Mechanisms underlying alterations in opioid sensitivity after neuropathy or persistent inflammation

在炎性疼痛动物模型中，吗啡等阿片类药物的镇痛效果较好，在外周神经损伤性疼痛动物中效果较差。先前的证据表明，阿片类药物在这些动物模型中的镇痛作用的改变可能取决于胆囊收缩素（CCK）水平的变化。CCK是脊髓神经元中的一种肽，具有抵消阿片类药物镇痛作用的作用。也有证据表明，炎症和周围神经损伤会导致脊髓背角神经营养因子或神经生长因子的改变。由于已知神经营养因子可以调节脊髓肽如CCK的水平，我们假设与炎症和神经损伤疼痛相关的阿片类镇痛的改变可能取决于神经营养因子诱导的脊髓CCK的改变。我们建议在外周性和中枢性炎症性疼痛和神经性疼痛的动物模型中研究CCK和神经营养因子在增强或减少阿片类镇痛中的作用。第一个目的将是检查在炎症大鼠中观察到的阿片镇痛增强是否通过脊髓给药各种神经营养因子抑制剂或神经营养因子受体而减弱。我们还将比较慢性脊髓给药神经营养素对抗神经性病变大鼠吗啡镇痛减少的能力。第二个目的是确定神经营养因子或神经营养因子抑制剂在naïve大鼠和炎症性疼痛或神经性疼痛的大鼠脊柱中是否会产生CCK水平的改变。第三个目的是研究中枢炎症和周围神经损伤是否会改变脊髓背角神经元细胞膜上的一种阿片受体（delta-opioid）的数量。我们认为，脊髓CCK水平及其对吗啡镇痛的影响在很大程度上受到神经营养因子的调节，delta-阿片受体向背角神经元膜或向背角神经元膜外的运动，在慢性疼痛模型中起着决定阿片镇痛敏感性的关键作用。

Opioid drugs like morphine are found to produce better pain relieving effects in animal models of inflammatory pain, and worse effects in animals with peripheral nerve injury pain. Previous evidence suggests that alterations in pain relieving or analgesic effects of opioids in these animal models may depend on changes in the levels of cholecystokinin (CCK). CCK is a peptide in spinal cord neurons that has effects that counteract the analgesic effects of opioids. There is also evidence that inflammation and peripheral nerve injury produce alterations in neurotrophins, or nerve growth factors, in the spinal cord dorsal horn. Since neurotrophins are known to regulate the levels of spinal peptides such as CCK, we hypothesize that alterations in opioid analgesia associated with inflammatory and nerve injury pain may depend on neurotrophin-induced alterations in spinal CCK. We propose to examine the roles of CCK and neurotrophins in the enhanced or reduced opioid analgesia in animal models of peripheral and central inflammatory pain and neuropathic pain. The first objective will be to examine whether the enhanced opioid analgesia observed in rats with inflammation is attenuated by spinal administration of inhibitors of various neurotrophins or receptors for neurotrophins. We will also compare the ability of chronic spinal administration of neurotrophins to counter decreased morphine analgesia in neuropathic rats. The second objective is to determine whether spinal administration of neurotrophins or neurotrophin inhibitors produce alterations in the spinal levels of CCK in both naïve rats and rats with inflammatory pain, or neuropathic pain. The third objective is to examine whether central inflammation and peripheral nerve injury produce alterations in the numbers of a type of opioid receptor (delta-opioid) that are on the cell membrane of neurons in spinal cord dorsal horn. We suggest that the levels of spinal CCK, and their influence on morphine analgesia, are regulated to an important extent by neurotrophins, and that movement of delta-opioid receptors, either to or away from the membrane of dorsal horn neurons, plays a critical role determining opioid analgesic sensitivity in chronic pain models.