Cellular actions of cannabinoids within the spinal cord dorsal horn in a neuropathic pain state

吗啡和其他阿片类药物是用于治疗中度至重度疼痛的最重要药物之一。然而，一些临床上重要的慢性疼痛状态对阿片类药物治疗相对不敏感，例如由神经系统损伤引起的神经性疼痛。人类和动物研究表明，植物大麻的活性成分THC和一些合成大麻类药物（大麻素）也具有镇痛或缓解疼痛的特性。动物研究表明，大麻素增强阿片类药物的镇痛作用。特别令人感兴趣的是发现大麻素减少与神经性疼痛的动物模型相关的异常疼痛症状，例如由神经损伤引起的疼痛。几个大脑区域在阿片类药物和大麻素的镇痛作用中起着关键作用。在以前的研究中，我已经确定了阿片类药物和大麻素在大脑内的单细胞中产生镇痛作用的细胞机制。此外，脊髓是疼痛刺激进入中枢神经系统的初始中继点，并且是阿片类和大麻素镇痛作用的主要部位。然而，脊髓内大麻素和阿片类药物作用的细胞机制，特别是在将上行疼痛信息传递到大脑的途径中，还不太清楚。此外，大麻素和阿片类药物在神经性疼痛状态下的细胞作用尚不清楚。拟议的研究将确定大麻素和阿片类药物在单个神经元中镇痛作用的细胞机制，这些神经元被确定为属于正常和神经损伤动物脊髓内的疼痛通路。这些技术有可能确定大麻素，阿片类药物和其他药物之间的镇痛组合，具有增强的治疗活性和减少的副作用。

Morphine and other opioids are among the most important drugs used to treat moderate to severe pain. However, some clinically important chronic pain states are relatively insensitive to opioid treatment, such as neuropathic pain which is caused by injury to the nervous system. Human and animal studies indicate that the active ingredient of the plant cannabis sativa, THC, and a number of synthetic cannabis-like drugs (cannabinoids) also have analgesic, or pain relieving properties. Animal studies have shown that cannabinoids potentiate the analgesic effects of opioids. Of particular interest is the finding that cannabinoids reduce the abnormal pain symptoms associated with animal models of neuropathic pain, such as that caused by nerve injury. Several brain regions play a pivotal role in the analgesic actions of both opioids and cannabinoids. In previous studies I have identified the cellular mechanisms by which opioids and cannabinoids produce their analgesic effects in single cells within the brain. In addition, the spinal cord is the initial relay point of painful stimuli entering the central nervous system and is a major site of opioids and cannabinoid analgesic actions. However, the cellular mechanisms underlying cannabinoid and opioid actions within the spinal cord, particularly in pathways which transmit ascending pain information to the brain, are less well understood. In addition, the cellular actions of cannabinoids and opioids in neuropathic pain states are unknown. The proposed study will determine the cellular mechanisms underlying the analgesic actions of cannabinoids and opioids in single neurons identified as belonging to pain pathways within the spinal cord in normal and nerve injured animals. These techniques have the potential to identify analgesic combinations between cannabinoids, opioids and other agents with enhanced therapeutic activity and reduced side effects.