Relationship between nociceptor activity, peripheral edema, spinal microglial activation and long-term hyperalgesia induced by formalin

To determine whether initial nociceptive inputs caused by subcutaneous inje ction of formalin into the hindpaw are necessary and/or sufficient for allo dynic behavior and microglial activation observed at one week following beh avior, we examined Sprague-Dawley rats under five test conditions. Test con dition 1. Formalin alone group (six rats), 5% formalin was injected subcuta neously into the dorsal side of the right hind paw. Test condition 2. Bupiv acaine/Formalin group (six rats), bupivacaine was injected into the ankle a rea and into the site of formalin injection 10 min before formalin injectio n. Test condition 3. Saline/Formalin group (six rats), saline was injected 10 min before formalin in the same manner as bupivacaine. Test condition 4. Formalin/Bupivacaine group 1 (six rats), bupivacaine was injected 10 min a fter formalin. Test condition 5. Formalin/Bupivacaine group 2 (six rats), b upivacaine was injected similarly 1h after formalin. The magnitude of paw e dema and paw withdrawal thresholds to mechanical stimuli applied to the pla ntar surface of the injected paw and on the dorsal surface of the contralat eral side were evaluated prior to and one week after formalin injection. Th e lumbar spinal cord was immunohistochemically processed at one week to ass ess the expression of a marker for activated microglia. The results showed: (i) pre-treatment with bupivacaine blocked both phases of formalin-evoked pain behaviors and the mechanical allodynia that developed one week post-fo rmalin injection, but did not block microglial activation; (ii) treatment w ith bupivacaine 1 h after formalin injection reduced paw edema and prevente d skin ulceration, but one week allodynia and microglial activation were st ill present; and (iii) prolonged spinal microglial activation was not depen dent on acute formalin-induced nociceptor activity, but was strongly associ ated with the amount of tissue destruction. Our studies suggest that: (i) t he central sensitization associated with the phase II of formalin-evoked be haviors and spinal microglial activation are both necessary to permit the d evelopment of the long-term hyperalgesia produced by the subcutaneous admin istration of formalin into the rat's hindpaw; and (ii) acute nociceptive in puts following formalin injection are not necessary for central microglial activation that may be triggered by nerve damage or prolonged signals from peripherally inflamed tissue (C) 2000 IBRO. Published by Elsevier Science L td. All rights reserved.