Adenosine and pain: Recent findings with directly and indirectly acting agents

The peripheral administration of adenosine agonists can produce pain inhibi tory effects due to adenosine A(1) receptor activation, and pain facilitato ry effects due to adenosine A(2) and A(3) receptor activation. Pain facilit atory effects for A(2)-like receptors result from interactions with endogen ous mediators like 5-hydroxytryptamine. Both pain facilitation and edema re sulting from local administration of A(3) agonists results from release of histamine and 5-hydroxytryptamine from mast cells. Local administration of adenosine kinase, but not adenosine deaminase inhibitors, produces a local antinociception, but no pronociception occurs at higher doses due to system ic (probably spinal) pain-suppressing mechanisms being recruited. In the sp inal cord, adenosine A(1) receptors produce antinociception. Inhibition of adenosine kinase, but not adenosine deaminase, also produces antinociceptio n, and exhibits a greater separation from motor effects. Adenosine A(1) rec eptor agonists, as well as inhibitors of adenosine kinase, exhibit the pote ntial for development as analgesic agents, both as local formulations, as w ell as systemically active agents. In both instances, a sufficient separati on from adverse effects will be required. Drug Dev. Res. 45:3 04-311, 1998. (C) 1998 Wiley-Liss, Inc.