NK1 antagonism modulates negative emotional processing in abstinent opioid dependent individuals and healthy controls

Background

Opioid dependence is a public health challenge in Europe, with heroin relapse rates estimated at 70% (Hser et al., 2015). The treatment goal of many opioid dependent (OD) individuals is to achieve abstinence. However, the risk of relapse is typically highest during this time. Emotional dysregulation is a risk factor for relapse in addiction, as negative reinforcement drives repeated drug use to alleviate negative affective states like stress and anxiety. The neurokinin-1 (NK1) receptor system has been implicated in modulating stress and anxiety responses, suggesting they may be a potential therapeutic target for preventing relapse. We tested the hypothesis that abstinent OD individuals would demonstrate heightened brain reactivity to negative affective (aversive) images compared with healthy controls (HC). We also explored the therapeutical potential of acute NK1 antagonism and hypothesised it would ‘normalise’ aberrant brain reactivity. 

Methods

OD (n=22) and matched HC (n=32) participants were assessed for differences in blood-oxygen-level-dependent (BOLD) signal in response to standardised aversive images from IAPS. Two hours prior to fMRI sessions, participants were administered an NK1 receptor antagonist (aprepitant [80mg] or vofopitant [10mg]) or placebo in a double-blind, pseudo-randomised, cross-over design. Aversive and neutral images were presented in a block design. We examined group and drug effects using whole-brain voxelwise mixed-effects analysis (cluster corrected Z>2.3, P<0.05) for the contrast aversive>neutral. 

Results

BOLD signal was higher in OD compared with HC during the placebo session in limbic regions including the hippocampus, thalamus and insula, and cortical regions including the lingual, precuneus and posterior cingulate gyri. In response to NK1 antagonism in OD only, BOLD signal was lower relative to placebo in the putamen, lingual and precuneus gyri, and other cortical regions including the occipital fusiform and orbitofrontal cortex. A group*drug interaction showed attenuated BOLD signal by NK1 antagonism in OD relative to HC in similar subcortical regions including the putamen, hippocampus, thalamus, insula, and amygdala, and cortical regions including the lingual, precuneus, occipital fusiform and orbitofrontal cortex.

Conclusion

BOLD signal was heightened in OD compared with HC in regions associated with negative emotional processing, suggesting dysregulation occurs in opioid dependence. Brain reactivity was differentially modulated by NK1 antagonism in OD and HC, where NK1 antagonism attenuated heightened BOLD response in OD relative to HC. The results suggest NK1 antagonism may have therapeutic potential in preventing relapse during opioid abstinence by attenuating heightened brain reactivity following exposure to negative stimuli. Future studies should explore whether NK1 antagonists produce subjective reductions in stress- and anxiety-related craving, which may indicate further clinical benefit.