Fentanyl enhancement of carrageenan-induced long-lasting hyperalgesia in rats: Prevention by the N-methyl-D-aspartate receptor antagonist ketamine

Abstract

Background: Tissue damage may produce hyperalgesia, allodynia, and persistent pain. The authors recently reported that fentanyl elicits analgesia but also activates N-methyl-D-aspartate-dependent pain facilitatory processes opposing analgesia. In nonsuffering rats, this leads to a long-lasting enhancement in pain sensitivity. The current study assessed whether fentanyl could amplify carrageenan-induced hyperalgesia. Methods: First, rats were injected once with carrageenan in a hind paw, with fentanyl (60 or 100 μg/kg each given four times at 15-min intervals [4 × 60 or 4 × 100]) or saline. Second, rats were injected with carrageenan twice without fentanyl (7-day interval), with the second injection either in the previously injected paw or in the other paw. Third, rats were injected twice with carrageenan in the same hind paw: the first ketamine injection was given (10 mg/kg each given three times at 5-h intervals) with or without fentanyl (4 × 60 μg/kg), and second injection was given without ketamine or fentanyl. The consequences of treatments on long-term hyperalgesia were examined by the paw-pressure vocalization test. Results: The long-lasting hyperalgesia induced by the first carrageenan injection was dose-dependently enhanced in both duration and magnitude in 4 × 60 or 4 × 100 μg/kg fentanyl-treated rats: 5 or 10 days, respectively, as compared with 2 days in saline-treated rats. Hyperalgesia observed in the hind paw contralateral to the first carrageenan injection was enhanced in fentanyl-treated rats. The second carrageenan injection, performed in any hind paw, induced an exaggerated hyperalgesia, especially in fentanyl-treated rats. Pretreatment with ketamine totally prevented the carrageenan- and fentanyl-induced enhancement of the long-lasting hyperalgesia. Conclusion: Central sensitization in inflammatory pain states is reinforced by an opiate treatment, which could be prevented by N-methy-D-aspartate receptos blockade.