Differential mediation of descending pain facilitation and inhibition by spinal 5HT-3 and 5HT-7 receptors

The rostroventromedial medulla (RVM) is an important source of descending modulatory systems that both inhibit and facilitate pain at the level of the spinal cord. Noxious stimuli can activate serotonergic neurons in the RVM and accelerate the turnover of 5-HT in the spinal cord. While numerous studies suggest a bidirectional role for serotonergic transmission at the spinal level, the subtypes of the 5-HT receptors that are associated with descending facilitation or inhibition have not been clearly determined. Here, we explore the relative contribution of spinal 5-HT7 and 5-HT3 receptors to antinociception or hyperalgesia associated with states of enhanced net descending inhibition or facilitation from the RVM. In uninjured rats, RVM microinjection of morphine produced dose-dependent antinociception in the noxious thermal paw flick test while RVM microinjection of CCK produced thermal hyperalgesia and tactile allodynia. Spinal administration of the 5-HT7 antagonist SB-269970, but not of the 5-HT3 antagonist ondansetron, blocked the antinociceptive effects of RVM morphine. In contrast, hyperalgesia induced by RVM-CCK was blocked by spinal ondansetron, but not by SB-269970. The antinociceptive effects of systemic morphine were also blocked by spinal SB-269970 but not ondansetron while hyperalgesia and allodynia resulting from SNL injury were blocked by spinal ondansetron, but not SB-269970. These studies suggest that descending pain inhibitory or facilitatory pathways from RVM act ultimately in the spinal cord in acute and chronic pain states through activation of 5-HT7 and 5-HT3 receptors, respectively.