NEUROPATHIC PAIN PROMOTES IMPULSIVE CHOICE PREFERENCE THROUGH ORBITOSTRIATAL DYSFUNCTION

Impulsive preference for smaller-immediate rewards over larger-delayed rewards is a hallmark of chronic pain patients; however, the underlying mechanisms and brain areas supporting this impulsive phenotype in the context of reward valence remain poorly understood. Here, we evaluated how neuropathic pain affects lateral orbitofrontal cortex (lOFC) and nucleus accumbens shell (NAcSh) activity during reward-delay associations, using a delayed gratification task (DGt) comprising two delivery contingencies: a smaller-immediate and a larger-delayed reward. To test this, rats were transfected in the lOFC with the GCaMP6f-calcium biosensor and in the NAcSh dLight1.2-dopamine biosensor enabling bulk neural activity recordings using in vivo fiber photometry. In addition, optogenetic approaches were employed to selectively enhance the activity of lOFC glutamatergic terminals projecting to the NAcSh at critical behavior epochs. lOFC-NAcSh activity was recorded 21 and 28 days following induction of neuropathic pain using the spared nerve injury (SNI) model. Our findings showed that SNI-treated rats exhibited a marked preference for smaller-immediate rewards. Neural recordings revealed that both experimental groups displayed comparable lOFC-NAcSh transient activity during immediate-reward trials. Moreover, control rats showed enhanced lOFC activity preceding delayed-reward trials, followed by increased NAcSh dopamine activity after choice. No significant differences were observed between testing sessions. Finally, optogenetic activation of lOFC-to-NAcSh pathway increased the frequency of immediate choices in both experimental groups. Together, these findings indicate that neuropathic pain disrupts orbitostriatal activity, leading to impaired time-reward associations and increased impulsive decision-making phenotypes.
Funding: FCT-project_10.54499/2022.05193.PTDC; EUGLOH-PhD-grant_10.54499/PRT/BD/154992/2023.