Inhibition of kynurenine 3-monooxygenase (KMO) reduces fentanyl and sucrose intake and relapse-like behaviour in rats.

BACKGROUND AND PURPOSE: Opioid use disorder, particularly involving fentanyl, poses major challenges due to high relapse rates and limited effectiveness of pharmacotherapies. The kynurenine pathway has emerged as a target for addiction treatment through its modulation of glutamatergic and dopaminergic neurotransmission. This study investigates the effects of kynurenine 3-monooxygenase (KMO) inhibition on fentanyl self-administration in rats.

EXPERIMENTAL APPROACH: Adult male rats received the KMO inhibitor, Ro 61-8048 during fentanyl self-administration. Responding was assessed across acquisition, maintenance, extinction and reinstatement. The involvement of nicotinic acetylcholine receptor α7 subunit (α7nAChR) was investigated using the positive allosteric modulator PNU-120596. Sucrose self-administration, locomotor activity and rotarod performance were also evaluated. Kynurenine pathway metabolites were quantified in plasma and nucleus accumbens using ultra-performance liquid chromatography-mass spectrometry.

KEY

RESULTS

Ro 61-8048 reduced fentanyl intake and active lever responding across all addiction phases. These effects were associated with increased kynurenic acid (KYNA) levels and altered kynurenine pathway metabolite profiles. PNU-120596 did not prevent Ro 61-8048 effects, indicating an α7nAChR-independent mechanism. Although Ro 61-8048 reduced sucrose self-administration and spontaneous locomotor activity, it did not affect rotarod performance, progressive ratio breakpoints nor did it produce aversive behaviour suggesting that KMO inhibition modulates the reinforcing strength of both drug and natural rewards, rather than inducing general behavioural suppression.

CONCLUSION AND IMPLICATIONS: KMO inhibition with Ro 61-8048 robustly attenuates fentanyl-directed behaviour and affects kynurenine pathway metabolism beyond a shift towards KYNA production. These findings support KMO inhibition as a potential therapeutic strategy for opioid use disorder and warrant further investigation into its underlying mechanisms and translational potential.