Persistent cardiovascular and behavioral nociceptive responses to subcutaneous formalin require peripheral nerve input

Abstract

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.

Identification of a New Class of Molecules, the Arachidonyl Amino Acids, and Characterization of One Member That Inhibits Pain

“…A combination of mechanisms appears to contribute to the phase 2 pain behavior. Both persistent peripheral nociceptor discharge and the ensuing central sensitization in the spinal cord are important in the initiation and maintenance of the spontaneous pain, allodynia and hyperalgesia (27)(28)(29)(30). This tonic pain phase has been likened to persistent postoperative pain (reviewed in Ref.…”

Antinociceptive and cardiovascular properties of esmolol following formalin injection in rats

“…The biphasic nociceptive behaviours as assessed by lifting following the formalin test has been extensively described. [8][9][10] The primary phase (Phase 1) response was immediate and lasted up to five minutes following formalin injection. Esmolol did not affect the Phase 1 response.…”

“…7 Models exploring acute pain pathways also exist, among them the conscious rat subjected to the formalin test. [8][9][10] The formalin test model produces a biphasic response: the early nociceptive response (0-5 min), possibly related to a C fibre activation and the late nociceptive response (10-35 min) that appears to be dependent on a combination of inflammatory reactions in the peripheral tissue and facilitation of spinal transmission. [11][12] Although the analgesic properties of alpha agonists in surgical patients have been extensively documented, 1 3 the role played by esmolol in the modulation of postoperative pain remains to be established.…”

Deficient Nonpeptidergic Epidermis Innervation and Reduced Inflammatory Pain in Glial Cell Line-Derived Neurotrophic Factor Family Receptor α2 Knock-Out Mice

“…The intact first-phase response in GFR␣2-KO mice suggests that functional chemonociceptor terminals mediating the acute phase are present in KO mouse skin. Inflammationinduced hyperactivity of C-fibers generates and sustains an elevated discharge of dorsal horn neurons (Pitcher and Henry, 2002), which is thought to be critical for the second, persistent phase formalin response (Tjolsen et al, 1992;Puig and Sorkin, 1995;Taylor et al, 1995). Thus, a parsimonious explanation for the reduced second-phase response in GFR␣2-KO mice would be weaker activation of the nonpeptidergic DRG neurons.…”