Friday, May 23, 2025
5/23/2025
Molecular and cellular mechanisms of cold allodynia - Project Summary In the somatosensory system, the detection of external signals, such as mechanical, thermal, and chemical stimuli, is critical for survival. Cutaneous nerve endings sense these changes in the environment, conveying this information first to the spinal cord via specialized sensory afferents that can discriminate between innocuous and noxious stimuli, the latter by pain-sensing nociceptors. 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. The menthol receptor, TRPM8 is the principal cold sensor in mammalian sensory neurons. This and cells expressing the ion channel are required for the sensations of both innocuous cool and noxious cold, heightened cold sensitivity that results with injury or disease and, paradoxically, the ability of cooling to relieve chronic pain and itch. These findings suggest that TRPM8 can centrally differentiate and propagate the distinct percepts of pleasant and therapeutic cooling from painful and aggravating sensations of cold. But how does this lone channel and the cells expressing it mediate these diverse physiological effects? We found that the glial cell-line derived neurotrophic factor-like ligand artemin (ARTN) and its receptor GFRα3 are required for injury-induced, TRPM8-dependent cold pain, the first evidence of a molecule that directly sensitizes cold in vivo. While the cellular and molecular transduction mechanisms used by this signaling complex to induce cold pain have yet to be defined, these findings point to the cohort of TRPM8+ afferents that express GFRa3 as cold nociceptors. We propose a model whereby injury of any etiology leads to cold allodynia via peripheral release of ARTN that acts on GFRa3 receptors on TRPM8 cells to increase their sensitivity to cold, transmitting this centrally via distinct neurocircuits. We propose to test this first by determining the cellular basis for ARTN and GFRα3 mediated cold sensitization. Second, we have generated a novel mouse genetic strategy to target the GFRa3+ and GFRa3- populations of TRPM8 afferents, allowing the lab to differentially study these two cell types and determine their necessity for acute cold signaling, for pathological cold pain, and for analgesic and anti-pruritic cooling in vivo. Lastly, it is critical to unbiasedly identify cold-tuned spinal cells to determine how the pleasant and painful aspects of cold are processed. We have adapted an innovative genetic approach to study cold-tuned spinal neurons molecularly, functionally, and behaviorally, allowing us to critically interrogate the processing of peripheral cold signals at this first important site for conveying somatosensory and nociceptive information. These studies will define the signal transduction pathways of cold and cold pain, providing not only insights into somatosensory signaling and the mechanisms that bring about pain associated with this modality, but also potential therapeutic interventions that use cold as a stimulus.
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