Neural Mechanisms for Enhanced Cannabinoid/Opioid Antinociception

描述(申请人提供)：吗啡等阿片类药物是治疗疼痛的最有效方法。不幸的是，这种阿片类止痛受到反复给药的耐受性的限制。大麻素也被证明有止痛作用，但这种抗伤害作用比阿片类药物产生的要温和得多。阿片类药物和大麻类药物的联合给药有可能增强这两类药物的止痛效果，减少对阿片类药物的耐受性。我们的初步数据和其他人发表的报告表明，阿片类药物和大麻类药物交替治疗可以增强阿片类药物和大麻类药物的镇痛效果。我们的数据显示，在被称为中脑导水管周围灰质(PAG)的大脑结构中反复注射大麻素HU-210，可在第二天增强向PAG注射吗啡的止痛效果。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。这项赠款提案的第一个目标(目标1)是测试这样一种假设，即在吗啡耐受大鼠的PAG内微量注射大麻素将增强其抗伤害效应。此外，这些PAG介导的作用将与延髓头端腹内侧(RVM)-PAG神经元的主要输出靶标-大麻素/阿片类药物的相互作用进行比较。将使大鼠对吗啡或HU-210耐受，然后测试向PAG或RVM注射HU-210或吗啡的增强止痛效果。第二个目标(目标2)是确定大麻素和类阿片之间的这种相互作用是如何发生的。特别是，将使用解剖学和电生理学技术来确定大麻素和阿片类药物是否与PAG中相同或不同的神经元相互作用。这些研究将深入了解大麻素/阿片类药物相互作用的机制。对这些机制的了解将有助于开发既能降低对阿片类药物的耐受性又能增强阿片类药物和大麻类药物的止痛效果的疼痛治疗方法。因此，这些简单但创新的实验可能会对改善疼痛的治疗产生重大影响。 公共卫生相关性： 持续性疼痛是一个严重的医学问题。尽管阿片类药物治疗剧烈疼痛的有效性随着反复给药而减弱，但事先使用大麻类药物似乎增强了吗啡的止痛效果。拟议的研究将检验阿片类药物和大麻类药物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。

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.