Vulnerability to chronic pain is found to depend on age and sex. Most patients with chronic pain are elderly women, especially with posttraumatic pain after bone fracture that prevails beyond the usual recovery period and develops into a complex regional pain syndrome (CRPS). There, a distal bone fracture seems to initiate a pathophysiological process with unknown mechanism. To investigate whether sex, age, and alpha adrenergic receptors also contribute to a CRPS-like phenotype in animals, we performed experiments on tibia-fractured mice. Those mice commonly are resilient to the development of a CRPS-like phenotype. However, we found them to be vulnerable to long-lasting pain after distal bone fracture when they were of old age. These mice expressed mechanical and thermal hypersensitivity, as well as weight-bearing and autonomic impairment following bone trauma, which persisted over 3 months. Site-specific and body side-specific glycinergic and α1D-noradrenergic receptor expression in the spinal cord and the contralateral locus coeruleus were misbalanced. Aged female tibia-fractured mice lost descending noradrenergic inhibition and displayed enhanced spinal activity on peripheral pressure stimuli. Together, changes in the noradrenergic, hence, glycinergic system towards excitation in the pain pathway-ascending and descending-might contribute to the development or maintenance of long-lasting pain. Conclusively, changes in the noradrenergic system particularly occur in aged female mice after trauma and might contribute to the development of long-lasting pain. Our data support the hypothesis that some patients with chronic pain would benefit from lowering the adrenergic/sympathetic tone or antagonizing α1(D).

中文翻译：

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在小鼠创伤后慢性疼痛模型中，老年女性单侧过敏，缺乏下行抑制，并且过度表达 α1D 肾上腺素受体。

研究发现，对慢性疼痛的脆弱性取决于年龄和性别。大多数慢性疼痛患者是老年女性，尤其是骨折后的创伤后疼痛，这种疼痛持续超过通常的恢复期，并发展成复杂的区域疼痛综合征（CRPS）。在那里，远端骨折似乎引发了机制未知的病理生理过程。为了研究性别、年龄和 α 肾上腺素能受体是否也会导致动物 CRPS 样表型，我们对胫骨骨折的小鼠进行了实验。这些小鼠通常能够抵抗 CRPS 样表型的发展。然而，我们发现，当他们年老时，远端骨折后很容易遭受长期疼痛。这些小鼠表现出机械和热过敏，以及骨创伤后的负重和自主神经损伤，并持续超过 3 个月。脊髓和对侧蓝斑中位点特异性和体侧特异性甘氨酸能和α1D-去甲肾上腺素能受体表达不平衡。老年雌性胫骨骨折小鼠失去了去甲肾上腺素能下降的抑制作用，并在外周压力刺激下表现出增强的脊柱活动。总之，去甲肾上腺素能系统以及甘氨酸能系统对疼痛通路（上升和下降）的兴奋的变化可能有助于长期疼痛的发展或维持。总之，去甲肾上腺素能系统的变化尤其发生在创伤后的老年雌性小鼠中，并可能导致长期疼痛的发生。我们的数据支持这样的假设：一些慢性疼痛患者可以从降低肾上腺素/交感神经张力或拮抗 α1(D) 中受益。