EARLY NOCICEPTIVE EVENTS INFLUENCE THE TEMPORAL PROFILE, BUT NOT THE MAGNITUDE, OF THE TONIC RESPONSE TO SUBCUTANEOUS FORMALIN - EFFECTS WITH REMIFENTANIL

Injection of dilute formalin into the hindpaw produces brief (phase 1) and persistent (phase 2) nociceptive responses in the rat. We recentl y reported that ongoing peripheral nerve input is required for the exp ression of behavioral and cardiovascular responses during phase 2. Her e we evaluated the contribution of central and peripheral sensitizatio n mechanisms, generated during phase 1, to the magnitude and temporal profile of phase 2. During phase 1, we administered analgesic doses of an ultrashort-acting opioid, remifentanil (i.v. administration from 0 -5 min after 5.0% formalin injection), or anesthetic concentrations of halothane (2.1%). Inhibition of phase I did not reduce the magnitude of flinching and cardiovascular responses during phase 2, but it did d elay their onset and/or termination. Longer remifentanil infusions (0- 15 or 0-30 min) produced even longer delays (up to 30 min) in the onse t and termination of flinching during phase 2; however, when remifenta nil was administered during the early part of phase 2 (15-30 or 15-45 min), it did not prolong the time to termination of phase 2. Continuou s infusion (10 mg/kg/hr i.v.) of a peripherally acting opiate antagoni st, naloxone methiodide, did not reduce the antinociception produced b y remifentanil during phase 1 but almost completely reversed the delay in the onset and termination of phase 2. We conclude that central sen sitization mechanisms during phase 1 do not influence the magnitude of phase 2. We also hypothesize that remifentanil interacts with periphe ral opioid receptors to impede the formalin-evoked synthesis and/or re lease of proinflammatory compounds during phase 1 and thus delay phase 2.