Behavioral effects of fentanyl in presence or absence of chronic neuropathic pain in male and female rats

Abstract

<b>Abstract ID 23939</b> <b>Poster Board 201</b> Mu opioid receptor (MOR) agonists are used clinically at times to treat chronic pain, yet there is debate about whether or not chronic pain alters the effects of opioid analgesics and their abuse liability. This project examined the extent to which chronic neuropathic pain altered the reinforcing, interoceptive, antihyperalgesic, and rate decreasing effects of fentanyl in male and female Sprague Dawley rats. It has been proposed that chronic pain causes opioid peptide release and tolerance due to continuous MOR activation; therefore, we hypothesized that chronic neuropathic pain would decrease the potency of fentanyl over the duration of chronic pain in all these behavioral measures and that the shift in the fentanyl dose effect curve would be greater in female than male rats. We surgically induced a spared nerve injury (SNI) that produces a persistent hyperalgesic state for at least 18 mo. Fentanyl dose response curves (and other drugs) in each behavioral assay were evaluated before surgery and after surgery for 2-6 months. We measured (a) fentanyl self-administration behavior by evaluating within session fentanyl dose effect curves on a fixed ratio 5 (FR5) schedule of reinforcement, (b) the discriminative stimulus effects of fentanyl in rats trained to discriminate 0.032 mg/kg fentanyl from saline, (c) the antihyperalgesic and antinociceptive effects of fentanyl as withdrawal latencies from a mechanical stimulus (Randall Selitto), and (d) the fentanyl-induced decreases in rates of responding under a FR5 schedule of reinforcement for sucrose-maintained responding. Fentanyl maintained self-administration behavior in all rats prior to sham (ED₅₀=1.04 +/- mcg/kg) or SNI surgery (ED₅₀=1.30 +/- mcg/kg); data are presented as intake (mcg earned/dose). While there was an initial decrease in responding post-surgery, fentanyl-maintained responding increased over 3-4 d to reach the pre-surgical average. These ED₅₀ values did not significantly change over 8 wks of chronic pain. Fentanyl produced dose-dependent increases in % fentanyl responding prior to sham (ED₅₀=0.01+/- 0.001 mg/kg) and SNI surgery (ED₅₀=0.013 +/- 0.001 mg/kg). We observed no significant changes in these ED₅₀ values over 6 mo of chronic pain. Fentanyl produced dose-dependent increases in withdrawal pressure prior to sham surgery (ED₅₀=0.019 +/- 0.002 mg/kg) and SNI surgery (ED₅₀=0.023 +/- 0.002 mg/kg) prior to SNI. The antihyperalgesic effects of fentanyl were not altered up to 6 months after either surgery. Fentanyl dose-dependently decreased rates of responding prior to sham surgery (IC₅₀=0.022 +/- 0.001 mg/kg) and SNI surgery (IC₅₀=0.019 +/- 0.001 mg/kg). The rate decreasing effects of fentanyl were not altered up to 6 mo. after either surgery. In conclusion, SNI-induced chronic pain did not alter the antihyperalgesic effects, rate decreasing effects, interoceptive effects, or reinforcing effects of fentanyl. In addition, there were no significant differences in the potency of fentanyl between males and females in any of the behavior measures. These results suggest that chronic pain alone likely does not alter the behavioral effects or the abuse potential of fentanyl. Ongoing and future experiments are evaluating the effects of partial MOR agonists and will evaluate motivation for fentanyl in the presence or absence of chronic pain.