Fentanyl and Carrageenan-induced Hyperalgesia Prevented by N -methyl-D-aspartate Antagonist. Rivat et al. (page 381)

In 78 rats, the team of Rivat et al.  assessed baseline nociceptive thresholds using the paw-pressure vocalization test on two successive days before beginning their experiments. On the study day, animals were randomly assigned to receive either a subcutaneous injection of fentanyl alternating with carrageenan in the left hind paw, or saline injections alternating with the carrageenan paw injections. Nociceptive thresholds were measured 2 and 4 h after the carrageenan and then daily. Carrageenan-induced inflammation was assessed by measuring hind paw diameters to determine the amount of swelling.

A second set of experiments involved a second carrageenan injection 7 days later in the saline-injected rats. Carrageenan injections were given in the same paw or the contralateral paw according to protocol. In another protocol, the first carrageenan injection was given to rats were administered ketamine injections either 30 min before, 4 h and 30 min, or 9 h and 30 min after the first saline or fentanyl injection. In this group of rats, a second carrageenan injection was also given 7 days later.

The carrageenan injection produced swelling in both fentanyl- and nonfentanyl-treated rats. The injection also decreased the nociceptive threshold 2 and 4 h after administration. Fentanyl initially opposed the hyperalgesic effect of carrageenan, but this effect disappeared 4 h later. The second set of carrageenan injections induced enhanced and long-lasting hyperalgesia when performed in the same hind paw, and also decreased the nociceptive threshold for the originally injected paw when the contralateral paw was injected. Ketamine totally prevented the enhancement of long-lasting hyperalgesia resulting from the second carrageenan injection. Nonketamine-treated rats exhibited hyperalgesia for up to 7 days versus  only 4 days in the rats treated with ketamine. The effects of ketamine were similar in the fentanyl-treated rats with hyperalgesia, with the long-lasting hyperalgesia lasting only 2 days versus  6 days in nonketamine treated rats.

The decrease of the nociceptive threshold shown several days after the first carrageenan injection in fentanyl-treated rats suggested that fentanyl's enhancement of pain sensitivity results from a central sensitization process. Indeed, the fentanyl-treated rats showed an exaggerated nociceptive response to the second carrageenan injection 7 days later, suggesting that the rats were rendered hypersensitive to the pain stimulus by the opioid administration. Thus opioid administration may contribute to preemptive hyperalgesia, not analgesia. N -methyl-D-aspartate receptor antagonist therapy may be beneficial to prevent or reduce development of pain sensitization.