Neural Mechanisms for Enhanced Cannabinoid/Opioid Antinociception

增强大麻素/阿片类镇痛作用的神经机制

• 批准号: 7640433
• 负责人: MICHAEL M MORGAN
• 金额: $ 7.48万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-15 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7640433
• 关键词: Absence of pain sensation; Acute; Agonist; Analgesics; Anatomy; Animals; Applications Grants; Attenuated; Brain; Cannabinoids; Chemosensitization; Conflict (Psychology); Data; Development; Dose; Effectiveness; Electrophysiology (science); Goals; Human; In Vitro; Injection of therapeutic agent; Lead; Mediating; Medical; Microinjections; Morphine; Nervous System Part; Nervous system structure; Neurons; Nociception; Opioid; Opioid Receptor; Output; Pain; Pain management; Pathway interactions; Persistent pain; Pharmaceutical Preparations; Publishing; Rattus; Recording of previous events; Reporting; Research; Site; Structure; System; Techniques; Testing; Therapeutic; behavioral pharmacology; cannabinoid receptor; effective therapy; improved; innovation; insight; interest; midbrain central gray substance; neuromechanism; patch clamp; public health relevance; research study; skills; transmission process

DESCRIPTION (provided by applicant): Opioids such as morphine are the most effective treatment for pain. Unfortunately, this opioid analgesia is limited by the development of tolerance with repeated administration. Cannabinoids also have been shown to have analgesic effects, but this antinociception is much more mild than that produced by opioids. The combined administration of opioids and cannabinoids has the potential to enhance the analgesic effects of both drug classes and reduce the development of tolerance to opioids. Our preliminary data and published reports by others show that alternating opioid and cannabinoid treatment can enhance the analgesic effects of both opioids and cannabinoids. Our data show that repeated injections of the cannabinoid HU-210 into a brain structure called the periaqueductal gray (PAG) enhances the analgesic effect of a morphine injection into the PAG on a subsequent day. This finding suggests that the ability of cannabinoids to enhance morphine antinociception is mediated by the PAG. The first objective of this grant proposal (Aim 1) is to test the hypothesis that the antinociceptive effect of microinjecting a cannabinoid into the PAG will be enhanced in morphine tolerant rats. In addition, these PAG mediated effects will be compared to cannabinoid/opioid interactions in the rostral ventromedial medulla (RVM)-the primary output target for neurons in the PAG. Rats will be made tolerant to either morphine or HU-210 and then tested for enhanced analgesia to injection of either HU-210 or morphine into the PAG or RVM. The second objective (Aim 2) is to determine how this interaction between cannabinoids and opioids occurs. In particular, anatomical and electrophysiological techniques will be used to determine whether cannabinoids and opioids interact on the same or different neurons in the PAG. These studies will provide insights into the mechanisms underlying cannabinoid/opioid interactions. An understanding of these mechanisms will allow the development of pain treatments that both reduce tolerance to opioids and enhance the analgesic effects of opioids and cannabinoids. Thus, these simple, but innovative experiments could have a significant impact on improving the treatment for pain. PUBLIC HEALTH RELEVANCE: Persistent pain is a serious medical problem. Although the effectiveness of opioids to treat severe pain diminishes with repeated administration, prior treatment with a cannabinoid appears to enhance the analgesic effects of morphine. The proposed studies will examine possible mechanisms for this potentiation between opioids and cannabinoids so better pain treatments can be developed.

描述（由申请人提供）：吗啡等阿片类药物是治疗疼痛最有效的药物。不幸的是，这种阿片类镇痛作用受到重复给药耐受性发展的限制。大麻素也被证明具有镇痛作用，但这种抗伤害作用比阿片类药物产生的要温和得多。阿片类药物和大麻素的联合给药有可能增强两种药物的镇痛作用，并减少对阿片类药物耐受性的发展。我们的初步数据和其他人发表的报告表明，交替阿片类药物和大麻素治疗可以增强阿片类药物和大麻素的镇痛作用。我们的数据表明，重复注射大麻素HU-210到大脑结构称为中脑导水管周围灰质（PAG）增强吗啡注射到PAG的镇痛作用在随后的一天。这一发现表明大麻素增强吗啡抗伤害感受的能力是由PAG介导的。本拨款提案的第一个目标（目标1）是检验以下假设：在吗啡耐受大鼠中，将大麻素微量注射到PAG中的抗伤害性作用将增强。此外，这些PAG介导的作用将与延髓头端腹内侧（RVM）中的大麻素/阿片类药物相互作用进行比较-PAG中神经元的主要输出靶点。使大鼠对吗啡或HU-210耐受，然后测试将HU-210或吗啡注射到PAG或RVM中的增强镇痛作用。第二个目标（目标2）是确定大麻素和阿片类药物之间的相互作用如何发生。特别是，解剖学和电生理学技术将用于确定大麻素和阿片类药物是否在PAG中的相同或不同神经元上相互作用。这些研究将为大麻素/阿片类药物相互作用的潜在机制提供见解。对这些机制的理解将允许开发疼痛治疗，既减少对阿片类药物的耐受性，又增强阿片类药物和大麻素的镇痛作用。因此，这些简单但创新的实验可能对改善疼痛治疗产生重大影响。 公共卫生相关性： 持续性疼痛是一个严重的医学问题。虽然阿片类药物治疗重度疼痛的有效性随着重复给药而降低，但大麻素的预先治疗似乎增强了吗啡的镇痛作用。拟议的研究将研究阿片类药物和大麻素之间这种增强作用的可能机制，以便开发更好的疼痛治疗方法。