Subsensitivity of serotonin and substance P receptors involved in nociception after repeated administration of a serotonin receptor agonist.

The antinociceptive effects of subcutaneous 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) and 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and the responses to intrathecal (i.th.) serotonin (5-HT) and substance P (SP) were examined in mice after repeated administration of 5-MeODMT (3 mg/kg every 30 min for 4 hours). Ninety min after the last injection of 5-MeODMT the basal tail-flick and hot-plate response latencies were unaltered, but the antinociceptive effects of 5-MeODMT (3 mg/kg) in the tail-flick and hot-plate tests and the antinociceptive effect of 8-OH-DPAT (0.5 mg/kg) in the hot-plate test were markedly reduced. The behavioral responses to i.th. 5-HT (4.0 micrograms) and SP (2.5, 5, and 10 ng) which include vigorous biting, licking and scratching of the caudal part of the body, were attenuated 90-120 min after withdrawal of 5-MeODMT treatment. It is suggested that repeated administration of 5-MeODMT downregulates the function of the 5-HT receptors mediating the antinociceptive effects of 5-MeODMT and 8-OH-DPAT. The rapid desensitization to the behavioral responses both to 5-HT and SP by 5-MeODMT pretreatment may reflect a functional interaction between 5-HT and SP in the spinal modulation of nociception.