A novel pharmacological target to prevent sustained-morphine-mediated pain sensit

描述（由申请人提供）：长期药物治疗后吗啡戒断暴露了对疼痛（痛觉过敏）和无害（异常性疼痛）刺激的自相矛盾的敏感性增强。脊髓小胶质细胞的激活被证明在疼痛敏感性的调节中起重要作用。有趣的是，最近发现CB 2-选择性大麻素激动剂有效地拮抗神经胶质激活。此外，我们的初步研究表明，全身共同管理的吗啡与CB 2激动剂完全减弱痛觉过敏和触觉异常性疼痛后，吗啡戒断大鼠。因此，我们打算探讨吗啡与CB 2选择性激动剂共同给药减弱持续吗啡介导的神经胶质激活的假设。具体目标是：一.确定吗啡处理的大鼠中CB 2激动剂介导的戒断性痛觉过敏和异常性疼痛的衰减的剂量-反应关系; II.确定吗啡和CB 2激动剂的持续全身共同施用对大鼠中脊髓小胶质细胞和星形胶质细胞活性以及对脊髓疼痛神经递质（CGRP）浓度的影响;和III.开发和表征原代新生大鼠脊髓小胶质细胞培养物作为未来的体外细胞模型，用于详细研究CB 2受体介导的小胶质细胞信号传导的分子机制。由于CB 2受体在神经元中以低浓度存在，因此这些药物表现出很少或没有CNS副作用。因此，阿片样物质和CB 2激动剂的共同给药预计将使用较低的吗啡剂量产生更持久的疼痛缓解，降低慢性疼痛治疗中危险副作用的可能性。 公共卫生相关性：长期吗啡治疗导致疼痛缓解逐渐下降。因此，临床医生需要使用稳定增加的吗啡剂量来管理严重的慢性疼痛（镇痛剂耐受性）。另一方面，更高的吗啡剂量更有可能引起严重的副作用，也可能导致药物成瘾。有趣的是，最近证明，持续暴露于吗啡实际上增加了患者对疼痛（痛觉过敏），甚至对正常无痛（异常性疼痛）刺激的敏感性，从而导致在治疗慢性疼痛时需要增加吗啡剂量。脊髓胶质细胞的激活被证明在持续吗啡治疗后对感觉刺激的这种矛盾敏化的发展中起着至关重要的作用。因此，发现神经胶质抑制剂可降低神经性疼痛敏感性和吗啡耐受性。在本提案中，我们打算探索一种新的药理学方法的效用-CB 2大麻素受体类型的激活-在持续的吗啡治疗过程中抑制脊髓小胶质细胞激活。通过防止神经胶质活化，阿片样物质和CB 2激动剂的共同治疗预计将产生更有效的疼痛缓解，而不会在持续治疗期间产生适应性疼痛致敏。因此，有了这样的药物组合，我们也许能够用较低的吗啡剂量实现更持久的疼痛缓解，降低治疗慢性疼痛时危险副作用和阿片类药物成瘾的可能性。

DESCRIPTION (provided by applicant): Morphine withdrawal after prolonged drug treatment unmasks a paradoxical augmented sensitivity to painful (hyperalgesia) and innocuous (allodynia) stimuli. Activation of spinal microglia was shown to play an important role in the regulation of pain sensitivity. Interestingly, recently it was found that CB2-selective cannabinoid agonists efficiently antagonize glial activation. In addition, our preliminary shows that systemic co-administration of morphine with a CB2 agonist completely attenuates hyperalgesia and tactile allodynia upon morphine withdrawal in rats. Therefore, we intend to explore the hypothesis that co- administration of morphine with a CB2-selective agonist attenuates sustained morphine- mediated glial activation. The specific aims the proposed work are: I. to determine dose- response relationships for CB2 agonist-mediated attenuation of withdrawal hyperalgesia and allodynia in morphine treated rats; II. to determine the effect of sustained systemic co- administration of morphine and a CB2 agonist on spinal microglia and astrocyte activity and on spinal pain neurotransmitter (CGRP) concentration in rats; and III. to develop and characterize a primary neonatal rat spinal microglia culture as a future in vitro cellular model for a detailed investigation of the molecular mechanism of CB2 receptor-mediated microglial signaling. Since CB2 receptors are present in low concentrations in neurons, these agents exhibit little or no CNS side effects. Therefore, co-administration of opioid and CB2 agonists is expected to produce longer-lasting pain relief using lower morphine doses, reducing the likelihood of dangerous side effects in the treatment of chronic pain. PUBLIC HEALTH RELEVANCE: Prolonged morphine treatment leads to a gradual decline of pain relief. Consequently, clinicians need to use steadily increasing morphine doses to manage severe chronic pain (analgesic tolerance). Higher morphine doses on the other hand are more likely to cause serious side effects and may also lead to drug addiction. Interestingly, recently it was demonstrated that sustained exposure to morphine actually increases the sensitivity of patients to painful (hyperalgesia) and even to normally painless (allodynia) stimuli, contributing to the need for increased morphine doses in the treatment of chronic pain. Activation of spinal glia was shown to play a crucial role in the development of such paradoxical sensitization to sensory stimuli upon sustained morphine treatment. Accordingly, glial inhibitors were found to reduce both neuropathic pain sensitization and morphine tolerance. In the present proposal we intend to explore the utility of a novel pharmacological approach -activation of the CB2 cannabinoid receptor type - to inhibit spinal microglia activation during sustained morphine treatment. By preventing glia activation, opioid and CB2 agonist co-treatment is expected to produce more efficient pain relief without adaptive pain sensitization during sustained treatment. Thus, with such drug combinations, we may be able to achieve longer- lasting pain relief with lower morphine doses, reducing the likelihood of dangerous side effects and opiate addiction in the treatment of chronic pain.