The overall effect on spinal neuronal activity is dependent on the interplay between excitatory and inhibitory mechanisms; thus, our data suggest that the overriding effects of ketanserin and ritanserin were
likely to be mediated through antagonism of the actions of 5-HT acting at 5-HT2A receptors leading to the reduction in neuronal responses observed in this study. The consequence of 5-HT2C receptor blockade, at these doses, on the evoked spinal neuronal responses is minimal by comparison, if 5-HT2C receptors do indeed have an antinociceptive role. Similarly, activation of 5-HT2A/2C receptors with DOI increased neuronal responses, click here an effect reversed by ketanserin, thus implicating a predominant 5-HT2A action. An alternative possibility, however, is that 5-HT2C receptors could also have pronociceptive effect on spinal nociceptive transmission. The primary source LDE225 research buy of descending serotonergic modulation of ascending nociceptive transmission from the spinal cord arises from the RVM (Millan, 2002). These serotonergic neurones can exert facilitatory or inhibitory influences onto dorsal horn neurones depending on the spinal 5-HT receptor subtype activated and the neuronal cell type within the RVM (Millan, 2002). Neurones within the RVM are classified into three types based upon their firing patterns in response to noxious thermal stimuli. ON-cells increase their firing immediately before a nocifensive
response and facilitate
nociception, while OFF-cells, considered to mediate inhibition, pause in their firing just prior to a nociceptive withdrawal reflex. Neutral cells do not appear to play a role in physiological pain (Heinricher et al., 2009). Descending facilitation requires the activation of pronociceptive ON cells (Porreca et al., 2001); however, the pharmacology of descending facilitatory pathways remains unclear, as recordings from RVM neurones suggests that 5-HT containing neurones Montelukast Sodium are neither ON nor OFF cells (Gao and Mason, 2000). However, converging evidence from recent immunohistochemical, behavioural and electrophyisological data suggests that a proportion of RVM cells activated by noxious stimuli are serotonergic. Furthermore, a facilitatory effect mediated by 5-HT, acting at spinal 5-HT3 receptors, was demonstrated in models of acute and chronic pain (Oatway et al., 2004, Rahman et al., 2004, Rahman et al., 2006, Suzuki et al., 2002, Suzuki et al., 2005 and Svensson et al., 2006). These studies focused on the pronociceptive 5-HT3 receptor, the only ligand gated cation channel of the 5-HT receptor family, and its role in mediating descending facilitation. The electrophysiological consequences of selectively blocking spinal 5-HT2A receptors on dorsal horn neuronal activity are similar to the effects we have previously seen with the selective 5-HT3R antagonist ondansetron (Suzuki et al., 2002).