A Sensory-Labeled Line for Cold: TRPM8-Expressing Sensory Neurons Define the Cellular Basis for Cold, Cold Pain, and Cooling-Mediated Analgesia

Neurobiology Section, Department of Biological Sciences, Neuroscience Graduate Program, Neurobiology Graduate Program, and Molecular and Computational Biology Graduate Program, University of Southern California, Los Angeles, California 90089.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 02/2013; 33(7):2837-48. DOI: 10.1523/JNEUROSCI.1943-12.2013
Source: PubMed


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.

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Available from: Wendy M Knowlton, Aug 12, 2015
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    • "Trigeminal neurons with the phenotype of specific cold thermoreceptors exhibit an ample range of thermal and menthol thresholds[52,72]. Such threshold differences are due to a variable expression of TRPM8 and of cold-sensitive Kv1 channels whose IK D current opposes cold-induced depolarization[32,41,52,75]. In our experiments in humans using an ointment containing 1mM menthol, a low concentration of the drug was detected in the tear film suggesting that under these conditions, only the fraction of lowest threshold cold thermoreceptors was activated. "
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    • "Mice lacking TRPM8 exhibited decreased sensitivity to cold surfaces that are normally avoided, as assessed by temperature preference and acetone-evoked flinch tests (Bautista et al. 2007; Colburn et al. 2007; Dhaka et al. 2007). Cold avoidance and icilin sensitivity were also reduced or absent in TRPM8 conditionally ablated mice, even though these animals appeared to have normal heat and mechanical pain sensitivity (Knowlton et al. 2013). In agreement with these findings, global knockout mice lacking both TRPM8 and TRPA1 were no different than knockout mice lacking only TRPM8 in their avoidance of innocuous and noxious cold stimuli (Knowlton et al. 2010). "
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    • "In behavioural tests , temperature deficit is evident only at mildly cooling range , and becomes insignificant at temperatures below 10°C . At the same time , obliteration of the neuronal line which gives rise to TRPM8 - positive neurons ( Mishra et al . 2011 ) or targeted ablation of TRPM8 neurons in adult mice ( Knowlton et al . 2013 ; Pogorzala et al . 2013 ) eliminates cold sensitivity in the full testable range . These data strongly suggest that TRPM8 - positive neurons contain an unidentified TRPM8 - independent molecular mechanism responsible for the detection of mildly and severely noxious cold . A growing body of evidence supports the notion that in addition "
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