Targeting the Ghrelin System for Novel Opioid Use Disorder Therapeutics

PROJECT SUMMARYThe coronavirus disease 2019 (Covid-19) pandemic erupted into the midst of the drug overdose crisis in the US.Over 60% of drug overdoses are linked to opioid analgesics, with repeated overdoses indicative of thedevelopment of opioid use disorder (OUD), a growing and life-threatening medical condition. Given that we areunable to decouple opioid-induced pain relief from opioid abuse and OUD at present, opioid analgesics willremain essential in medicine and their use is likely to co-occur with Covid-19 illness. Opioid medications generallyenhance viral replication, pathogenesis, and infectious disease progression, in part via weakening the immunesystem. The SARS-CoV-1 virus is neuroinvasive and neurovirulent and is linked to progressive central nervoussystem (CNS) symptoms (e.g., confusion, delirium, dysphoria), aligning with symptomatology seen in someCovid-19 patients. As for other viruses, SARS-CoV-2 immunopathology and disease progression will prove tobe a function of virus pathogenesis and host vulnerability, one of which may be chronic opioid use in painmanagement and/or OUD. These findings inspire the urgent need to understand how opioids impact specifichost vulnerability factors and cofactors, and how medications proposed to treat Covid-19 affect opioid signaling,particularly within single cells that control CNS actions of opioids. Initial observations suggest that host factorsinvolved in SARS-CoV-2 cellular entry are altered in the brains of heroin users. We recently reported that brain-region specific expression of immune cytokines and chemokines tracks with lifetime fentanyl intake in rats,suggesting that opioid exposure regulates host viral entry and immune function relevant to Covid-19 infection.Given the concurrent Covid-19 and overdose crises, the chronic use of opioids in pain management, the growingproblem of OUD as well as illegal abuse of opioid drugs, we propose two specific aims of immediate relevanceto predicting Covid-19 disease severity and appropriate therapeutics in opioid-exposed OUD patients. Basedupon this premise, we will test the hypothesis that withdrawal from chronic fentanyl self-administration in maleand female rats will impact key targets that mediate SARS-CoV-2 infection in identified single cells in CNS viasingle-nuclei RNAseq transcriptomics (Aim 1) and that acute or chronic Covid-19 medication candidates willalter signaling profiles of opioids (e.g., fentanyl, buprenorphine) in a cellular system (Aim 2). We expect todiscover altered markers of host viral entry and immunological status in identified single CNS cells followingchronic fentanyl self-administration, establishing the potential for enhanced neurological damage in Covid-19patients. We also expect to demonstrate interactions between Covid-19 medications and opioid signaling whichpredict potential interactions in vivo. These innovative aims are consistent with the goals of NOT-DA-20-047 todetermine if opioid exposure is a risk factor for the onset and progression of Covid-19.