In Vivo Investigation of the Relationship Between Kappa Opioid Receptor and Suicidal Behavior in PTSD

The goal of this study is to investigate the role of the kappa opioid receptor (KOR) in posttraumatic stress disorder (PTSD), a condition associated with markedly elevated risk for all forms of suicidal behavior. Despite awareness of the increased risk associated with PTSD, available pharmacological interventions are often at best partially effective, and rarely reduce suicide risk. Investigation of molecular mechanisms subserving PTSD and suicide risk specifically is an essential next step to both promote development of novel treatments and facilitate risk prevention in this population. Emerging evidence implicates KOR in PTSD and suicidal behavior. KOR plays critical roles in hyperarousal, emotional numbing and dysregulation, and dissociation  “all of which are central to PTSD and related to suicide risk. Postmortem studies have shown an association between KOR and death by suicide. Further, KOR antagonists can produce antidepressant, anxiolytic, and even anti-suicidal effects. Moreover, a recent trial supports the potential efficacy of KOR antagonists in reducing PTSD symptom severity. Importantly, KOR agents' effect on dopamine is modest relative to drugs of abuse, reducing concerns about abuse potential. Here, we propose a novel investigation of KOR availability of in individuals with PTSD using positron emission tomography (PET), a brain imaging technique, and radioligand [11C]EKAP which binds selectively to KOR in the brain (Aim 1). Given the high prevalence of suicide-related behavior in PTSD, we will also evaluate the association between KOR availability, suicide attempt and scan day suicidal ideation (Aim 2). Lastly, we will evaluate the association between pain tolerance, impulsivity, and executive dysfunction "key endophenotypes associated with suicide risk” and KOR availability (Aim 3). Results of this study will provide critical insight into the relationship between KOR, PTSD symptom presentation, and suicidal behavior, and have the potential to inform development of KOR targeted medications to reduce suicide risk in PTSD.