ADP has opposing effects on behavioral nociceptive thresholds in the presence and absence of P2Y1. ADP has opposite effects on withdrawal latencies to noxious heat stimuli (Hargreaves test) in the presence and absence of P2Y1. A) P2Y1-/- mice show a deficit in thermal hyperalgesia at day 3 following CFA injection, compared to wildtype mice. B) Injection of ADP into the hindpaw of naïve mice caused thermal hyperalgesia in wildtype mice, but hypoalgesia in P2Y1-/- mice. C) Mice were injected with ADP in the hindpaw three days after CFA injection and thermal response thresholds were measured. ADP injection had no effect on thermal thresholds in inflamed wildtype mice, but reversed thermal hyperalgesia in P2Y1-/- mice. D) Hindpaw injection of MRS2500, a P2Y1 antagonist, in inflamed wildtype mice acutely reversed thermal hyperalgesia compared to saline injection. Injection of either IDP (E) or UDPG (F) into the inflamed hindpaw reversed inflammation-evoked thermal hyperalgesia. n = 10 mice/cohort.