RVM CCK, Pain, and Opioid Tolerance

描述(由申请人提供)：最近的证据表明，此外 对于止痛，阿片类药物在两种临床前都会产生意想不到的、矛盾的疼痛 和临床环境。在吗啡的情况下，阿片类药物诱导的疼痛限制不是 不仅急性抗伤害性作用强，而且似乎促进作用降低。 持续暴露的抗伤害作用(即行为阿片类药物 抗伤害性耐受)。阻断吗啡引起的疼痛的手法 也阻断了持续存在的抗伤害感受性效力的下降 吗啡，这表明阿片类药物诱导的疼痛可能是一种重要的 对该药物具有抗伤害耐受性的成分。在这些操纵中 对吗啡引起的疼痛和抗伤害性耐受的阻断是最重要的 延髓腹内侧区注射利多卡因及双侧病变 背外侧索(DLF)提示强直性主动下行疼痛 调节(促进)系统，维持吗啡诱导的疼痛和 抗伤害性耐受。使用吗啡进行的观察是否延长了 对其他阿片受体选择性不同的激动剂的作用尚不清楚。这 提案假设吗啡促进大鼠脑内CCK的释放 RVM随后促进阿片类药物诱导的疼痛和抗伤害感受性 “宽容。”支持这种可能性的是初步数据，它们表明 RVM CCK在未暴露于阿片类药物的动物身上产生“疼痛”，而阿片类药物可被阻断 DLF病变。此外，急性和持续的吗啡增加了 RVM中的CCK-LI。三个目标将检验这一假设。AIM 1将调查 急性局部或全身吗啡后RVM中CCK-LI的释放， 这一效应的时程以及阿片受体介导这一效应。 目标2将讨论持续的全身吗啡在调节 促进RVM CCK-LI释放、时程及其与疼痛的相关性 阿片受体在缓释期促进RVM CCK-Li释放的作用 阿片类药物输送。目标3确定RVM CCK拮抗剂是否阻止 发展阿片类药物引起的疼痛，预防或逆转脊髓或全身疼痛 阿片类抗伤害性耐受性。这些研究将确定是否 阿片类药物诱导的RVM CCK释放代表紧张性驱动力 维持吗啡或阿片类药物引起的疼痛和抗伤害性耐受。这个 研究为阿片类药物耐受的生理机制提供了新的见解 以及可用于预防阿片类药物引起的疼痛和 抗伤害性耐受。这些方法可能会持续有效地 吗啡或阿片类药物及其在治疗慢性或延迟性疼痛中的应用 各州。

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.