Intrathecal 5-methoxy-N,N-dimethyltryptamine in mice modulates 5-HT1 and 5-HT3 receptors.

Intrathecal injection of 5-MeO-DMT, a serotonin receptor agonist, produces antinociceptive (pain-blocking) effects in mice across three behavioral tests: tail-flick, substance P, and NMDA assays. It prolonged tail-flick latency at doses of 4.6-92 nmol per mouse, an effect blocked by 5-HT3 and GABAA receptor antagonists but not by several other serotonin receptor blockers. 5-MeO-DMT inhibited biting behavior and increased scratching induced by substance P; the inhibition of biting was antagonized by 5-HT1B and GABAA antagonists, while enhanced scratching involved multiple serotonin and GABAA receptors. NMDA-induced biting was also inhibited by 5-MeO-DMT, blocked by 5-HT1B, 5-HT3, and GABAA antagonists. These findings suggest 5-MeO-DMT may promote serotonin release.

Study at a glance

Abstract

The antinociceptive effects of intrathecally administered 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), a potent 5-HT receptor agonist, were studied in three behavioral tests in mice: the tail-flick test and the intrathecal substance P and N-methyl-D-aspartic acid (NMDA) assays. Intrathecal administration of 5-MeO-DMT (4.6-92 nmol/mouse) produced a significant prolongation of the tail-flick latency. This action was blocked by 5-HT3 and gamma-aminobutyric acidA (GABAA) receptor antagonists but not by 5-HT2, 5-HT1A, 5-HT1B or 5-HT1S receptor antagonists. Binding studies indicated that 5-MeO-DMT had very low affinity for 5-HT3 receptors. 5-MeO-DMT inhibited biting behavior while increasing scratching behavior induced by intrathecally administered substance P. The inhibition of biting behavior was antagonized by intrathecal co-administration of 5-HT1B and GABAA receptor antagonists while 5-HT1A, 5-HT1S, 5-HT2 and 5-HT3 receptor antagonists had no effect. 5-MeO-DMT-enhanced scratching behavior was inhibited by all the antagonists used except ketanserin and bicuculline, suggesting the involvement of 5-HT1A, 5-HT1B, 5-HT1S, 5-HT3 and GABAA receptors. NMDA-induced biting behavior was inhibited by 5-MeO-DMT pretreatment; this action was antagonized by 5-HT1B, 5-HT3 and GABAA receptor antagonists. The involvement of these receptors in 5-MeO-DMT action suggests that it may promote release of 5-HT (5-hydroxytryptamine, serotonin).