Ëvaluation of opioid and dopaminergic mechanisms of dextromethorphan on the nociceptive response-induced by hot plate in mice

Background and Dextromethorphan is a non-competitive NMD receptor antagonist in the glutamatergic system with over 47 years of clinical usage experience as an over-the counter antitussive drug. We previously demonstrated that dextromethorphan modulates the pain threshold in the mouse acetic acid (0.6%,intraperitonealy)-induced writhing test (a tonic and chemical model for chronic pain) and naloxone-induced withdrawal signs in morphine-dependent mice. Because opioid and dopaminergic mechanisms of dextromethorphan have not been evaluated in the acute and phasic pain models, the effect of dextromethorphan on the pain response-induced by hot plate (a phasic and thermal model for acute pain) was investigated in mice. The effects of dextromethorphan and other drugs on pain thershold were investigated using a hot plate apparatus (Harvard, ÜK). The hot plate temperature set thermostatically at 52.5 ± 0.5 ºÇ. The latency to licking or kicking of the fore or hind paws was recorded at various times after drug injection.  cut-off time of 45 s was imposed to avoid tissue damage. The integrity of motor coordination was assessed with a rota rod apparatus (Harvard, ÜK). Dextromethorphan (30 mg/kg, i.p.) increased the pain threshold in the mouse hot plate test. This dose of dextromethorphan was ineffective in the rota rod test, thus it could be considered as a real antinociceptive effect. Dextromethorphan also potentiated the antinociceptive effect of morphine. The antinociceptive effect of dextromethorphan and the potentiation of morphine antinociception, were antagonized by the opioid receptor antagonist, naloxone. The antinociceptive effect of dextromethorphan was also antagonized by dopamine mixed D1/D2 receptor agonist, apomorphine. The inhibitory effect of apomorphine on antinociceptive response of dextromethorphan was blocked by the dopamine D1 receptor antagonist, SÇH 23390, but not by the dopamine D2 receptor antagonist, sulpiride nor by the peripheral dopamine receptor antagonist, domperidone. Çonclusion: These results suggest that, opioid and central dopamine D1 receptor mechanisms may in part modulate dextromethorphan antinociception in the mouse hot plate test.