Peripheral adenosine A2A receptors are involved in carrageenan-induced mechanical hyperalgesia in mice

Here we studied the role of peripheral adenosine A2A receptors in mechanical hyperalgesia during inflammation using mice lacking the A2A receptors. Unilateral s.c. administration of the local inflammatory agent λ-carrageenan induced profound mechanical hyperalgesia 24 h after administration in the ipsilateral hind paw in wild-type mice. In homozygous mice lacking the A2A receptors, carrageenan-induced hyperalgesia was significantly reduced compared to wild type controls. The reduction in inflammatory hyperalgesia seen in A2A receptor knock-out mice was not associated with changes in paw edema. CGS 21680, a selective A2A receptor agonist, produced significantly more mechanical hyperalgesia in wild type females than in wild type males upon direct s.c. injection into the hindpaw whereas it had no effect upon systemic administration. The hyperalgesic effect of CGS 21680 was markedly reduced in the A2A knock-out mice of both sexes. Subcutaneous ZM-241,385, a selective A2A receptor antagonist, injected into the hindpaw reduced the mechanical hyperalgesia following carrageenan in female mice, but not in males. The results indicate that activation of peripheral adenosine A2A receptors during inflammation is associated with mechanical hyperalgesia, and that this effect is more prominent in females than in males.