Project Summary This new R61/R33 application responds to NOT-NS-22-095: “Development and Validation of Pain-Related Models and Endpoints to Facilitate Non-Addictive Analgesic Discovery.” In 2017, the National Institutes of Health launched the HEAL initiative, and one major goal of this initiative has been to develop new, non-addicting analgesics. Analgesic drug discovery depends on preclinical models of pain and analgesia for early-stage evaluation of candidate therapeutics, but conventional models that rely on reflex-withdrawal responses elicited by thermal or mechanical stimuli have significant deficits in face and predictive validity. To address these deficits, we have spent more than a decade developing and refining novel behavioral endpoints that focus on pain-related depression of normal behavior. Assays of pain-depresse behavior improve face validity because behavioral depression and functional impairment are cardinal signs of pain diagnosis, and restoration of normal function and behavior is often a major goal of pain treatment. These assays also significantly improve predictive validity by eliminating false-positive effects with drugs that produce motor impairment. This application seeks funding for further validation of a new procedure for use in mice that measures unconditioned locomotor activity in a complex environment as a new type of assay for pain-depressed behavior. Preliminary data suggest that the procedure elicits high and replicable baseline behavior, reliable depression by an acute visceral pain stimulus, and reversal of pain effects by clinically effective analgesics as positive controls but not by two prominent classes of non-analgesics as negative controls. The procedure also has attributes to promote replicability of results, efficiency of experimental design, assessment of sex as a biological variable, and quantitative objectivity of data collection. Proposed studies for further validation would proceed in two phases. In the first R61 phase (Year 1), we propose further studies to meet three milestones. (1) Further validate our procedure with additional positive and negative controls against our visceral acute pain model. (2) Evaluate selectivity of drug effects to restore behavioral depression by acute pain in comparison to behavioral depression by a non-pain treatment (lithium chloride). (3) Evaluate sensitivity of behavioral endpoints to models of more sustained cutaneous and visceral inflammatory pain (intraplantar complete Freund’s adjuvant, Ipl CFA; post-surgical abdominal-incision, AI). In the second R33 phase (Years 2-3), we propose to collaborate with colleagues at VCU and Wake Forest University to scale up and extend the model in three ways. (1) Extend from ICR outbred mice to an inbred strain commonly used to generate gene-altered mice (C57BL/6J). (2) Extend to three additional disease models of chronic pain (mononeuropathy pain using spared nerve injury, SNI; irritable bowel disease, IBD; sickle-cell anemia, SCA). (3) Evaluate independent replication of key results at a partner academic institution (Wake Forest University). Successful completion of the project would provide a comprehensive empirical foundation for broad use of this procedure in efforts to discover non-opioid non-addicting analgesic drugs.

This new R61/R33 application seeks to address the unmet need for reliable, efficient, and objective preclinical procedures to improve translational predictive validity in analgesic drug discovery. The crisis of opioid abuse and overdose deaths has stimulated the effort to develop non-opioid, non-addicting analgesics, and this effort depends in part on preclinical procedures for analgesic efficacy testing with high predictive validity in general and resistance to false-positive effects in particular. Here we propose a new procedure with excellent potential to have high sensitivity to analgesics, selectivity for analgesics vs. non-analgesics, and additional attributes to promote replicability of results, efficiency in experimental design, and objective and quantitative data collection.