The cellular mechanisms of cold allodynia

About This Grant

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 unique among somatosensory modalities in that cold provides an innocuous analgesic sensation at mild temperatures but is also painfully noxious 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. Lastly, we have shown that TRPM8 is also critical for migraine-like pain in rodents, consistent with human genetic studies. 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 as well as migraines, the first evidence of a molecule that directly sensitizes TRPM8 in vivo. While the cellular and molecular transduction mechanisms used by this signaling complex to induce sensitization have yet to be defined, these findings point to the cohort of TRPM8+ afferents that express GFRa3 as 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. A conserved pathway may also work in the meninges for migraine-like pain. We propose to test this first by determining the cellular basis for ARTN and GFRα3 mediated TRPM8 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 in vitro and determine their necessity for acute cold signaling, for pathological cold pain, for analgesic and anti-pruritic cooling, and migraine-like pain in vivo. Lastly, it is critical to unbiasedly identify TRPM8-tuned spinal cells to determine how the pleasant and painful aspects of cold are processed. We have adapted an innovative genetic approach to study TRPM8-tuned spinal neurons molecularly, functionally, and behaviorally, allowing us to determine if the activation of cephalic cutaneous TRPM8 can alleviate localized cutaneous allodynia associated with migraines. 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.