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

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 γ-aminobutyric acid_A (GABA_A) receptor antagonists but not by 5-HT₂, 5-HT_1A, 5-HT_1B or 5-HT_1S 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-HT_1B and GABA_A receptor ntagonists while 5-HT_1A, 5-HT_1S, 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-HT_1A, 5-HT_1B, 5-HT_1S, 5-HT₃ and GABA_A receptors. NMDA-induced biting behavior was inhibited by 5-MeO-DMT pretreatment; this action was antagonized by 5-HT_1B, 5-HT₃ and GABA_A receptor antagonists. The involvement of these receptors in 5-MeO-DMT action suggests that it may promote release of 5-HT (5-hydroxytryptamine, serotonin).