Tissue injury elicits both
hypersensitivity to evoked stimuli and ongoing, stimulus-independent
pain. We previously demonstrated that
pain relief elicits reward in nerve-injured rats. This approach was used to evaluate the temporal and mechanistic features of
inflammation-induced ongoing
pain.
RESULTS: Intraplantar Complete
Freund's Adjuvant (CFA) produced
thermal hyperalgesia and guarding behavior that was reliably observed within 24 hrs and maintained, albeit diminished, 4 days post-administration. Spinal
clonidine produced robust conditioned place preference (
CPP) in CFA treated rats 1 day, but not 4 days following CFA administration. However, spinal
clonidine blocked CFA-induced
thermal hyperalgesia at both post-CFA days 1 and 4, indicating different time-courses of ongoing and evoked
pain. Peripheral nerve block by
lidocaine administration into the popliteal fossa 1 day following intraplantar CFA produced a robust preference for the
lidocaine paired chamber, indicating that injury-induced ongoing
pain is driven by afferent fibers innervating the site of injury. Pretreatment with
resiniferatoxin (RTX), an ultrapotent
capsaicin analogue known to produce long-lasting desensitization of TRPV1 positive afferents, fully blocked CFA-induced thermal
hypersensitivity and abolished the
CPP elicited by administration of popliteal fossa
lidocaine 24 hrs post-CFA. In addition, RTX pretreatment blocked guarding behavior observed 1 day following intraplantar CFA. In contrast, administration of the selective
TRPV1 receptor antagonist,
AMG9810, at a dose that reversed CFA-induced
thermal hyperalgesia failed to reduce CFA-induced ongoing
pain or guarding behavior.
CONCLUSIONS: These data demonstrate that
inflammation induces both ongoing
pain and evoked
hypersensitivity that can be differentiated on the basis of time course. Ongoing
pain (a) is transient, (b) driven by peripheral input resulting from the injury, (c) dependent on TRPV1 positive fibers and (d) not blocked by
TRPV1 receptor antagonism. Mechanisms underlying excitation of these afferent fibers in the early post-injury period will offer insights for development of novel
pain relieving strategies in the early post-traumatic period.