ANTINOCICEPTION INDUCED BY INTRATHECAL COADMINISTRATION OF SELECTIVE ADENOSINE RECEPTOR AND SELECTIVE OPIOID RECEPTOR AGONISTS IN MICE

Intrathecal administration of adenosine or adenosine analogs causes an tinociception. 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 a ctions varies between different pharmacologic effects of opioid agonis ts and may vary after selective activation of different opioid recepto r subtypes. A series of investigations using isobolographic analysis w ere designed to examine the functional significance of adenosine in an tinociception induced by opioid receptor-selective agonists in the mou se tail-flick assay. Combinations of A(1) or A(2) adenosine receptor-s elective agonists were coadministered in a constant dose ratio with mu , delta or kappa opioid receptor-selective agonists. Additive interact ions were observed for adenosine agonists coad-ministered with mu opio id receptor selective agonists. Synergism was generally observed after coadministration of adenosine receptor agonists with agonists selecti ve for either delta-1 or delta-2 opioid receptors. A synergistic inter action was also observed after coadministration of an A(1) adenosine r eceptor agonist with a kappa opioid receptor agonist. Observations rep orted with mu opioid receptor selective agonists are consistent with e arlier reports demonstrating opioid-mediated adenosine release as one mechanism of opioid-induced antinociception. Results with combinations of adenosine agonists and delta or kappa opioid receptor agonists app ear inconsistent with delta or kappa opioid receptor-mediated release of adenosine, and suggest a more complex functional interaction betwee n adenosine and delta or kappa opioid spinal systems.