Contribution of spinal glutamatergic receptors to the antinociception caused by agmatine in mice

This study was designed to evaluate the role of spinal glutamatergic receptors in the antinociception elicited by agmatine in mice. Intraperitoneal (i.p.) administration of agmatine (1.0–100.0 mg/kg) dose dependently inhibited the nociceptive response induced by intrathecal (i.t.) injection of glutamate, N-methy-d-aspartate (NMDA) and (±)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (trans-ACPD), with mean ID50 values of 16.7, 6.8 and 27.0 mg/kg, respectively. However, agmatine completely failed to affect the nociception induced by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) or kainic acid (kainate). Agmatine injected by i.t. route (10–100 μg/site) also produced dose-related inhibition of NMDA- and trans-ACPD-induced biting response with mean ID50 values of 29.6 and 36.0 μg/site, respectively. The nitric oxide synthase inhibitor Nω-nitro-l-arginine (l-NOARG) (75.0 mg/kg, i.p.) also consistently inhibited glutamate-, NMDA- and trans-ACPD-induced nociception (41 ± 13, 100 and 83 ± 6%, of inhibition, respectively) but had no effect on the same response caused by AMPA and kainate agonists. The selective NMDA receptor antagonist (5S,10R)-(+)-5-Methyl-10,11-dihydro-5H-dibenzo[a,d] (MK-801) at a low dose (0.05 mg/kg, i.p.) inhibited the nociceptive response caused by both glutamate and NMDA agonists (inhibitions of 35 ± 1 and 72 ± 2%, respectively). At a high dose, MK-801 (0.5 mg/kg, i.p.) significantly inhibited the biting response induced by i.t. administration of all the glutamatergic agonists tested: glutamate, AMPA, NMDA, kainate and trans-ACPD, with inhibitions of 49 ± 8, 84 ± 16, 84 ± 3, 76 ± 8 and 97 ± 2%, respectively. Together, these results provide experimental evidence indicating that agmatine given systemically and spinally produce marked antinociception at spinal sites in mice. Furthermore, an interaction with glutamate receptors, namely NMDA and trans-ACPD, metabotropic and NMDA-ionotropic origin, by a mechanism similar to that of nitric oxide (NO) inhibitors, seems to account for the agmatine antinociceptive action.