Novel Non-Opioid Based Therapeutics for Chronic Neuropathic Pain.

Chronic neuropathic pain is currently a major health issue in U.S. complicated by the lack of non-opioid analgesic alternatives. Our investigations led to the discovery of major signaling pathways involved in the transition of acute to chronic neuropathic pain and the identification of several targets for therapeutic intervention. Our translational approach has facilitated the advancement of novel medicines for chronic neuropathic pain that are in advanced clinical development and clinical trials.

Behavioral characterization of G-protein-coupled receptor 160 knockout mice.

ABSTRACT: Neuropathic pain is a devastating condition where current therapeutics offer little to no pain relief. Novel nonnarcotic therapeutic targets are needed to address this growing medical problem. Our work identified the G-protein-coupled receptor 160 (GPR160) as a potential target for therapeutic intervention. However, the lack of small-molecule ligands for GPR160 hampers our understanding of its role in health and disease. To address this void, we generated a global Gpr160 knockout (KO) mouse using CRISPR-Cas9 genome editing technology to validate the contributions of GPR160 in nociceptive behaviors in mice. Gpr160 KO mice are healthy and fertile, with no observable physical abnormalities. Gpr160 KO mice fail to develop behavioral hypersensitivities in a model of neuropathic pain caused by constriction of the sciatic nerve. On the other hand, responses of Gpr160 KO mice in the hot-plate and tail-flick assays are not affected. We recently deorphanized GPR160 and identified cocaine- and amphetamine-regulated transcript peptide (CARTp) as a potential ligand. Using Gpr160 KO mice, we now report that the development of behavioral hypersensitivities after intrathecal or intraplantar injections of CARTp are dependent on GPR160. Cocaine- and amphetamine-regulated transcript peptide plays a role in various affective behaviors, such as anxiety, depression, and cognition. There are no differences in learning, memory, and anxiety between Gpr160 KO mice and their age-matched and sex-matched control floxed mice. Results from these studies support the pronociceptive roles of CARTp/GPR160 and GPR160 as a potential therapeutic target for treatment of neuropathic pain.

CARTp/GPR160 mediates behavioral hypersensitivities in mice through NOD2.

ABSTRACT: Neuropathic pain is a debilitating chronic condition that remains difficult to treat. More efficacious and safer therapeutics are needed. A potential target for therapeutic intervention recently identified by our group is the G-protein coupled receptor 160 (GPR160) and the cocaine- and amphetamine-regulated transcript peptide (CARTp) as a ligand for GPR160. Intrathecal administration of CARTp in rodents causes GPR160-dependent behavioral hypersensitivities. However, the molecular and biochemical mechanisms underpinning GPR160/CARTp-induced behavioral hypersensitivities in the spinal cord remain poorly understood. Therefore, we performed an unbiased RNA transcriptomics screen of dorsal horn spinal cord (DH-SC) tissues harvested at the time of peak CARTp-induced hypersensitivities and identified nucleotide-binding oligomerization domain-containing protein 2 (Nod2) as a gene that is significantly upregulated. Nucleotide-binding oligomerization domain-containing protein 2 is a cytosolic pattern-recognition receptor involved in activating the immune system in response to bacterial pathogens. While NOD2 is well studied under pathogenic conditions, the role of NOD2-mediated responses in nonpathogenic settings is still not well characterized. Genetic and pharmacological approaches reveal that CARTp-induced behavioral hypersensitivities are driven by NOD2, with co-immunoprecipitation studies indicating an interaction between GPR160 and NOD2. Cocaine- and amphetamine-regulated transcript peptide-induced behavioral hypersensitivities are independent of receptor-interacting protein kinase 2 (RIPK2), a common adaptor protein to NOD2. Immunofluorescence studies found NOD2 co-expressed with endothelial cells rather than glial cells, implicating potential roles for CARTp/NOD2 signaling in these cells. While these findings are based only on studies with male mice, our results identify a novel pathway by which CARTp causes behavioral hypersensitivities in the DH-SC through NOD2 and highlights the importance of NOD2-mediated responses in nonpathogenic settings.

Training and education in religion/spirituality within APA-accredited clinical psychology programs: 8 years later.

This study was a follow up investigation of Brawer et al.'s (Prof Psychol Res Pr 33(2):203-206, 2002) survey of education and training of clinical psychologists in religion/spirituality. Directors of clinical training were surveyed to determine whether changes had occurred in the coverage of religion and spirituality through course work, research, supervision, and in the systematic coverage of the content area. Results indicated an increased coverage in the areas of supervision, dedicated courses, inclusion as part of another course, and research. There was no increase in systematic coverage, but significantly more programs provided at least some coverage. The current study also assesses other areas of incorporation as well as directors' opinions regarding the importance of religion/spirituality in the field of psychology.