Long-lasting hyperalgesia induced by fentanyl in rats - Preventive effect of ketamine

Background: It has been reported that mu-opioid receptor activation leads t o a sustained increase in glutamate synaptic effectiveness at the N-methyl- D-aspartate (NMDA) receptor level, a system associated with central hyperse nsitivity to pain. One hypothesis is that postoperative pain may result par tly from the activation of NMDA pain facilitatory processes induced by opia te treatment per se. The authors tested here the effectiveness of the opiat e analgesic fentanyl for eliciting a delayed enhancement in pain sensitivit y. Methods: The consequences of four bolus injections (every 15 min) of fentan yl (20-100 mu g/kg per injection, subcutaneously) on immediate (for several hours) and long-term (for several days) sensitivity to nociceptive stimuli in the rat (paw-pressure vocalization test) were evaluated. The effects of the combination of the NMDA-receptor antagonist ketamine (10 mg/kg, subcut aneously) with fentanyl also were assessed. Results: Fentanyl administration exhibited a biphasic time-dependent effect : first, an early response (for 2-5 h) associated with a marked increase in nociceptive threshold (analgesia), and second, a later response associated with sustained lowering of the nociceptive threshold (5 days for the longe st effect) below the basal value (30% of decrease for the maximal effect) i ndicative of hyperalgesia. The higher the fentanyl dose used, the more pron ounced was the fentanyl-induced hyperalgesia. Ketamine pretreatment, which had no analgesic effect on its own, enhanced the earlier response (analgesi a) and prevented the development of long-lasting hyperalgesia. Conclusions: Fentanyl activates NMDA pain facilitatory processes, which opp ose analgesia and lead to long-lasting enhancement in pain sensitivity.