Artemin, a Glial Cell Line-Derived Neurotrophic Factor Family Member, Induces TRPM8-Dependent Cold Pain
Artemin, a Glial Cell Line-Derived Neurotrophic Factor Family Member, Induces TRPM8-Dependent Cold Pain
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DOI：
10.1523/jneurosci.5765-12.2013
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发表时间：
2013-07-24
影响因子：
5.3
通讯作者：
McKemy, David D.
中科院分区：
文献类型：
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作者：
Lippoldt, Erika K.;Elmes, Russell R.;McKemy, David D.
与损伤或疾病相关的慢性疼痛可由感觉传入神经的功能障碍引起，由此疼痛感测神经元（伤害感受器）的激活阈值降低。神经营养因子控制伤害感受器的发育和存活，但也通过激活其同源受体诱导致敏，这部分归因于离子通道功能的调节。热痛由瞬时受体电位（TRP）家族的通道介导，包括冷和薄荷醇受体TRPM8。虽然已经表明TRPM8参与冷过敏，但这种疼痛模式的分子机制尚不清楚。使用微阵列分析来鉴定TRPM8神经元中富集的小鼠基因，我们发现胶质细胞系源性神经营养因子（GDNF）家族受体GFR α 3在具有冷伤害感受器的神经化学特征的TRPM8感觉神经元亚群中表达。此外，我们发现artemin，一种引起热痛觉过敏的特异性GFR α 3配体，在小鼠中以TRPM 8依赖性方式强烈致敏冷反应。相反，GFR α 1和GFR α 2不与TRPM 8共表达，它们各自的配体GDNF和neurturin不诱导冷痛，而它们确实引起热痛觉过敏。神经生长因子诱导轻度冷致敏，与TRPM 8神经元中的TrkA表达一致。然而，缓激肽未能改变冷敏感性，即使它的受体表达在TRPM 8神经元的子集。这些结果第一次表明，只有选择的神经营养因子通过TRPM 8在体内诱导冷致敏，不同于能够促进热痛觉过敏的广泛的促痛剂。
Chronic pain associated with injury or disease can result from dysfunction of sensory afferents whereby the threshold for activation of pain-sensing neurons (nociceptors) is lowered. Neurotrophic factors control nociceptor development and survival, but also induce sensitization through activation of their cognate receptors, attributable, in part, to the modulation of ion channel function. Thermal pain is mediated by channels of the transient receptor potential (TRP) family, including the cold and menthol receptor TRPM8. Although it has been shown that TRPM8 is involved in cold hypersensitivity, the molecular mechanisms underlying this pain modality are unknown. Using microarray analyses to identify mouse genes enriched in TRPM8 neurons, we found that the glial cell line-derived neurotrophic factor (GDNF) family receptor GFR alpha 3 is expressed in a subpopulation of TRPM8 sensory neurons that have the neurochemical profile of cold nociceptors. Moreover, we found that artemin, the specific GFR alpha 3 ligand that evokes heat hyperalgesia, robustly sensitized cold responses in a TRPM8-dependent manner in mice. In contrast, GFR alpha 1 and GFR alpha 2 are not coexpressed with TRPM8 and their respective ligands GDNF and neurturin did not induce cold pain, whereas they did evoke heat hyperalgesia. Nerve growth factor induced mild cold sensitization, consistent with TrkA expression in TRPM8 neurons. However, bradykinin failed to alter cold sensitivity even though its receptor expresses in a subset of TRPM8 neurons. These results show for the first time that only select neurotrophic factors induce cold sensitization through TRPM8 in vivo, unlike the broad range of proalgesic agents capable of promoting heat hyperalgesia.