Antinociceptive Effects of Fentanyl and Non-opioid Drugs in Methocinnamox-treated Rats

Abstract

<b>Abstract ID 17113</b> <b>Poster Board 411</b> Methocinnamox (MCAM) is a long acting μ-opioid receptor antagonist and potential novel treatment for opioid use disorder. MCAM antagonizes the antinociceptive effects of μ-opioid receptor agonists for 2 weeks or longer. However, this long duration of action could make the clinical use of MCAM challenging as μ-opioid receptor agonists are frequently used for pain management. Therefore, alternative drugs to provide pain relief would need to be identified. In this experiment, 24 male Sprague Dawley rats were used to study the antinociceptive effects of fentanyl and non-opioid drugs, in the presence and absence of MCAM, using the complete Freund’s adjuvant (CFA) model of inflammatory pain. For these studies, 12 rats received MCAM and 12 rats received 10% β-cyclodextrin vehicle. Half of the animals from each of these treatment groups were treated with CFA i.pl. (n=6/group), or saline i.pl. (n=6/group). Hypersensitivity to mechanical stimulation was measured using a von Frey anesthesiometer. The antinociceptive effects of fentanyl (0.01-0.1 mg/kg, i.p.), ketamine (17.8-56 mg/kg, i.p.), gabapentin (32-100 mg/kg, i.p.), meloxicam (3.2-10 mg/kg, i.p.), and Δ⁹-tetrahydrocannabinol (THC, 1-10 mg/kg, i.p.) were tested in all animals in a pseudorandom order every 3 days following a single s.c. administration of MCAM (10 mg/kg) or vehicle. Following completion of antinociception studies, the same doses of each drug were studied for effects on motor performance using a rotarod apparatus. Intraplantar administration of CFA induced hypersensitivity to mechanical stimulation. Fentanyl dose-dependently alleviated CFA-evoked mechanical hypersensitivity (i.e., antinociception) in vehicle-treated rats (up to 105% reversal), but not in MCAM-treated rats. Fentanyl did not impair motor performance in either group. THC (up to 82% reversal), ketamine (up to 66% reversal), and gabapentin (up to 46% reversal) dose-dependently alleviated CFA-evoked mechanical hypersensitivity in both the MCAM- (n=6), and vehicle-treated groups (n=6). Meloxicam failed to alter CFA-evoked mechanical hypersensitivity in either group. THC, gabapentin, and meloxicam did not affect motor performance in either group. Ketamine dose-dependently impaired motor performance in both the MCAM- and vehicle-treated groups (up to 71% reduction in latency to fall). These data suggest that ketamine, gabapentin and THC could be effective treatments for inflammatory pain under conditions of long term μ-opioid receptor antagonism. This work was supported by grant AQ-0039 from the Welch Foundation, and NIDA grant T32DA031115 (CPF).