# Molecular and cellular mechanisms of cold allodynia

> **NIH NIH R01** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2020 · $360,938

## Abstract

Project Summary
The detection of external stimuli such as temperature is critical for survival, yet inappropriate responses to
temperature do have a significant negative impact on overall health. The sensations and the physiological
effects of cold are distinct among somatosensory modalities in that cold provides a pleasant, soothing
sensation at mild temperatures, but is also agonizing as temperatures decrease. Remarkably, how this one
somatosensory modality mediates this diverse range of physiological effects is not known. The menthol
receptor TRPM8 is considered the principal cold sensor in mammalian sensory neurons, but the irritant
receptor TRPA1 have also been associated with cold pain. Mice lacking TRPM8 channels retain some limited
cold sensitivity, but we find that ablation of TRPM8-expressing neurons in mice abolishes essentially all acute
cold and cold pain behaviors, results implying TRPM8-independent cold transduction mechanisms in TRPM8+
neurons. TRPA1 channels appear to serve no role in acute cold, but likely contribute to injury-induced cold
pain. TRPM8 and TRPA1 are not co-expressed, yet the interplay between TRPA1 and TRPM8 after injury has
not been examined, nor have the molecular and cellular mechanisms leading to injury-induced sensitization.
Recently, we found that the glial cell-line derived neurotrophic factor-like (GDNF) ligand artemin is a mediator
of TRPM8-dependent cold pain, and that the artemin receptor GFRα3 is required for pathological cold
allodynia. However, the molecular and cellular mechanisms whereby this pathway leads to cold allodynia is not
known. Here we propose to use a combination of molecular, cellular, behavioral, and pharmacological
approaches to fill in these gaps in our knowledge of the mechanisms underlying cold sensation. First, we will
determine the role of TRPM8 and TRPA1 channels in cold allodynia. Second, we define the cellular basis for
artemin-induced cold hypersensitivity. Third, we will test the necessity of the classical GFRα co-receptor Ret in
cold allodynia and determine if other candidate co-receptors mediate this form of pathology. Lastly, we will
generate transgenic mice in which genetically defined subpopulations of TRPM8 neurons are conditionally
ablated in vivo to determine if innocuous cool, noxious cold, and analgesia are mediated cell autonomously. At
the conclusion of these studies, we will have defined a signal transduction pathway leading to cold pain, and if
these stimuli are transmitted via distinct neural circuits to mediate the range of behavioral and physiological
responses to cold temperatures.

## Key facts

- **NIH application ID:** 9955378
- **Project number:** 5R01NS106888-03
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** David D McKemy
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $360,938
- **Award type:** 5
- **Project period:** 2018-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9955378

## Citation

> US National Institutes of Health, RePORTER application 9955378, Molecular and cellular mechanisms of cold allodynia (5R01NS106888-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9955378. Licensed CC0.

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