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 pronociceptive in a number of animal and human models. Recent evidence has implicated adenosine as a significant mediator in the inflammatory process. In this study using rats, we have examined the effect of adenosine and of selective adenosine A₁ and A₂ 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 increased flinching in both phases in a dose-dependent manner. The highest dose of adenosine had no behavioral effect on its own. The adenosine A₂ receptor agonist 2-p-(2-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 A₁ receptor agonist N⁶-cyclohexyladenosine produced only systemic behavioral effects as determined by contralateral application. The flinching response to 2.5% formalin was significantly decreased by the adenosine A₂ receptor antagonist 3,7-dimethyl-1-propargylxanthine (DMPX). In contrast, 8-cyclopentyl-1,3-dimethylxanthine (CPT), the selective adenosine A₁ receptor antagonist augmented the response to 2.5% formalin. The non-selective adenosine receptor antagonist caffeine had no significant effect over a wide range of doses. In summary, exogenous adenosine enhances nociception in the formalin test, probably via a peripheral A₂ receptor-mediated action. Endogenous adenosine, acting at both A₁ and A₂ receptors, appears to be involved in the formalin-induced inflammatory response. This activation of adenosine A₁ and A₂ receptors may have opposing effects on nociceptive input.