Mechanisms of endogenous cannabinoid mediated analgesia within the midbrain

虽然吗啡等阿片类止痛剂是治疗中重度疼痛最重要的药物，但其有效性受到耐受性和呼吸抑制等副作用的限制。此外，临床相关的神经病理性慢性疼痛综合征(由神经系统损害引起)对阿片类药物相对耐药。动物研究表明，植物大麻的活性成分THC和一些合成大麻素在急性疼痛模型中具有止痛作用，有趣的是，在慢性神经病理性疼痛模型中也具有止痛作用。不幸的是，大麻素也会产生一系列不良副作用。服用THC等大麻素通过激活称为大麻素受体的细胞表面蛋白来模拟人体自身的大麻素(内源性大麻素)的活动，从而产生生理效应。内源性大麻素神经递质系统正在成为潜在的治疗靶点。例如，最近的研究表明，生理应激源诱导的镇痛作用部分是由大脑中的内源性大麻素介导的。此外，新的内源性大麻素分解抑制剂在焦虑和慢性疼痛的动物模型中也有一定的疗效。已知有几个大脑区域在外源性和内源性大麻素的止痛作用中发挥关键作用。在以前的研究中，我已经确定了外源性应用阿片类药物和大麻类药物在单个脑细胞中产生止痛作用的细胞机制。然而，内源性大麻素在这些脑区的作用机制尚不清楚。这项拟议的研究将确定内源性释放的大麻素在正常动物和慢性疼痛状态下的细胞作用。平行研究将检验内源性大麻素系统在疼痛动物模型中的调节作用。这些技术有可能发现新的内源性大麻素止痛药物疗法，以提高疗效和减少副作用。

While opioid analgesics such as morphine are the most important drugs used to treat moderate to severe pain, their usefulness is limited by side effects such as tolerance and respiratory depression. In addition, clinically relevant neuropathic chronic pain syndromes (caused by nervous system damage) are relatively resistant to opioids. Animal studies have shown that the active ingredient of the plant Cannabis sativa, THC, and a number of synthetic cannabinoids are analgesic in acute pain models, and interestingly, in chronic neuropathic pain models. Unfortunately, cannabinoid also produce a spectrum of adverse side-effects. Administered cannabinoids such as THC produce their physiological effects by mimicking the actions of the body's own cannabinoids (endocannabinoids) by activating cell-surface proteins, called cannabinoid receptors. The endocannabinoid neurotransmitter system is emerging as a potential therapeutic target. For example, it has recently been shown that analgesia induced by physiological stressors is partly mediated by endocannabinoids within the brain. In addition, novel endocannabinoid breakdown inhibitors have some efficacy in animal models of anxiety and chronic pain. Several brain regions are known to play a pivotal role in the analgesic actions of exogenous and endogenous cannabinoids. In previous studies I have identified the cellular mechanisms by which exogenously applied opioids and cannabinoids produce their analgesic effects in single brain cells. However, the mechanisms of endocannabinoid actions within these brain regions are unknown. The proposed study will determine the cellular actions of endogenously released cannabinoids in normal animals and in chronic pain states. Parallel studies will examine the effect of modulation of the endocannabinoid system in animal models of pain. These techniques have the potential to identify novel endocannabinoid analgesic pharmacotherapies with enhanced efficacy and reduced side effects.