Spinal antinociception evoked by the triterpene 3β, 6β, 16β-trihydroxylup-20(29)-ene in mice: Evidence for the involvement of the glutamatergic system via NMDA and metabotropic glutamate receptors

The present study investigated the possible involvement of the glutamatergic and neurokinin systems in the antinociception caused by triterpene 3β, 6β, 16β-trihydroxylup-20(29)-ene (TTHL) in mice. TTHL given by intraperitoneal (i.p., 2.1–65.5 µmol/kg), intraplantar (i.pl., 6.5–65.5 nmol/paw) or intrathecal (i.t., 21.8–655 nmol/site) routes, produced dose-dependent inhibition of glutamate-induced nociception with ID50 values of 12 µmol/kg; 34.2 nmol/paw; 233.8 nmol/site and inhibitions of 78 ± 6; 82 ± 4 and 77 ± 8%, respectively. I.t. injection of TTHL (6.5–218 nmol/site, co-administered) also caused significant and dose-dependent reduction of nociceptive response induced by i.t. injection of glutamate (175 nmol/site), with ID50 value of 54.5 nmol/site and inhibition of 51 ± 6%. Moreover, TTHL (65.5 nmol/site) co-injected by i.t. route with agonist caused marked reduction of nociceptive responses induced by N-methyl-d-aspartate (NMDA, 450 pmol/site), (±)-1-aminocyclopentane-trans-1,3 dicarboxylic acid (trans-ACPD, 10 nmol/site) and substance P (100 pmol/site), with inhibitions of 81 ± 7; 79 ± 7; 81 ± 11%, respectively. Conversely, TTHL had no effect on α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA, 135 pmol/site) and kainic acid (kainate, 110 pmol/site)-induced nociception. Moreover, the association of sub-effective doses of TTHL (6.5 nmol/site, i.t.) and MK-801(1 nmol/site, i.t.; non-competitive NMDA antagonist) or (RS)-MCPG (30 nmol/site, i.t.; non-selective group I/group II metabotropic glutamate receptor antagonist) produced a synergic antinociceptive effect in the nociception induced by NMDA or trans-ACPD, respectively. Together, these results provide experimental evidence for the involvement of the glutamatergic system (NMDA and metabotropic glutamate receptors) in the antinociceptive action caused by TTHL in mice.