Tweety-homolog 1 (Ttyh1) is expressed in neural tissue and has been implicated in the generation of several brain diseases. However, its functional significance in pain processing is not understood. By disrupting the gene encoding Ttyh1, we found a loss of Ttyh1 in nociceptors and their central terminals in Ttyh1-deficient mice, along with a reduction in nociceptor excitability and synaptic transmission at identified synapses between nociceptors and spinal neurons projecting to the periaqueductal grey (PAG) in the basal state. More importantly, the peripheral inflammation-evoked nociceptor hyperexcitability and spinal synaptic potentiation recorded in spinal-PAG projection neurons were compromised in Ttyh1-deficient mice. Analysis of the paired-pulse ratio and miniature excitatory postsynaptic currents indicated a role of presynaptic Ttyh1 from spinal nociceptor terminals in the regulation of neurotransmitter release. Interfering with Ttyh1 specifically in nociceptors produces a comparable pain relief. Thus, in this study we demonstrated that Ttyh1 is a critical determinant of acute nociception and pain sensitization caused by peripheral inflammation.

Tweety-homolog 1 (Ttyh1) 在神经组织中表达，并与几种脑部疾病的产生有关。然而，它在疼痛处理中的功能意义尚不清楚。通过破坏编码 Ttyh1 的基因，我们发现 Ttyh1 缺陷小鼠的伤害感受器及其中央末端中 Ttyh1 缺失，同时伤害感受器兴奋性和突触传递在已识别的伤害感受器和脊髓神经元之间投射到导水管周围灰质 (PAG ) 处于基础状态。更重要的是，在脊髓 PAG 投射神经元中记录的外周炎症诱发的伤害感受器过度兴奋和脊髓突触增强在 Ttyh1 缺陷小鼠中受到损害。对脉冲比和微型兴奋性突触后电流的分析表明来自脊髓伤害感受器末端的突触前 Ttyh1 在调节神经递质释放中的作用。特别是在伤害感受器中干扰 Ttyh1 会产生类似的疼痛缓解。因此，在这项研究中，我们证明 Ttyh1 是由外周炎症引起的急性伤害感受和疼痛敏感的关键决定因素。