ADENOSINE KINASE AND ADENOSINE-DEAMINASE INHIBITION MODULATE SPINAL ADENOSINE-INDUCED AND OPIOID AGONIST-INDUCED ANTINOCICEPTION IN MICE

Endogenous purinergic systems mediating antinociception, and their interactions with opioids, were characterized following intrathecal (i.t.) administration of inhibitors of adenosine clearance in mice. 5'-Amino,5'-deoxyadenosine (5'-NH(2)dAdo), an inhibitor of adenosine kinase, induced significant antinociception after i.t. injection and enhanced antinociception induced by selected opioids (i.t.). Isobolographic analysis of antinociception following coadministration (i.t.) of 5'-NH(2)dAdo with opioids revealed additive interactions with mu-, and synergistic interactions with delta-, opioid receptor-selective agonists. Inhibitors of adenosine deaminase, deoxycoformycin and erythro-9-(2-hydroxy-3nonyl) adenine (EHNA), generally failed to induce antinociception when administered (i.t.) alone or to enhance opioid (i.t.)-induced antinociception. Adenosine (i.t.)-induced antinociception, however, was significantly enhanced by either 5'-NH(2)dAdo or deoxycoformycin. These results confirm different physiologic roles for adenosine kinase and adenosine deaminase in spinal purinergic systems. 5'-NH(2)dAdo interactions with opioid receptor-selective agonists demonstrate significant, but heterogeneous interactions between endogenous adenosine and opioid spinal systems mediating antinociception.