Nociceptin/Orphanin FQ receptor agonism attenuates behavioral and neural responses to conditioned aversive stimuli

The nociceptin/orphanin FQ peptide (NOP) receptor has emerged as a promising anxiolytic target, as its activation has been shown to reduce anxiety-related behaviors in rodents. However, the mechanisms underlying these effects are not well understood. Here, we investigated the effects of the selective NOP receptor agonist SCH-221510 (SCH; 0.01-0.1 mg/kg, IM) on behavioral and neural responses to aversive stimuli in squirrel monkeys (n=3). Subjects underwent Pavlovian fear conditioning, wherein a visual conditioned stimulus (CS) was paired with the presentation of an aversive stimulus. Event-related fMRI was conducted in awake subjects to evaluate CS-evoked neural responses. Behavioral and neural responses to the CS were assessed across three experimental phases: pre-conditioning (Pre-C), post-conditioning (Post-C), and Post-C with SCH administration. In behavioral assessments, CS presentation during Post-C elicited a robust suppression of ongoing operant responding, which was absent during Pre-C and significantly attenuated by SCH treatment (0.1 mg/kg). Functional magnetic resonance imaging (fMRI) results revealed that, relative to Pre-C, CS presentation during Post-C was associated with increased BOLD activity in brain regions previously implicated in fear processing (e.g., amygdala), expression and regulation (e.g., prefrontal cortex; PFC), as well as sensory integration. Critically, SCH (0.1 mg/kg) administration significantly attenuated CS-induced neural activation in these regions. Furthermore, resting-state functional connectivity analysis revealed that SCH administration decreased connectivity between the PFC and the amygdala, while enhancing connectivity among subregions of the PFC. Collectively, these findings suggest that NOP receptor agonism may attenuate conditioned responses to aversive stimuli by modulating functional interactions within the PFC–amygdala circuit.