COMPLEX ROLE OF PERIPHERAL ADENOSINE IN THE GENESIS OF THE RESPONSE TO SUBCUTANEOUS FORMALIN IN THE RAT

When applied peripherally, adenosine has been shown to be pronocicepti ve in a number of animal and human models. Recent evidence has implica ted adenosine as a significant mediator in the inflammatory process. I n this study using rats, we have examined the effect of adenosine and of selective adenosine A(1) and A(2) receptor agonists and antagonists on the response to a subcutaneous injection of formalin into the rat hindpaw. Adenosine co-injected with formalin 0.5% significantly increa sed flinching in both phases in a dose-dependent manner. The highest d ose of adenosine had no behavioral effect on its own. The adenosine A( 2) receptor agonist -carboxyethyl)phenethylamino-5'-N-ethylcarboxamido adenosine hydrochloride (CGS-21680), at a dose of 1.5 nmol, increased flinching associated with 0.5% formalin injection but at higher doses produced depressant effects due to systemic absorption. The adenosine A(1) receptor agonist N-6-cyclohexyladenosine produced only systemic behavioral effects as determined by contralateral application. The fli nching response to 2.5% formalin was significantly decreased by the ad enosine A(2) receptor antagonist 3,7-dimethyl-1-propargylxanthine (DMP X). In contrast, 8-cyclopentyl-1,3-dimethylxanthine (CPT), the selecti ve adenosine A(1) receptor antagonist augmented the response to 2.5% f ormalin. The non-selective adenosine receptor antagonist caffeine had no significant effect over a wide range of doses. In summary, exogenou s adenosine enhances nociception in the formalin test, probably via a peripheral A(2) receptor-mediated action. Endogenous adenosine, acting at both A(1) and A(2) receptors, appears to be involved in the formal in-induced inflammatory response. This activation of adenosine A(1) an d A(2) receptors may have opposing effects on nociceptive input.