Formalin-evoked activity in identified primary afferent fibers: systemic lidocaine suppresses phase-2 activity

Abstract

Formalin injected subcutaneously into the paw is a frequently used pain assay; it evokes an initial period of licking and flinching followed by a period of quiescence and last by a second period of intense and protracted licking and flinching. The prominent second phase is believed to reflect the development of a central (spinal cord) facilitation. This conclusion is based on the assumption that formalin evokes an initial burst of activity in fine afferent fibers, followed by prolonged low levels of activity in C fibers. Detailed reports substantiating this essential assumption have not been published. Thus, we recorded in situ from single sural nerve fibers, identified by their conduction velocity and modality, in the barbiturate anesthetized rat. Following formalin (2.5%, 50 microliters) injection into their receptive fields, phase-1 activity was prominent in A beta and A delta fibers as well as in high-threshold C nociceptive afferent fibers. Phase-2 activity was observed in A delta fibers with receptive fields in hairy skin and in all mechanically sensitive C fibers. Mean phase-2 activity in these fibers was 1/2-2/3 of the magnitude achieved in phase 1. Mechanically insensitive fibers and A delta and C fibers with receptive field centers outside of the injection zone began firing 15 min or more post-injection and would contribute to phase-2, but not phase-1, behavioral activity. Intravenous infusion of low doses of lidocaine yielding plasma levels of 3.6-7.9 micrograms/ml administered during phase 2 blocked formalin-evoked activity in primary afferent fibers in a dose-related fashion without blocking either electrically or mechanically evoked activity. Effective plasma doses were comparable to those found to relieve neuropathic pain. These data indicate that phase 2 in the formalin test is more closely related to ongoing afferent input than had previously been thought.

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.…”

The affective component of pain in rodents: Direct evidence for a contribution of the anterior cingulate cortex

“…It is clear that dilute formalin activates nociceptive primary afferent fibers (A␦ and c fibers) (32) and that s.c. formalin injection is painful to humans (33). This evidence has helped to establish the formalin test as a valid animal model of persistent pain.…”

Gene knockdown with intrathecal siRNA of NMDA receptor NR2B subunit reduces formalin-induced nociception in the rat

“…6,22 During the second phase, there is a low, but nonzero level of peripheral afferent activity. 27 Examination of the firing of dorsal horn neurons reveals a prominent biphasic response pattern with the first phase corresponding to the initial elevation in afferent input, while the second phase is believed to reflect a state of facilitated processing driven by the moderate ongoing peripheral input. 2 Afferent input evokes release of excitatory amino acids and peptides that lead to the initiation of a state of facilitation, mediated in part by activation of NMDA subtype glutamate receptors.…”