Zhang Mingjun, Ni Ziyun, Ma Jun, Liu An, Liu Ying, Lou Qianqian, Dong Wan-Ying, Zhang Zhi, Li Juan, Cao Peng
Department of Anesthesiology, The First Affiliated Hospital of USTC, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Hefei National Laboratory for Physical Sciences at the Microscale, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230026, China.
Department of Physiology, School of Basic Medical Sciences, Anhui Medical University, Hefei, 230022, China.
Nat Commun. 2025 Apr 17;16(1):3639. doi: 10.1038/s41467-025-58851-x.
The neural mechanisms underlying sex-specific pain, in which males and females exhibit distinct responses to pain, remain poorly understood. Here we show that in a mouse model of male-specific pain hypersensitivity response to pain conditioning environments (contextual pain hypersensitivity model), elevated free-testosterone leads to hyperactivity of glutamatergic neurons in the medial preoptic area (Glu) through activation of androgen receptor signaling, which in turn induces contextual pain hypersensitivity in male mice. Although not observed in naïve female mice, this pain phenotype could be induced in females via chronic administration of testosterone propionate. In addition, Glu neurons send excitatory inputs to GABAergic neurons in the ventrolateral periaqueductal gray (GABA) that are required for contextual pain hypersensitivity. Our study thus demonstrates that testosterone/androgen receptor signaling enhances Glu→ GABA pathway activity, which drives a male-specific contextual pain hypersensitivity, providing insight into the basis of sexually dimorphic pain response.
男性和女性对疼痛表现出不同反应的性别特异性疼痛背后的神经机制仍知之甚少。在此我们表明，在对疼痛条件环境的雄性特异性疼痛超敏反应小鼠模型（情境性疼痛超敏模型）中，游离睾酮水平升高通过雄激素受体信号激活导致内侧视前区（Glu）的谷氨酸能神经元活动亢进，进而诱导雄性小鼠出现情境性疼痛超敏。虽然在未接触过的雌性小鼠中未观察到这种情况，但通过长期给予丙酸睾酮可在雌性小鼠中诱导出这种疼痛表型。此外，Glu神经元向腹外侧导水管周围灰质（GABA）中的GABA能神经元发送兴奋性输入，这是情境性疼痛超敏所必需的。因此，我们的研究表明，睾酮/雄激素受体信号增强了Glu→GABA通路的活性，从而驱动了雄性特异性情境性疼痛超敏，为性别二态性疼痛反应的基础提供了见解。
