Inhibition of Nociception-induced Spinal Sensitization by Anesthetic Agents

Abstract

Subcutaneous injection of dilute formalin in the hind paw of the rat produces a biphasic nociceptive response. Initial C-fiber activity is accompanied by flinching of the paw for about 5 min (phase 1), followed by cessation of activity and resumption of flinching beginning 15 min after injection and lasting about 40 min or more (phase 2). The second phase depends on changes in dorsal horn cell function that occur shortly after the initial C-fiber discharge. It was previously shown that isoflurane, administered during phase 1, reduced phase 2 activity, but a combination of isoflurane and nitrous oxide given throughout phase 1 did not suppress spinal sensitization. The same model was used to determine the effects of several inhalation and intravenous anesthetic agents on phase 2 of the formalin test. The formalin test was carried out on male Sprague-Dawley rats. Animals anesthetized briefly with halothane to facilitate formalin injection, were compared to animals that received 1 MAC anesthesia from 5 min before to 6 min after formalin injection using halothane, enflurane, isoflurane, desflurane, or 70% N2O, or a combination of nitrous oxide plus 1 MAC halothane. Animals that were given intravenous saline immediately before injection of formalin were compared to animals given either 20 mg/kg intravenous thiopental just before formalin injection or 10 mg/kg intravenous propofol just before and 3 mg/kg immediately after formalin injection. Flinches/minute were counted at 1 and 5 min after formalin injection and thereafter at 5-min intervals for 1 h. The total of 1- and 5-min flinches were considered phase 1 activity and the total of 10-60-min flinches were considered phase 2. Total phase 2 activity was compared between groups using one-way analysis of variance. Animals that received halothane, enflurane, isoflurane, desflurane, or nitrous oxide during phase 1 demonstrated a significant decrease in phase 2 activity when compared to controls, while those that received a combination of nitrous oxide and halothane exhibited no difference. Animals that received intravenous thiopental anesthesia during phase 1 demonstrated no difference in phase 2 activity when compared to controls, whereas those that received propofol during phase 1 demonstrated a significant decrease of phase 2 activity. Volatile anesthetics or nitrous oxide significantly suppress spinal sensitization, whereas the combination of nitrous oxide plus halothane causes no suppression. Thiopental does not affect spinal sensitization, whereas propofol causes significant suppression. These results may have important implications regarding the development of postoperative pain.