Is and cholestasis. Overall, the present study compared characteristics of spinally administered bombesin-related peptides versus morphine for eliciting scratching in mice. Vast Epigenetics differences observed in the magnitude of scratching induced by morphine versus bombesin, GRP and NMB suggested that rodents may not be the ideal species to examine pruritus induced by intrathecal opioids. This study is the first to provide detailed pharmacological evidence that spinal GRPr and NMBr independently drive scratching whereas bombesin elicits scratching through receptor mechanisms independent of GRPr and NMBr. Most importantly, GRPr antagonists at functionally receptor-selective doses can block only the spinal GRP-elicited scratching. At higher doses, GRPr antagonists may generally suppress scratching mediated by different receptors, but it could be confounded by the nonselective behavioral effects in mice such as impairment of motor function. Together, the present study not only improves the understanding of itch neurotransmission in the spinal cord but also lays out the pharmacological basis for the development of GRPr and NMBr antagonists for the treatment of pruritus.AcknowledgmentsWe thank Yue Liu, Roxanne Daban, Colette Cremeans and Erin Gruley for technical assistance with data collection.Author ContributionsConceived and designed the experiments: DS MK. Performed the experiments: DS. Analyzed the data: DS MK. Wrote the paper: DS MK.
The identification of urinary biomarkers of kidney disease may be easier to accomplish than the identification of biomarkers for other diseases such as cancer. The biomarker identification pipeline has been divided into two separate stages: discovery and validation [1]. However, despite substantial interest and investment, only a few novel urinary biomarkers are currently used in clinical practice [2]. Clinical use is limited because comprehensive, profiling-based differential proteomics methods, which have limited sample throughput because of their prolonged sample analysis, are generally used in the discovery phase [3]. Profiling is also easily influenced by the preferential detection of highly abundant proteins. As a result of this bias, the detection in urine of less abundant proteins, which are believed to be more specific, is suppressed. Furthermore, highly abundant plasma proteins, which exhibit similar changes under many different renal conditions and lack specificity, are repeatedly identified [4]. These circumstances are often aggravated by proteinuria as a comorbidity [5]. Advances in targeted proteomic technologies simultaneously allow the quantification of hundreds of proteins with better sample throughput, high sensitivity, and high specificity [6?]. The disadvantages of profiling methods can be avoided by using targeted proteomic technologies in the discovery phase. The key is to target the right proteins. Kidney origin proteins in urine include proteins that are secreted or shed by the cells and tissues of the kidney and proteinsthat leak into the fluid from aged or damaged tissue. Injury to different renal cells is expected to generate different proteins in urine, which may be more representative of the state of the kidney [9] and may be more readily detectable than the tumor-associated proteins that are released early in oncogenesis. Identifying quantitative changes in kidney origin protein levels in urine may yield inhibitor information that is pertinent to the functions of renal cells and has a greater cha.Is and cholestasis. Overall, the present study compared characteristics of spinally administered bombesin-related peptides versus morphine for eliciting scratching in mice. Vast differences observed in the magnitude of scratching induced by morphine versus bombesin, GRP and NMB suggested that rodents may not be the ideal species to examine pruritus induced by intrathecal opioids. This study is the first to provide detailed pharmacological evidence that spinal GRPr and NMBr independently drive scratching whereas bombesin elicits scratching through receptor mechanisms independent of GRPr and NMBr. Most importantly, GRPr antagonists at functionally receptor-selective doses can block only the spinal GRP-elicited scratching. At higher doses, GRPr antagonists may generally suppress scratching mediated by different receptors, but it could be confounded by the nonselective behavioral effects in mice such as impairment of motor function. Together, the present study not only improves the understanding of itch neurotransmission in the spinal cord but also lays out the pharmacological basis for the development of GRPr and NMBr antagonists for the treatment of pruritus.AcknowledgmentsWe thank Yue Liu, Roxanne Daban, Colette Cremeans and Erin Gruley for technical assistance with data collection.Author ContributionsConceived and designed the experiments: DS MK. Performed the experiments: DS. Analyzed the data: DS MK. Wrote the paper: DS MK.
The identification of urinary biomarkers of kidney disease may be easier to accomplish than the identification of biomarkers for other diseases such as cancer. The biomarker identification pipeline has been divided into two separate stages: discovery and validation [1]. However, despite substantial interest and investment, only a few novel urinary biomarkers are currently used in clinical practice [2]. Clinical use is limited because comprehensive, profiling-based differential proteomics methods, which have limited sample throughput because of their prolonged sample analysis, are generally used in the discovery phase [3]. Profiling is also easily influenced by the preferential detection of highly abundant proteins. As a result of this bias, the detection in urine of less abundant proteins, which are believed to be more specific, is suppressed. Furthermore, highly abundant plasma proteins, which exhibit similar changes under many different renal conditions and lack specificity, are repeatedly identified [4]. These circumstances are often aggravated by proteinuria as a comorbidity [5]. Advances in targeted proteomic technologies simultaneously allow the quantification of hundreds of proteins with better sample throughput, high sensitivity, and high specificity [6?]. The disadvantages of profiling methods can be avoided by using targeted proteomic technologies in the discovery phase. The key is to target the right proteins. Kidney origin proteins in urine include proteins that are secreted or shed by the cells and tissues of the kidney and proteinsthat leak into the fluid from aged or damaged tissue. Injury to different renal cells is expected to generate different proteins in urine, which may be more representative of the state of the kidney [9] and may be more readily detectable than the tumor-associated proteins that are released early in oncogenesis. Identifying quantitative changes in kidney origin protein levels in urine may yield information that is pertinent to the functions of renal cells and has a greater cha.
