Effects of opioid antagonism on functional MRI correlates of explicit and implicit threat processing in healthy volunteers

BACKGROUND: We need to identify novel, tractable therapeutic targets for anxiety disorders. Converging evidence suggests the endogenous opioid system plays a role in modulating affective processing, but its contribution to regulation of threat processing in humans remains unclear. AIMS: We investigated the neural correlates of non-specific opioid antagonism on explicit and implicit regulation of threatening stimuli in healthy volunteers, using functional magnetic resonance imaging (fMRI). METHOD: In a randomised, double-blind, placebo-controlled, crossover design, 38 healthy participants received the opioid antagonist naltrexone (50 mg) or placebo before completing two tasks during fMRI: (a) a cognitive emotional reappraisal task probing explicit regulation and (b) a face-viewing task probing implicit processing. RESULTS: = 0.044) without impairing regulation success. Explicit regulation in the reappraisal task engaged lateral prefrontal regions similarly across drug conditions. However, naltrexone attenuated ventromedial prefrontal cortex, thalamus and caudate activation when viewing negative images. Naltrexone additionally altered ventromedial prefrontal cortex activity and in task-positive regions including right premotor area and frontal pole compared with placebo when viewing emotional faces. In particular, naltrexone increased left middle frontal gyrus activity when viewing fearful faces. CONCLUSIONS: Our results support a role for opioid signalling in automatic emotional regulation, but not in explicit regulation. Furthermore, naltrexone appeared to diminish activity in task-positive regions in response to emotional faces. These findings are consistent with a model where endogenous opioids 'fine-tune' affective responses to both negative and positive stimuli. Future research should explore dose-response effects, kappa-opioid contributions and whether similar results are seen in clinical populations.