Hindpaw injection of
formalin produces acute (Phase 1) and persistent (Phase 2) nociceptive behaviors. This model has provided critical evidence supporting a contribution of central sensitization (hyperexcitability of spinal neurons) to the expression of persistent
pain. Here, we evaluated the contribution of ongoing peripheral nerve inputs to Phase 2
pain responses. In addition to
pain behavior (flinching), we measured
formalin-evoked increases in arterial pressure and heart rate; these 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 exhibited robust increases in blood pressure in the absence of
pain behavior, indicating cardiovascular responses did not reflect somatomotor-cardiovascular coupling. Animals obtained from Charles River exhibited slightly larger Phase 2 flinching and heart rate responses compared to those obtained from Bantin and Kingman, suggesting cardiovascular-related
pain responses can vary with the source of animal. We next evaluated the contribution of ongoing peripheral nerve activity to the expression of the Phase 2 pressor,
tachycardia, and flinch responses. After 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 pressor,
tachycardia and behavioral responses only when injected into the paw that received
formalin (2.5% or 10.0%). We conclude that persistent ongoing activity in peripheral afferent fibers during Phase 2 is required for the persistent
pain evoked by
formalin.