RVM CCK, Pain, and Opioid Tolerance

描述（由申请人提供）：最近的证据表明，此外， 镇痛，阿片类药物产生意想不到的，矛盾的疼痛，在两个临床前 和临床环境。在吗啡的情况下，阿片类药物引起的疼痛限制了 不仅有急性镇痛功效，而且似乎还能促进 持续暴露所见的抗伤害感受（即，行为阿片 抗伤害耐受性）。阻断吗啡引起的疼痛的手法 也可以阻止持续的抗伤害性效力的下降， 吗啡，这表明阿片类药物引起的疼痛可能是一个重要的 对这种药物的抗伤害耐受性的组成部分。在这些操作中， 阻断吗啡引起的疼痛和抗伤害性耐受是吻侧的 延髓腹内侧（RVM）注射利多卡因和双侧病变 背外侧索（DLF）提示紧张性活动性下行疼痛 调节（易化）系统，维持吗啡诱导的疼痛， 抗伤害耐受性吗啡的观察结果是否 与具有不同阿片样物质受体选择性的其它激动剂的结合是未知的。这 一项提案假设吗啡增强胆囊收缩素（CCK）的释放， RVM然后促进阿片类药物诱导的疼痛和抗伤害性 “宽容。“支持这种可能性的初步数据显示， RVM CCK在未暴露于阿片类药物的动物中产生“疼痛”， DLF病变。此外，急性和持续的吗啡增加释放 RVM中的CCK-LI。三个目标将检验这一假设。目标1将调查 急性局部或全身吗啡后RVM中CCK-LI的释放， 这种效应的时间过程和介导这种效应的阿片受体。 目的2将讨论持续全身吗啡在调节 增强RVM CCK-LI释放，其时间过程和与疼痛的相关性，以及 阿片受体介导的RVM CCK-LI释放增强 阿片类药物输送。目的3确定RVM CCK拮抗剂是否能阻止 阿片样物质诱导的疼痛的发展，并防止或逆转脊髓或全身 阿片类镇痛耐受性这些研究将确定， 阿片诱导的RVM CCK释放代表紧张性驱动力， 维持吗啡或阿片样物质诱导的疼痛和抗伤害性耐受。的 研究为阿片耐受的生理机制提供了新的见解 以及可能用于预防阿片类药物引起的疼痛的策略， 抗伤害耐受性这些方法可以允许持续的功效， 吗啡或阿片样物质及其在治疗慢性或长期疼痛中的用途 states.

DESCRIPTION (provided by applicant): Recent evidence suggests that, in addition to analgesia, opioids produce unexpected, paradoxical pain in both preclinical and clinical settings. In the case of morphine, opioid-induced pain limits not only acute antinociceptive efficacy but also appears to promote the decreased antinociception seen with sustained exposure (i.e., behavioral opioid antinociceptive tolerance). Manipulations which block morphine-induced pain also block the decrease in antinociceptive potency seen with sustained morphine, suggesting that opioid-induced pain may represent an important component of antinociceptive tolerance to this drug. Among the manipulations which block morphine-induced pain and antinociceptive tolerance are rostral ventromedial medulla (RVM) injection of lidocaine and bilateral lesions of the dorsolateral funiculus (DLF) suggesting a tonically active descending pain modulatory (facilitatory) system which maintains morphine-induced pain and antinociceptive tolerance. Whether the observations made with morphine extend to other agonists of differing opioid receptor selectivity is not known. This proposal hypothesizes that morphine enhances cholecystokinin (CCK) release in the RVM which then promotes opioid-induced pain and antinociceptive "tolerance." Supporting this possibility are preliminary data which show that RVM CCK produces "pain" in animals not exposed to opioids which is blocked by DLF lesions. Additionally, acute and sustained morphine increases release of CCK-LI in the RVM. Three aims will test this hypothesis. Aim 1 will investigate the release of CCK-LI in the RVM following acute local or systemic morphine, the time-course of this effect and the opioid receptor mediating this effect. Aim 2 will address the actions of sustained systemic morphine in regulating enhanced RVM CCK-LI release, its time-course and correlation to pain, and the opioid receptor mediating enhancement of RVM CCK-LI release during sustained opioid delivery. Aim 3 determines if an RVM CCK antagonist prevents the development of opioid induced pain and prevents or reverses spinal or systemic opioid antinociceptive tolerance. These studies will determine if opioid-induced release of RVM CCK represents the tonic driving force which maintains morphine- or opioid-induced pain and antinociceptive tolerance. The studies offer new insights into physiological mechanisms of opioid tolerance and strategies which might be employed to prevent opioid-induced pain and antinociceptive tolerance. These approaches may allow for sustained efficacy of morphine or opioids and their use in the treatment of chronic or prolonged pain states.