Mechanisms underlying alterations in opioid sensitivity after neuropathy or persistent inflammation

阿片类药物如吗啡在炎症性疼痛的动物模型中产生更好的疼痛缓解效果，而在周围神经损伤疼痛的动物中产生更差的效果。先前的证据表明，阿片类药物在这些动物模型中的疼痛缓解或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引起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调节脊髓肽（如CCK）的水平，因此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。我们建议检查CCK和神经营养因子的作用，在增强或减少阿片类镇痛在外周和中枢炎症性疼痛和神经病理性疼痛的动物模型。第一个目的是检查是否增强阿片类镇痛观察到的大鼠炎症是衰减脊髓给药的各种神经营养因子或神经营养因子受体的抑制剂。我们还将比较神经营养因子的慢性脊髓给药对抗神经病大鼠吗啡镇痛减少的能力。第二个目的是确定脊髓给药神经营养因子或神经营养因子抑制剂是否会改变未处理大鼠和炎症性疼痛或神经性疼痛大鼠脊髓CCK水平。第三个目的是检查中枢炎症和周围神经损伤是否会导致脊髓背角神经元细胞膜上的一种阿片受体（δ-阿片受体）数量的改变。我们认为，脊髓CCK的水平，以及它们对吗啡镇痛的影响，调节到一个重要的程度由神经营养因子，和δ-阿片受体的运动，无论是或远离背角神经元的膜，起着决定阿片类镇痛药的敏感性在慢性疼痛模型中的关键作用。

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.