Spinal 5-HT₃ receptor-mediated antinociception: Possible release of GABA

Although 5-HT is clearly involved in spinal analgesia, its mode of action remains obscure, perhaps because it has multiple and often opposing effects mediated by its multiple receptor subtypes. This investigation uses selective agonists and antagonists directed at the most recently defined class of 5-HT receptors (5-HT₃ receptors) in behavioral and electrophysiological studies of nociception in the spinal cord of rodents. The results demonstrate uniformly inhibitory effects of a selective 5-HT₃ agonist on responses to noxious stimuli. Intrathecally administered 2-methyl 5-HT produced dose-dependent antinociception in the tail-flick test and inhibited behaviors elicited by intrathecally administered agonists for excitatory amino acid and neurokinin receptors, namely NMDA and substance P (SP). All 20 dorsal horn neurons we examined, which projected to the brain and responded to both noxious stimuli and NMDA, were inhibited in a current-related manner by this 5-HT₃ agonist applied iontophoretically. Both the behavioral and electrophysiological effects were blocked not only by the 5-HT₃ antagonists zacopride and ICS 205-930, but also by antagonists to the inhibitory amino acid GABA. Therefore, 5-HT via an action at 5-HT₃ receptors may evoke release of GABA, which may in turn inhibit nociceptive transmission at a site postsynaptic to terminals of primary afferent fibers. If the descending serotonergic analgesic system in humans operates similarly, understanding it may enable the development of new nonopioid, nonaddictive analgesics.