Fentanyl enhancement of carrageenan-induced long-lasting hyperalgesia in rats: prevention by the N-methyl-D-aspartate receptor antagonist ketamine.
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 microg/kg each given four times at 15-min intervals [4 x 60 or 4 x100]) 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 x 60 microg/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 x 60 or 4 x 100 microg/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.


CONCLUSIONS
Central sensitization in inflammatory pain states is reinforced by an opiate treatment, which could be prevented by N-methyl-D-aspartate receptors blockade.
Rivat
Cyril
C
INSERM U 259, Bordeaux, France, and Pain Analgesia INSERM Network, Bordeaux, France.
Laulin
Jean-Paul
JP
Corcuff
Jean-Benoît
JB
Célèrier
Evelyne
E
Pain
Laure
L
Simonnet
Guy
G
D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D002351:Carrageenan; D004357:Drug Synergism; D005283:Fentanyl / Q000494:pharmacology*; D005528:Foot / Q000473:pathology; D006930:Hyperalgesia / Q000139:chemically induced* / Q000473:pathology; D008297:Male; D017288:Pain Threshold / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects
D000701:Analgesics, Opioid; D016194:Receptors, N-Methyl-D-Aspartate; D002351:Carrageenan; D005283:Fentanyl