Long-Lasting Inflammation and Long-Term Hyperalgesia After Subcutaneous Formalin Injection Into the Rat Hindpaw

Abstract Subcutaneous formalin injection is widely used as a nociceptive stimulus in the rat. This procedure evokes overt behaviors that last about 90 minutes. However, little is known about the duration of paw inflammation and alterations in pain sensitivity to noxious stimuli after 2 hours. We studied the nociceptive responses to thermal and mechanical stimuli 2 hours to 4 weeks after formalin injection into the dorsal or plantar side of the hindpaw. Thirty-two adult male Sprague-Dawley rats were divided into 3 groups: In group I, 50 μL of 5% formalin was injected into the plantar side (n = 12); in group II, 50 μL of 5% formalin was injected into the dorsal side (n = 12); in group III, 50 μL saline was injected into the dorsal or plantar side of the hindpaw (n = 8). Nociceptive responses to thermal and mechanical stimuli applied to the dorsal or plantar surfaces of the injected and the contralateral hindpaws were recorded. The injection of formalin into the rat's hindpaw produced a hypoalgesic region around the injection site. In contrast, hyperalgesic responses to thermal and mechanical stimulation were induced on the opposite surface of the injected hindpaw as well as in the contralateral noninjected hindpaw. The hyperalgesic responses, which were observed 2 hours after formalin administration, were enhanced 1 to 3 days after injection and lasted 3 to 4 weeks. These results suggest that peripheral inflammation after subcutaneous formalin injection produces a long-lasting sensitization. Possible mechanisms for these changes in nociception are discussed.