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

The peripheral administration of adenosine agonists can produce pain inhibitory effects due to adenosine A₁ receptor activation, and pain facilitatory effects due to adenosine A₂ and A₃ receptor activation. Pain facilitatory effects for A₂-like receptors result from interactions with endogenous mediators like 5-hydroxytryptamine. Both pain facilitation and edema resulting from local administration of A₃ 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 systemic (probably spinal) pain-suppressing mechanisms being recruited. In the spinal cord, adenosine A₁ receptors produce antinociception. Inhibition of adenosine kinase, but not adenosine deaminase, also produces antinociception, and exhibits a greater separation from motor effects. Adenosine A₁ receptor agonists, as well as inhibitors of adenosine kinase, exhibit the potential for development as analgesic agents, both as local formulations, as well as systemically active agents. In both instances, a sufficient separation from adverse effects will be required.