Mechanisms underlying alterations in opioid sensitivity after neuropathy or persistent inflammation

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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.