# A Novel Assay to Improve Translation in Analgesic Drug Development

> **NIH NIH R33** · VIRGINIA COMMONWEALTH UNIVERSITY · 2024 · $861,479

## Abstract

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, ...

## Key facts

- **NIH application ID:** 10985018
- **Project number:** 4R33NS133217-02
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** Sidney S Negus
- **Activity code:** R33 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $861,479
- **Award type:** 4N
- **Project period:** 2023-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10985018

## Citation

> US National Institutes of Health, RePORTER application 10985018, A Novel Assay to Improve Translation in Analgesic Drug Development (4R33NS133217-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10985018. Licensed CC0.

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