互作用的佐剂所产生的镇痛反应中的性别和种族差异。 最后，我们将进一步描述阿片类药物对安慰剂镇痛的贡献。 这些研究将提供急需的关于阿片类镇痛药反应的性别差异的知识，并应为更有效、更有针对性的疼痛治疗提供针对性别的建议。