Dana-Farber Cancer Institute and Department of Neurobiology, Harvard Medical School, 1 Jimmy Fund Way, Boston, MA 02115, USA.
Neuron. 2010 Nov 4;68(3):543-56. doi: 10.1016/j.neuron.2010.09.008.
Itch can be suppressed by painful stimuli, but the underlying neural basis is unknown. We generated conditional null mice in which vesicular glutamate transporter type 2 (VGLUT2)-dependent synaptic glutamate release from mainly Nav1.8-expressing nociceptors was abolished. These mice showed deficits in pain behaviors, including mechanical pain, heat pain, capsaicin-evoked pain, inflammatory pain, and neuropathic pain. The pain deficits were accompanied by greatly enhanced itching, as suggested by (1) sensitization of both histamine-dependent and histamine-independent itch pathways and (2) development of spontaneous scratching and skin lesions. Strikingly, intradermal capsaicin injection promotes itch responses in these mutant mice, as opposed to pain responses in control littermates. Consequently, coinjection of capsaicin was no longer able to mask itch evoked by pruritogenic compounds. Our studies suggest that synaptic glutamate release from a group of peripheral nociceptors is required to sense pain and suppress itch. Elimination of VGLUT2 in these nociceptors creates a mouse model of chronic neurogenic itch.
瘙痒可以被疼痛刺激抑制，但潜在的神经基础尚不清楚。我们生成了条件性敲除小鼠，其中主要由 Nav1.8 表达的伤害感受器中的囊泡谷氨酸转运体 2 (VGLUT2) 依赖性突触谷氨酸释放被消除。这些小鼠表现出疼痛行为缺陷，包括机械痛、热痛、辣椒素诱发痛、炎症痛和神经病理性痛。疼痛缺陷伴随着瘙痒的极大增强，这表明 (1) 组胺依赖性和非组胺依赖性瘙痒途径的敏化，以及 (2) 自发性搔抓和皮肤损伤的发展。引人注目的是，皮内注射辣椒素会促进这些突变小鼠的瘙痒反应，而不是对照同窝仔鼠的疼痛反应。因此，辣椒素的共同注射不再能够掩盖由瘙痒性化合物引起的瘙痒。我们的研究表明，来自一组外周伤害感受器的突触谷氨酸释放对于感知疼痛和抑制瘙痒是必需的。这些伤害感受器中 VGLUT2 的消除产生了一种慢性神经源性瘙痒的小鼠模型。
