Long-lasting Hyperalgesia Induced by Fentanyl in Rats

TLDR

Mu‑opioid receptor activation increases glutamate at NMDA receptors, a mechanism that may underlie postoperative pain through central hypersensitivity. The study examined whether fentanyl induces a delayed increase in pain sensitivity (hyperalgesia) in rats. Four subcutaneous fentanyl boluses (20–100 µg kg⁻¹) were given every 15 min and nociceptive thresholds were measured over hours and days; ketamine (10 mg kg⁻¹) was also tested in combination. Fentanyl produced an early analgesic phase (2–5 h) followed by sustained hyperalgesia lasting up to 5 days, dose‑dependent, which ketamine prevented and amplified the early analgesia.

Abstract

Background It has been reported that mu-opioid receptor activation leads to a sustained increase in glutamate synaptic effectiveness at the N-methyl-D-aspartate (NMDA) receptor level, a system associated with central hypersensitivity to pain. One hypothesis is that postoperative pain may result partly from the activation of NMDA pain facilitatory processes induced by opiate treatment per se. The authors tested here the effectiveness of the opiate analgesic fentanyl for eliciting a delayed enhancement in pain sensitivity. Methods The consequences of four bolus injections (every 15 min) of fentanyl (20-100 microg/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, subcutaneously) 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 longest effect) below the basal value (30% of decrease for the maximal effect) indicative of hyperalgesia. The higher the fentanyl dose used, the more pronounced was the fentanyl-induced hyperalgesia. Ketamine pretreatment, which had no analgesic effect on its own, enhanced the earlier response (analgesia) and prevented the development of long-lasting hyperalgesia. Conclusions Fentanyl activates NMDA pain facilitatory processes, which oppose analgesia and lead to long-lasting enhancement in pain sensitivity.