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* To whom correspondence should be addressed. E-mail: heinricm{at}ohsu.edu.
The analgesic actions of opioids can be modified by endogenous "anti-opioid" peptides, among them cholecystokinin (CCK). CCK is also now thought to have a broader, pro-nociceptive, role, and contributes to hyperalgesia in inflammatory and neuropathic pain states. The aim of the present experiments was to determine whether anti-opioid and pro-nociceptive 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 the present study, we used microinjection of a higher dose of CCK into the RVM to test whether activation of on-cells could explain the pro-nociceptive 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 pro-nociceptive effects of this peptide are mediated by actions on different RVM cell classes.
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