Antinociceptive and anti-inflammatory properties of an adenosine kinase inhibitor and an adenosine deaminase inhibitor

Spinal administration of an adenosine kinase inhibitor, alone or in combina tion with an adenosine deaminase inhibitor, produces antinociception in inf lammatory pain tests. In the present study, we examined the antinociceptive and anti-inflammatory effects produced by the peripheral (intraplantar) ad ministration of 5'-amino-5'-deoxyadenosine (an adenosine kinase inhibitor), 2'- deoxycoformycin (an adenosine deaminase inhibitor), and combinations o f both agents in the carrageenan-induced thermal hyperalgesia and paw oedem a model in the rat. When injected in the ipsilateral paw immediately prior to carrageenan injection, both agents produced antinociception only at the highest dose (1 mu mol), whereas a reduction in paw swelling was evident at a lower dose (300 nmol). Significant augmentation in both the antinocicept ive and anti-inflammatory effects was seen when 5'-amino-5'-deoxyadenosine and 2'-deoxycoformycin were co-administered in equimolar doses at all dose levels. Both effects were mediated via activation of adenosine receptors, a s indicated by blockade by an adenosine receptor antagonist. When administe red into the contralateral paw, 1 mu mol 5'-amino-5'-deoxyadenosine + 1 mu mol 2'-deoxycoformycin produced prominent antinociception, indicating a sys temic drug activity. There was only a modest reduction in paw oedema in the carrageenan-injected (ipsilateral) paw, suggesting that much of this activ ity was locally mediated. Reversal of systemic effects on thermal threshold s by an intrathecal adenosine receptor antagonist implicates a spinal site of action in this instance. An ipsilateral administration of 1 mu mol 5'-am ino-5'-deoxyadenosine, but not 1 mu mol 2'-deoxycoformycin, reduced carrage enan-induced c-Fos expression in the spinal dorsal horn, and this was furth er reduced by the peripheral co-injection of the two agents. These results provide evidence for a predominantly spinal antinociceptive effect and a pr edominantly peripheral anti-inflammatory effect produced by inhibitors of a denosine kinase and adenosine deaminase. (C) 1999 Elsevier Science B.V. All rights reserved.