Chronic neuropathic pain alters reversal learning and prefrontal cortex activation without generalized deficits in reward-related behavior.

Chronic pain is associated with neuropsychiatric comorbidities characterized by impairments in cognitive and behavioral flexibility, yet the direct impact of chronic pain on reward-guided behavior remains poorly understood. Here, we investigated how chronic neuropathic pain altered sucrose-reinforced behavior across multiple behavioral assays with distinct cognitive-behavioral demands in male and female mice. Mice underwent spared nerve injury (SNI) or sham surgery and were tested in operant sucrose self-administration, reversal learning, and extinction training. The impact of acute mechanical stimulation on sucrose seeking was also assessed. SNI produced stable mechanical hypersensitivity without affecting acquisition or extinction of sucrose self-administration, indicating intact baseline acquisition and sucrose seeking. In contrast, chronic neuropathic pain selectively altered behavioral flexibility: SNI females exhibited faster initial acquisition of reversal learning, while SNI mice as a group showed impaired inhibition of responding on the previously reinforced lever during early reversal. Acute mechanical stimulation suppressed sucrose seeking in males, but not in females, independent of chronic pain status. At the neural level, mechanical stimulation differentially modulated medial prefrontal cortex (mPFC) activity, increasing infralimbic c-Fos expression in SNI mice while decreasing it in sham controls relative to non-stimulated animals. There was no evidence of chronic mPFC hyperactivity as indexed by ΔFosB expression. Together, these findings demonstrate that chronic neuropathic pain did not globally disrupt sucrose reward-related behavior, but instead selectively altered behavioral flexibility and pain–reward interactions in a sex-dependent manner, with accompanying alterations in mPFC engagement following aversive stimulation. • Chronic pain is often associated with impaired behavioral flexibility. • Spared nerve injury (SNI) had distinct effects on behavior in male and female mice. • Acquisition and extinction of sucrose self-administration were not impacted by SNI. • SNI facilitated reversal learning in female, but not male, mice. • Acute painful stimulation suppressed reward seeking in male, but not female, mice.