Neural Mechanisms for Enhanced Cannabinoid/Opioid Antinociception

描述（由申请人提供）：阿片类药物如吗啡是治疗疼痛最有效的药物。不幸的是，这种阿片类镇痛药由于反复给药产生耐受性而受到限制。大麻素也被证明有镇痛作用，但这种镇痛作用比阿片类药物产生的效果要温和得多。阿片类药物和大麻素联合使用有可能增强两种药物的镇痛作用，并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，阿片类药物和大麻素交替治疗可以增强阿片类药物和大麻素的镇痛作用。我们的数据显示，将大麻素HU-210反复注射到一种叫做导水管周围灰质（PAG）的大脑结构中，在随后的一天中，吗啡注射到PAG中的镇痛效果会增强。这一发现表明大麻素增强吗啡抗痛觉的能力是由PAG介导的。本拨款提案的第一个目标（目的1）是验证在吗啡耐受大鼠中向PAG微注射大麻素的抗痛觉作用将被增强的假设。此外，这些PAG介导的作用将与大麻素/阿片相互作用在吻侧腹内侧延髓（RVM）中进行比较，RVM是PAG神经元的主要输出靶点。将使大鼠对吗啡或HU-210耐受，然后对PAG或RVM注射HU-210或吗啡进行增强镇痛试验。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是如何发生的。特别是，解剖学和电生理技术将用于确定大麻素和阿片类药物是否在PAG中相同或不同的神经元上相互作用。这些研究将为大麻素/阿片类药物相互作用的机制提供见解。了解这些机制将有助于开发既能降低对阿片类药物耐受性又能增强阿片类药物和大麻素镇痛作用的疼痛治疗方法。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。

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.