ADENOSINE A(3) RECEPTOR ACTIVATION PRODUCES NOCICEPTIVE BEHAVIOR AND EDEMA BY RELEASE OF HISTAMINE AND 5-HYDROXYTRYPTAMINE

This study evaluated the pain enhancing properties of the adenosine A( 3) receptor agonist N-6-benzyl-5'-N-ethylcarboxamidoadenosine (N-6-ben zyl-NECA) by assessing behavioural effects following s.c. administrati on alone to the dorsal hindpaw of the rat, or in combination with a lo w concentration of formalin (0.5%). Edema formation was monitored by d etermining paw volume with plethysmometry. N-6-benzyl-NECA (0.005-10 n mol) produced a dose-related increase in intrinsic flinching behaviour s, as well as an increase in phase 2A flinch responses in the presence of formalin. Intrinsic effects were blocked by the histamine H-1 rece ptor antagonist mepyramine and the 5-hydroxytryptamine(2) (5-HT2) rece ptor antagonist ketanserin, but not by other 5-HT receptor antagonists or adenosine A(1) or A(2) receptor antagonists. N-6-benzyl-NECA also produced an increase in paw volume, both alone and in the presence of formalin, with higher doses being required to produce this effect than for the flinch response. The increase in paw volume was also blocked by mepyramine and ketanserin but not by other antagonists. These resul ts indicate both a nociceptive response and a proinflammatory response resulting in edema formation following activation of adenosine A(3) r eceptors which is mediated by both 5-HT and histamine released most li kely from mast cells. (C) 1997 Elsevier Science B.V. (C) 1997 Elsevier Science B.V.