Sex Differences in the Effects of Early Life Stressors in a Rat Model of Myofascial Low Back Pain

IF 3.4 2区医学 Q1 ANESTHESIOLOGY

European Journal of Pain Pub Date : 2025-08-28 DOI:10.1002/ejp.70114

Deepika Singhal, Lin Li, Wolfgang Greffrath, Rolf-Detlef Treede

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Abstract

Background

Chronic primary low back pain (cpLBP) is prevalent worldwide. Adverse childhood experiences (ACEs) increase the risk of cpLBP. Here, we explored ACEs as a predisposing factor for adult cpLBP using a rodent model.

Methods

During adolescence, male and female Wistar rats underwent repeated restraint stress (RS) for one hour daily for 12 days or social isolation (SI) for 29 days; controls were handled daily. In adulthood, acute cpLBP was mimicked by NGF or saline injections into the lumbar multifidus muscle. Deep muscular hypersensitivity was assessed using the pressure pain threshold (PPT) of multifidus (MF) and gastrocnemius muscles (GS). Cutaneous mechanical hypersensitivity was measured with paw withdrawal threshold (PWT).

Results

SI had smaller effects than RS in adolescence (d = −0.87 vs. −1.20) and adulthood (d = −0.33 vs. −0.48). RS and SI had a moderate impact in adolescent females (Cohen's d = −0.69), while males experienced a strong sensitisation (d = −1.42), with persistence into adulthood only in males (d = −0.52). Sensitivity to change was lower for PPT of GS (d = −0.71) than PPT of MF (d = −1.09) or PWT (d = −1.17). PPT of the injected MF dropped in stressed females both to saline (d = −0.447) and NGF (d = −0.568) but not in males. Both early life stress models induced immediate muscular and cutaneous hypersensitivity that recovered partly in adulthood.

Conclusions

Males were more susceptible to manifest sensitisation by stress than females, whereas females exhibited a memory trace (latent sensitisation), causing hyperalgesia upon the second hit in adulthood. The differential stress sensitivity may contribute to the higher prevalence of cpLBP in females.

Significance Statement

Chronic primary low back pain (cpLBP) is prevalent worldwide, particularly in women. Adverse childhood experiences (ACEs) increase the risk of cpLBP. Using a rat model of cpLBP and two early life stressors, we report that male rats were more susceptible to manifest sensitisation by stress, whereas female rats exhibited a memory trace, causing behavioural signs of hyperalgesia upon the second hit in adulthood (noxious muscle stimulation). The differential stress sensitivity may contribute to the higher prevalence of cpLBP in women.

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早期生活应激源对大鼠肌筋膜下腰痛模型影响的性别差异

背景慢性原发性腰痛（cpLBP）在世界范围内普遍存在。不良童年经历（ace）会增加发生cpLBP的风险。在这里，我们使用啮齿动物模型探讨ace作为成人cpLBP的易感因素。方法在青春期，雄性和雌性Wistar大鼠每天进行1小时的重复约束应激（RS），持续12 d或社会隔离（SI），持续29 d；控制每天都在进行。在成年期，通过神经生长因子或生理盐水注入腰椎多裂肌来模拟急性cpLBP。采用多裂肌（MF）和腓肠肌（GS）的压痛阈值（PPT）评估深肌超敏反应。用足部退缩阈值（PWT）测定皮肤机械超敏反应。结果SI在青春期（d = - 0.87 vs. - 1.20）和成年期（d = - 0.33 vs. - 0.48）的影响小于RS。RS和SI对青春期女性有中等影响（Cohen’s d = - 0.69），而男性经历了强烈的敏感化（d = - 1.42），只有男性持续到成年（d = - 0.52）。GS组PPT对变化的敏感性（d = - 0.71）低于MF组PPT （d = - 1.09）和PWT组PPT （d = - 1.17）。应激雌性注射MF的PPT在生理盐水（d = - 0.447）和NGF （d = - 0.568）下均下降，而雄性没有。两种早期生活压力模型都会引起立即的肌肉和皮肤过敏，并在成年后部分恢复。结论雄性比雌性更容易出现明显的应激致敏，而雌性则表现出记忆痕迹（潜伏致敏），在成年期第二次应激时引起痛觉过敏。不同的应激敏感性可能是导致女性cpLBP患病率较高的原因。慢性原发性腰痛（cpLBP）在世界范围内普遍存在，尤其是女性。不良童年经历（ace）会增加发生cpLBP的风险。利用大鼠cpLBP模型和两种早期生活压力源，我们报告了雄性大鼠更容易受到压力的明显敏化，而雌性大鼠表现出记忆痕迹，在成年后第二次受到刺激（有害肌肉刺激）时引起痛觉过敏的行为迹象。不同的应激敏感性可能是导致女性cpLBP患病率较高的原因。

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来源期刊

European Journal of Pain 医学-临床神经学

CiteScore

7.50

自引率

5.60%

发文量

163

审稿时长

4-8 weeks

期刊介绍： European Journal of Pain (EJP) publishes clinical and basic science research papers relevant to all aspects of pain and its management, including specialties such as anaesthesia, dentistry, neurology and neurosurgery, orthopaedics, palliative care, pharmacology, physiology, psychiatry, psychology and rehabilitation; socio-economic aspects of pain are also covered. Regular sections in the journal are as follows: • Editorials and Commentaries • Position Papers and Guidelines • Reviews • Original Articles • Letters • Bookshelf The journal particularly welcomes clinical trials, which are published on an occasional basis. Research articles are published under the following subject headings: • Neurobiology • Neurology • Experimental Pharmacology • Clinical Pharmacology • Psychology • Behavioural Therapy • Epidemiology • Cancer Pain • Acute Pain • Clinical Trials.