Opioid-induced
hyperalgesia is characterized by
hypersensitivity to innocuous or noxious stimuli during sustained
opiate administration. Microinjection of
lidocaine into the rostral ventromedial medulla (RVM), or dorsolateral funiculus (DLF) lesion, abolishes
opioid-induced
hyperalgesia, suggesting the importance of descending
pain facilitation mechanisms. Here, we investigate the possibility that
cholecystokinin (CCK), a pronociceptive
peptide, may drive such descending facilitation from the RVM during continuous
opioid administration. In
opioid-naive rats, CCK in the RVM produced acute tactile and thermal
hypersensitivity that was antagonized by the
CCK2 receptor antagonist L365,260 or by DLF lesion. CCK in the RVM also acutely displaced the spinal
morphine antinociceptive dose-response curve to the right. Continuous systemic
morphine elicited sustained tactile and thermal
hypersensitivity within 3 d. Such
hypersensitivity was reversed in a time-dependent manner by L365,260 in the RVM, and blockade of CCK2 receptors in the RVM also blocked the rightward displacement of the spinal
morphine antinociceptive dose-response curve. Microdialysis studies in rats receiving continuous
morphine showed an approximately fivefold increase in the basal levels of CCK in the RVM when compared with controls. These data suggest that activation of CCK2 receptors in the RVM promotes mechanical and thermal
hypersensitivity and antinociceptive tolerance to
morphine. Enhanced, endogenous CCK activity in the RVM during sustained
morphine exposure may diminish spinal
morphine antinociceptive potency by activating descending
pain facilitatory mechanisms to exacerbate spinal nociceptive sensitivity. Prevention of
opioid-dose escalation in
chronic pain states by
CCK receptor antagonism represents a potentially important strategy to limit unintended enhanced clinical
pain and
analgesic tolerance