Tramadol antinociception is potentiated by clonidine through α2-adrenergic and I2-imidazoline but not by endothelin ETA receptors in mice

Tramadol is a centrally acting analgesic that acts via μ-opioid agonism and by blocking the neuronal uptake of norepinephrine and serotonin. Clonidine potentiates the antinociceptive effects of tramadol; however the receptors involved in this potentiation have not been studied. Endothelin ETA receptor antagonists potentiate antinociceptive effects of morphine and oxycodone; however the effects of endothelin ETA receptor antagonists on tramadol antinociception have not been evaluated. This study was conducted to determine the effect of clonidine on tramadol antinociception; the role of opioid, α2-adrenergic and I2-imidazoline receptors in clonidine potentiation of tramadol antinociception; and the effect of endothelin ETA receptor antagonists in modulating tramadol antinociception. Antinociceptive (tail-flick and hot-plate) latencies were measured in male Swiss Webster mice treated with tramadol; clonidine plus tramadol; or antagonists plus tramadol. Mice were pretreated with naloxone (opioid antagonist), yohimbine (α2-adrenoceptor antagonist), idazoxan (α2-adrenoceptor/I2-imidazoline antagonist), BMS182874 or BQ123 (endothelin ETA receptor antagonists) to study the involvement of these receptors. Tramadol produced a dose dependent increase in antinociceptive latencies. Tramadol antinociception was partially blocked by naloxone but not by yohimbine or idazoxan. Clonidine potentiated tramadol antinociception; potentiation was blocked by naloxone, yohimbine and idazoxan. Idazoxan produced a more pronounced blockade of potentiation than yohimbine. BMS182874 or BQ123 had no effect on tramadol antinociception, indicating that endothelin ETA receptors are not involved in tramadol antinociception in mice. Results demonstrate the involvement of opioid but not α2-adrenergic/I2-imidazoline receptors in tramadol antinociception and that opioid, α2-adrenergic and I2-imidazoline receptors are involved in clonidine potentiation of tramadol antinociception.