Mechanisms underlying alterations in opioid sensitivity after neuropathy or persistent inflammation

研究发现，吗啡等阿片类药物在炎症性疼痛的动物模型中具有较好的止痛效果，而在周围神经损伤疼痛的动物模型中效果较差。先前的证据表明，在这些动物模型中，阿片类药物的止痛或镇痛效果的变化可能取决于CCK水平的变化。CCK是脊髓神经元中的一种多肽，具有抵消阿片类药物止痛作用的作用。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变化。由于已知神经营养因子调节脊髓多肽水平，如CCK，我们推测与炎性和神经损伤痛相关的阿片类镇痛的变化可能依赖于神经营养因子诱导的脊髓CCK的变化。我们建议在外周和中枢炎性疼痛和神经病理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药物镇痛中的作用。第一个目标是检查在炎症大鼠身上观察到的增强阿片类止痛是否通过脊髓给予各种神经营养因子的抑制剂或神经营养因子受体的抑制剂来减弱。我们还将比较神经病变大鼠长期脊髓注射神经营养素对抗吗啡镇痛减弱的能力。第二个目标是确定脊髓注射神经营养因子或神经营养因子抑制剂是否会改变幼稚大鼠和有炎症性疼痛或神经病理性疼痛的大鼠的脊髓CCK水平。第三个目的是检测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(β-阿片受体)的数量。我们认为，脊髓CCK的水平及其对吗啡镇痛的影响在很大程度上受神经营养因子的调节，并且在慢性疼痛模型中，阿片受体的运动在决定阿片类药物的敏感性方面起着关键作用。

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.