Spinal and peripheral adenosine A1 receptors contribute to antinociception by tramadol in the formalin test in mice

Abstract

Tramadol, an analgesic used alone or combined with acetaminophen, has a complex mechanism of action involving opioid and amine mechanisms. In this study, we explored the involvement of spinal and peripheral adenosine A1 receptors in antinociception by tramadol, and determined whether spinal serotonin 5-HT7 receptors were linked to spinal A1 receptor actions. Antinociception was examined using the 2% formalin test in mice. Tramadol was administered systemically (intraperitoneal) or peripherally (intraplantar). Caffeine (non-selective A1/A2A receptor antagonist) and SCH58261 (selective A2A receptor antagonist) were given systemically, while DPCPX (selective A1 receptor antagonist) was given systemically, spinally (lumbar puncture), or peripherally. Systemic tramadol 35mg/kg produced antinociception against phase 2 formalin-evoked flinching behaviors, particularly in the earlier parts (phase 2A). Systemic caffeine (10mg/kg) and DPCPX (1mg/kg), but not SCH58261 (3mg/kg), inhibited antinociception by systemic tramadol. Spinal DPCPX 3μg also inhibited the action of systemic tramadol. Spinal SB269970 (selective 5-HT7 receptor antagonist) 3–10μg did not alter the effect of systemic tramadol. Intraplantar tramadol produced antinociception against flinching behaviors, and this action was reversed by intraplantar DPCPX 4.5μg administered on the ipsilateral, but not contralateral, side. Intraplantar DPCPX also reversed antinociception by systemic tramadol. These results indicate that adenosine A1 receptors contribute to antinociception by tramadol in the mouse formalin model, and that spinal and peripheral sites are involved in these actions. 5HT7 receptors in the spinal cord do not appear to be involved in the recruitment of A1 receptor mechanisms when tramadol is given systemically in this model.