title: Neural basis for the hyperalgesic action of cholecystokinin in the rostral ventromedial medulla.
abstract: The analgesic actions of opioids can be modified by endogenous "anti-opioid" peptides, among them cholecystokinin (CCK). CCK is now thought to have a broader, pronociceptive role, and contributes to hyperalgesia in inflammatory and neuropathic pain states. The aim of this study was to determine whether anti-opioid and pronociceptive actions of CCK have a common underlying mechanism. We showed previously that a low dose of CCK microinjected into the rostral ventromedial medulla (RVM) blocked the analgesic effect of systemically administered morphine by preventing activation of off-cells, which are the antinociceptive output of this well characterized pain-modulating region. At this anti-opioid dose, CCK had no effect on the spontaneous activity of these neurons or on the activity of on-cells (hypothesized to facilitate nociception) or "neutral cells" (which have no known role in pain modulation). In this study, we used microinjection of a higher dose of CCK into the RVM to test whether activation of on-cells could explain the pronociceptive action of this peptide. Paw withdrawal latencies to noxious heat and the activity of a characterized RVM neuron were recorded in rats lightly anesthetized with methohexital. CCK (30 ng/200 nl) activated on-cells selectively and produced behavioral hyperalgesia. Firing of off-cells and neutral cells was unaffected. These data show that direct, selective activation of RVM on-cells by CCK is sufficient to produce thermal hyperalgesia and indicate that the anti-opioid and pronociceptive effects of this peptide are mediated by actions on different RVM cell classes.
authors.affiliation: Dept. Neurological Surgery, L-472, Oregon Health and Science Univ., Portland, OR 97239, USA. heinricm@ohsu.edu
authors.forename: Mary M
authors.initials: MM
authors.lastname: Heinricher
authors.forename: Miranda J
authors.initials: MJ
authors.lastname: Neubert
mesh_terms: D000758:Anesthesia; D000818:Animals; D002766:Cholecystokinin / Q000008:administration & dosage / Q000494:pharmacology*; D004558:Electric Stimulation; D006358:Hot Temperature; D006930:Hyperalgesia / Q000139:chemically induced* / Q000503:physiopathology*; D007267:Injections; D008297:Male; D008526:Medulla Oblongata / Q000502:physiology*; D008845:Microinjections; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D010147:Pain Measurement / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D002766:Cholecystokinin