Tramadol - agmatine interaction and investigation of possible mechanisms in experimental acute pain model

A central analgesic agent tramadol has been declared to act by partially opiatergic, noradrenergic and serotonergic mechanisms. Although ongoing studies show that some other mechanisms may also involve in the effect of tramadol, but the precise mechanism has not been determined yet. On the other hand, agmatine, suggested as a new neurotransmitter in the brain has been showed that to elicit antiallodynic and antihyperalgesic effects in the neurophatic pain and to enhance morphine antinociception.The aim of the present study was to investigate the possible effects of agmatine and agmatine-tramadol combination on nociception by using the tail-flick method, an acute analgesic test in mice. We also evaluated the mechanism of the potentiating effect of agmatine on tramadol-induced antinociception by pretreatment with nitric oxide modulators such as L-arginine and L-NAME and NMDA receptor blocker MK-801.Male Balb/c mice were used in all experiments. The antinociceptive effect was determined in mice by using tail-flick test. Drugs were administered in 30 min interval. Tail-flick test was performed 30 min after the last drug injection. Tail-flick latencies (TFL) were record as second and the results were expressed as the mean ± SEM. One-way analysis of variance followed by a post-hoc Student Newman-Keuls test was used for the statistical analysis.Tramadol and agmatine significantly increased the TFL of mice when compared to the control group. Agmatine enhanced the antinociceptive effect of tramadol. L-arginine and L-NAME did not change the TFL of agmatine, but L-arginine decreased whereas L-NAME enhanced the antinociceptive effect of agmatine + tramadol combination. MK-801 pretreatment did not changed the TFL of agmatine, tramadol or agmatine-induced potentiation of the tramadol effect.Our results demonstrate that agmatine combination with tramadol produces an antinociceptive enhancement and this effect does not seem to be mediated via nitrergic system or NMDA receptors. Administration of agmatine-tramadol and/or agmatine-tramadol-L-NAME combinations may also provide an effective therapeutic strategy for future medical treatment of pain.