A sensory-labeled line for cold: TRPM8-expressing sensory neurons define the cellular basis for cold, cold pain, and cooling-mediated analgesia.
A sensory-labeled line for cold: TRPM8-expressing sensory neurons define the cellular basis for cold, cold pain, and cooling-mediated analgesia.
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DOI：
10.1523/jneurosci.1943-12.2013
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发表时间：
2013-02-13
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影响因子：
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通讯作者：
McKemy DD
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作者：
Knowlton WM;Palkar R;Lippoldt EK;McCoy DD;Baluch F;Chen J;McKemy DD
许多初级感觉神经元是多模态的，对多种刺激方式（化学，热或机械）做出反应，但每种方式都有不同的识别方式。虽然多模态意味着刺激编码发生在更高的中心，如脊髓或大脑，最近的感觉神经元消融研究发现，不同的方式的行为反应需要不同的亚群，这表明存在特定的标记线在感觉传入的水平。在这里，我们提供的证据表明，神经元表达TRPM 8，在哺乳动物中正常的冷反应所需的冷门控通道和薄荷醇门控通道，代表了一个标记线只为冷感觉。我们研究了成年小鼠中条件性消融TRPM 8+神经元的行为意义，发现与缺乏TRPM 8通道（Trpm 8 −/−）的动物一样，TRPM 8神经元耗尽（消融）的动物对寒冷到痛苦的低温不敏感。消融的动物对有害的寒冷几乎没有表现出厌恶，并且不能区分寒冷和偏好的温暖温度，这是一种比Trpm 8 −/−小鼠更深刻的表型，Trpm 8 −/−小鼠只表现出部分避冷和偏好行为。除了急性反应，与炎症和神经损伤相关的冷痛在消融和Trpm 8 −/−小鼠中显著减弱。此外，在两种基因型中，神经损伤后冷却诱导的镇痛作用均被消除。最后，热，机械和本体感觉行为是正常的消融小鼠，表明TRPM 8神经元是其他躯体感觉方式。总之，这些数据表明，虽然Trpm 8 −/−小鼠中仍然存在一些有限的冷敏感性，但TRPM 8神经元是低温诱发的行为反应所必需的。
Many primary sensory neurons are polymodal, responding to multiple stimulus modalities (chemical, thermal, or mechanical), yet each modality is recognized differently. While 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+ 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. Lastly, 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 while some limited cold sensitivity remains in Trpm8−/− mice, TRPM8 neurons are required for the breadth of behavioral responses evoked by cold temperatures.