Cholecystokinin in the Rostral Ventromedial Medulla Mediates Opioid-Induced Hyperalgesia and Antinociceptive Tolerance

Abstract

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 opioidinduced 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 CCK 2 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 CCK 2 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 CCK 2 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.

Non-Nociceptive Environmental Stress Induces Hyperalgesia, Not Analgesia, in Pain and Opioid-Experienced Rats

“…This suggests that pronociceptive systems other than NMDA receptor systems are involved in the long-term expression of SIH. Anti-opioid peptides, such as dynorphin, cholecystokinin, and neuropeptide FF might be good candidates because they have been reported to be involved in opioidinduced hyperalgesia (Vanderah et al, 2000;Xie et al, 2005;Simonin et al, 2006). Studies are in progress to evaluate the role of such endogenous anti-opioid systems in the development of pain vulnerability observed in rats following pain and opioid experiences as reported in this study.…”

Activation of Spinal Cholecystokinin and Neurokinin-1 Receptors Is Associated With the Attenuation of Intrathecal Morphine Analgesia Following Electroacupuncture Stimulation in Rats

“…The RVM, which includes the nucleus raphe magnus and the medullary reticular formation, has been identified as a critical region with respect to nociceptive processing and control (31,32). Recently Xie et al (33) reported that CCK in the RVM engages in descending pain facilitatory pathways to enhance spinal nociceptive transmission and attenuate opioid antinociception. Thus, we cannot rule out the possibility that the descending projections from RVM to the spinal cord as well as the interneurons in the spinal dorsal horn might be the origin of CCK in the dorsal horn.…”

Pharmacodynamic and Pharmacokinetic Studies of Agmatine after Spinal Administration in the Mouse

“…The pharmacological parameters presented in Table 1 were calculated using the using the pharmacological statistics software FlashCalc version 4.3.2 (Dr. Michael Ossipov, University of Arizona, Tucson, AZ) (Wells et al, 2001;Xie et al, 2005), which is based on the methods described by Tallarida and Murray (1987) and Tallarida (2000). A minimum of three doses was used for each drug.…”