Involvement of serotonin in nociceptive pathways

New approaches in the design of analgesics emerged from the discovery that serotonin (5HT) is involved in the descending system (brain to spinal cord) that inhibits signals from peripheral nociceptors. However, the simple hypothesis that 5HT is a transmitter in this system requires elaboration, since not all agonists of 5HT are analgesics. In this commentary, the following questions are discussed: (a) do 5HT systems influence all responses to all types of noxious stimuli?, (b) is a 5HT synapse a necessary link in the analgesic system, (c) what is the location of the relevant 5HT receptor?, and (d) what is the relevant 5HT receptor subtype? The need for more adequate definition of the relevant 5HT receptor is stressed. Once this is achieved, a more rational approach to analgesic drug discovery will be provided by the design of selective agonists of this receptor.