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

描述（由申请人提供）：长期药物治疗后的吗啡戒断揭示了对疼痛（痛觉过敏）和无害（异常性痛觉）刺激的矛盾增强敏感性。脊髓小胶质细胞的激活在疼痛敏感性的调节中起重要作用。有趣的是，最近发现cb2选择性大麻素激动剂有效地拮抗神经胶质活化。此外，我们的初步研究表明，吗啡与CB2激动剂的全身联合用药可以完全减轻吗啡戒断后大鼠的痛觉过敏和触觉异常痛。因此，我们打算探讨吗啡与cb2选择性激动剂的联合使用是否会减弱吗啡介导的神经胶质细胞的持续激活。该研究的具体目的是：1 .确定CB2激动剂介导的吗啡治疗大鼠戒断性痛觉过敏和异位性疼痛衰减的剂量-反应关系；2。确定吗啡和CB2激动剂持续全身联合给药对大鼠脊髓小胶质细胞和星形胶质细胞活性以及脊髓疼痛神经递质（CGRP）浓度的影响；ⅲ。开发和表征新生大鼠脊髓小胶质细胞培养，作为未来的体外细胞模型，用于详细研究CB2受体介导的小胶质细胞信号传导的分子机制。由于CB2受体在神经元中以低浓度存在，这些药物对中枢神经系统的副作用很小或没有。因此，阿片类药物和CB2激动剂的联合使用有望在使用较低吗啡剂量的情况下产生更持久的疼痛缓解，减少慢性疼痛治疗中危险副作用的可能性。

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.