PERSISTENT CARDIOVASCULAR AND BEHAVIORAL NOCICEPTIVE RESPONSES TO SUBCUTANEOUS FORMALIN REQUIRE PERIPHERAL-NERVE INPUT

Hindpaw injection of formalin produces acute (Phase 1) and persistent (Phase 2) nociceptive behaviors. This model has provided critical evid ence supporting a contribution of central sensitization (hyperexcitabi lity of spinal neurons) to the expression of persistent pain. Here, we evaluated the contribution of ongoing peripheral nerve inputs to Phas e 2 pain responses. In addition to pain behavior (flinching), we measu red formalin-evoked increases in arterial pressure and heart rate; the se cardiovascular responses were also biphasic in nature. The arterial pressure response correlated highly with behavior, and was dependent on formalin concentration (0.625-5.0%), indicating that it was largely driven by noxious input. Lightly anesthetized (0.7% halothane) rats e xhibited robust increases in blood pressure in the absence of pain beh avior, indicating cardiovascular responses did not reflect somatomotor -cardiovascular coupling. Animals obtained from Charles River exhibite d slightly larger Phase 2 flinching and heart rate responses compared to those obtained from Bantin and Kingman, suggesting cardiovascular-r elated pain responses can vary with the source of animal. We next eval uated the contribution of ongoing peripheral nerve activity to the exp ression of the Phase 2 presser, tachycardia, and flinch responses. Aft er Phase 1 subsided, but before Phase 2 began, we locally anesthetized the ipsilateral or contralateral (control) hindpaw with a hydrophilic lidocaine derivative, QX-314 (2%). Intraplantar QX-314 blocked Phase 2 presser, tachycardia and behavioral responses only when injected int o the paw that received formalin (2.5% or 10.0%). We conclude that per sistent ongoing activity in peripheral afferent fibers during Phase 2 is required for the persistent pain evoked by formalin.