Antinociception induced by intrathecal coadministration of selective adenosine receptor and selective opioid receptor...

Intrathecal administration of adenosine or adenosine analogs causes antinociception. In addition, opioid-induced antinociception is mediated, in part, by spinal adenosine release. Recent investigations from our laboratory suggest the significance of adenosine in opioid-mediated actions varies between different pharmacologic effects of opioid agonists and may vary after selective activation of different opioid receptor subtypes. A series of investigations using isobolographic analysis were designed to examine the functional significance of adenosine in antinociception induced by opioid receptor-selective agonists in the mouse tail-flick assay. Combinations of A1 or A2 adenosine receptor-selective agonists were coadminstered in a constant dose ratio with mu, delta or kappa opioid receptor-selective agonists. Additive interactions were observed for adenosine agonists coadministered with mu opioid receptor selective agonists. Synergism was generally observed after coadministration of adenosine receptor agonists with agonists selective for either delta-1 or delta-2 opioid receptors. A synergistic interaction was also observed after coadministration of an A1 adenosine receptor agonist with a kappa opioid receptor agonist. Observations reported with mu opioid receptor selective agonists are consistent with earlier reports demonstrating opiod-mediated adenosine release as one mechanism of opioid-induced antinociception. Results with combinations of adenosine agonists and delta or kappa opioid receptor agonists appear inconsistent with delta or kappa opioid receptor-mediated release of adenosine, and suggest a more complex functional interaction between adenosine and delta or kappa opioid spinal system.