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A sensory-labeled line for cold: TRPM8-expressing sensory neurons define the cellular basis for cold, cold pain, and cooling-mediated analgesia.

Many primary sensory neurons are polymodal, responding to multiple stimulus modalities (chemical, thermal, or mechanical), yet each modality is recognized differently. Although polymodality implies that stimulus encoding occurs in higher centers, such as the spinal cord or brain, recent sensory neuron ablation studies find that behavioral responses to different modalities require distinct subpopulations, suggesting the existence of modality-specific labeled lines at the level of the sensory afferent. Here we provide evidence that neurons expressing TRPM8, a cold- and menthol-gated channel required for normal cold responses in mammals, represents a labeled line solely for cold sensation. We examined the behavioral significance of conditionally ablating TRPM8-expressing neurons in adult mice, finding that, like animals lacking TRPM8 channels (Trpm8(-/-)), animals depleted of TRPM8 neurons ("ablated") are insensitive to cool to painfully cold temperatures. Ablated animals showed little aversion to noxious cold and did not distinguish between cold and a preferred warm temperature, a phenotype more profound than that of Trpm8(-/-) mice which exhibit only partial cold-avoidance and -preference behaviors. In addition to acute responses, cold pain associated with inflammation and nerve injury was significantly attenuated in ablated and Trpm8(-/-) mice. Moreover, cooling-induced analgesia after nerve injury was abolished in both genotypes. Last, heat, mechanical, and proprioceptive behaviors were normal in ablated mice, demonstrating that TRPM8 neurons are dispensable for other somatosensory modalities. Together, these data show that, although some limited cold sensitivity remains in Trpm8(-/-) mice, TRPM8 neurons are required for the breadth of behavioral responses evoked by cold temperatures.

Pubmed ID: 23407943


  • Knowlton WM
  • Palkar R
  • Lippoldt EK
  • McCoy DD
  • Baluch F
  • Chen J
  • McKemy DD


The Journal of neuroscience : the official journal of the Society for Neuroscience

Publication Data

February 13, 2013

Associated Grants

  • Agency: NINDS NIH HHS, Id: NS054069
  • Agency: NINDS NIH HHS, Id: NS078530
  • Agency: NINDS NIH HHS, Id: R01 NS054069
  • Agency: NINDS NIH HHS, Id: R21 NS078530

Mesh Terms

  • Analgesia
  • Animals
  • Behavior, Animal
  • Cell Lineage
  • Cold Temperature
  • Diphtheria Toxin
  • Hand Strength
  • Hot Temperature
  • Immunohistochemistry
  • Mice
  • Mice, Knockout
  • Microarray Analysis
  • Nerve Fibers
  • Pain
  • Pain Insensitivity, Congenital
  • Physical Stimulation
  • Proprioception
  • Real-Time Polymerase Chain Reaction
  • Sensory Receptor Cells
  • TRPM Cation Channels
  • Thermosensing