Novel KOR Antidepressant and Analgesic Strategies

Abstract

The broad goal of this thesis has been to gain a better understanding of the mechanisms involved in depression and pain. These disorders are highly prevalent in our society and present an extreme burden for our economy, healthcare system, and the individuals affected by them. The kappa opioid receptor (KOR) is a key mediator of the stress response and has been extensively studied in both animal models and clinical trials investigating pain and depression. Further, activation of this receptor by the endogenous stress peptide dynorphin produces signaling through both the G proteins and -arrestin to produce both analgesia and dysphoria, respectively. Although KOR-directed therapeutics are currently being developed, more research is necessary before they are ready to compete with currently prescribed treatments. This thesis begins by describing two key issues in the use of KOR therapeutics by identifying both A) sexually dimorphic signaling in response to KOR activation mediated by the presence of estrogen in female mice; and B) a novel administration schedule of the receptor-inactivating KOR antagonist norBNI, producing long-lasting inactivation of KOR at dramatically lower doses than previously used. The results of these studies will aid in the design of novel KOR-directed drugs and future clinical trials in the treatment of pain and depression. This thesis continues by exploring the effects of stress mediated activation of KOR on the serotonin system. First, I demonstrate that repeated forced swim stress significantly increases serotonin transporter reuptake rates as mediated by translocation to the plasma membrane in the ventral striatum. Lastly, I examine stress-induced changes in gene expression in the dorsal raphe nucleus, utilizing RiboTag protocols to focus investigations on the serotonergic neurons in the region. RNAseq was used to analyze changes in this population and the effect of pretreating animals with a KOR antagonist was evaluated. The results of these studies identify novel risk factors and targets in the development of kappa therapeutics.