PT  - JOURNAL ARTICLE
AU  - Lulek, Courtney F.
AU  - Maulik, Malabika
AU  - Guindon, Josee
AU  - Rorabaugh, Boyd R.
AU  - Henderson-Redmond, Angela N.
AU  - Morgan, Daniel J.
TI  - The Role of Peroxiredoxin 6 (PRDX6) in Cannabinoid-Induced Antinociception
AID  - 10.1124/jpet.501.925280
DP  - 2024 Jun 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 501
VI  - 389
IP  - S3
4099  - http://jpet.aspetjournals.org/content/389/S3/501.short
4100  - http://jpet.aspetjournals.org/content/389/S3/501.full
SO  - J Pharmacol Exp Ther2024 Jun 01; 389
AB  - Abstract ID 92528Poster Board 501Cannabinoid-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.