The Role of Peroxiredoxin 6 (PRDX6) in Cannabinoid-Induced Antinociception

Abstract ID 92528 Poster Board 501 Cannabinoid-based therapies potentially offer a safer, non-opioid alternative for the management of chronic pain, but tolerance to cannabinoids like delta-9-tetrahydrocannabinol (Δ⁹-THC) may limit their therapeutic utility. Blocking peroxiredoxin 6 (PRDX6) activation has been shown to attenuate the development of morphine tolerance, and PRDX6 activation in morphine tolerance is at least partially mediated through phosphorylation by c-Jun N-terminal kinase (JNK). JNK signaling has also been shown to modulate tolerance to the antinociceptive effects of cannabinoids, including Δ⁹-THC and CP55,940, in an agonist-specific manner. As such, the purpose of this study was to determine whether pharmacological inhibition or genetic disruption of PRDX6 would alter Δ⁹-THC- and/or CP55,940-induced antinociception and/or tolerance. The acute antinociceptive dose response effects of Δ⁹-THC (0 to 100 mg/kg) or CP55,940 (0 to 1.0 mg/kg) were tested across a range of doses using the tail-flick test. The dose response effects of these cannabinoids on hypothermia was also measured. Consistent with previous findings in our lab, male mice were, overall, more sensitive to the antinociceptive effects of Δ⁹-THC than female mice. Across both sexes, KO mice exhibited a decreased acute antinociceptive response to Δ⁹-THC (but not CP55,940) compared to their WT counterparts. Cannabinoid-induced hypothermia did not differ as a function of genotype. Male C57Bl/6 mice pretreated with the PRDX6 antagonist, MJ33 (1.25 mg/kg) and male PRDX6 KO mice were also assessed for tolerance to Δ⁹-THC-mediated antinociception and hypothermia. In contrast to our hypothesis, inhibition of PRDX6 using genetic or pharmacological approaches blunts Δ⁹-THC-mediated antinociception. However, no difference in tolerance to the effects of Δ⁹-THC was detected in either PRDX6 KO or MJ33-treated WT mice compared to WT or vehicle-treated WT controls. These results suggest that PRDX6 likely plays a role in modulating Δ⁹-THC-induced antinociception, and future studies should examine whether these changes are mediated through JNK-dependent pathways. This research was supported by NIDA Grant R01DA044999.