The role of the periaqueductal gray-rostral ventromedial medulla (RVM) system in descending inhibition of nociception has been studied for over 30 years. The neural basis for this antinociceptive action is reasonably well understood, with strong evidence that activation of a class of RVM neurons termed 'off-cells' exerts a net inhibitory effect on nociception. However, it has recently become clear that this system can facilitate, as well as inhibit pain. Although the mechanisms underlying the facilitation of nociception have not been conclusively identified, indirect evidence points to activation of a class of neurons termed 'on-cells' as mediating descending facilitation. Here we used focal infusion of the tridecapeptide neurotensin within the RVM in lightly anesthetized rats to activate on-cells selectively. Neurotensin has been shown in awake animals to produce a dose-related, bi-directional effect on nociception when applied within the RVM, with hyperalgesia at low doses, and analgesia at higher doses. Using a combination of single cell recording and behavioral testing, we now show that on-cells are activated selectively by low-dose neurotensin, and that the activation of on-cells by neurotensin results in enhanced nociceptive responding, as measured by the paw withdrawal reflex. Furthermore, higher neurotensin doses recruit off-cells in addition to on-cells, producing behavioral antinociception. Selective activation of on-cells is thus sufficient to produce hyperalgesia, confirming the role of these neurons in facilitating nociception. Activation of on-cells likely contributes to enhanced sensitivity to noxious stimulation or reduced sensitivity to analgesic drugs in a variety of conditions.

Heinricher, Mary M. and Miranda J. Neubert. Neural basis for the hyperalgesic action of cholecystokinin in the rostral ventromedial medulla. J Neurophysiol 92: 1982, 2004. First published May 19, 2004 10.1152/jn.00411.2004. 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 antiopioid 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.