Grant: Project Grant

Opioid use disorder (OUD) is one of the most challenging forms of addiction facing opioid users, their loved ones, and the Canadian health care system. Many individuals (~22/day) die from apparent opioid toxicity. Treatment options for OUD are limited and rely on opioid substitution/agonist therapy, opioid tapering and behavioural therapy. Relapse rates after treatment are high and there are no non-opioid therapies to prevent relapse. Therefore, preclinical animal research investigating the brain mechanisms behind this problem and to identify novel targets is critically needed to advance treatment options and understand the neurobiology of this disease. This proposal addresses this need by characterizing how dually released neuropeptides modulates their receptors in a brain circuit that is critical for incentive motivation and underlies craving for addictive drugs. We will test the idea that after repeated opioid treatment, the effects of the lateral hypothalamic neuropeptides, orexin and dynorphin differentially alter activity dopamine neurons in the ventral tegmental area (VTA) of the brain, a region key to governing the motivational value of cues that can drive craving. We will test if chronic opioids increase orexin signaling and decrease dynorphin signaling resulting in an increase in activity of the VTA dopamine projection to the basolateral amygdala. We will test if this neural circuitry change is involved in relapse to fentanyl seeking in mice. Our results will provide a preclinical foundation to support the development of anti-craving medicines targeted at the orexin/dynorphin system.