Adenosine kinase and adenosine deaminase inhibition modulate spinal adenosine- 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'-NH2dAdo), 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'-NH2dAdo 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, however, was significantly enhanced by either 5'-NH2dAdo or deoxycoformycin. These results confirm different physiologic roles for adenosine kinase and adenosine deaminase in spinal purinergic systems. 5'-NH2dAdo interactions with opioid receptor-selective agonists demonstrate significant, but heterogeneous interactions between endogenous adenosine and opioid spinal systems mediating antinociception.
Keil
G J
GJ
College of Pharmacy, Oregon State University, Corvallis 97331.
DeLander
G E
GE
D000241:Adenosine / Q000378:metabolism / Q000494:pharmacology; D000243:Adenosine Deaminase / Q000819:agonists*; D058892:Adenosine Deaminase Inhibitors; D000248:Adenosine Kinase / Q000037:antagonists & inhibitors*; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D007278:Injections, Spinal; D008297:Male; D051379:Mice; D010147:Pain Measurement / Q000187:drug effects; D015649:Pentostatin / Q000494:pharmacology; D011957:Receptors, Opioid / Q000819:agonists*; D013116:Spinal Cord / Q000201:enzymology / Q000378:metabolism*
D058892:Adenosine Deaminase Inhibitors; D000700:Analgesics; D011957:Receptors, Opioid; D015649:Pentostatin; D000248:Adenosine Kinase; D000243:Adenosine Deaminase; D000241:Adenosine