Rat Hindlimb amputation model shows analgesia and sexually dimorphic cold hypersensitivity with immediate targeted muscle reinnervation

IF 4 2区医学 Q1 CLINICAL NEUROLOGY

Journal of Pain Pub Date : 2025-06-12 DOI:10.1016/j.jpain.2025.105460

Jose Lucas Zepeda, Gabriella Mraz, Elizabeth Roth, Dorothee Weihrauch, Gwendolyn Hoben

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引用次数: 0

Abstract

Targeted muscle reinnervation (TMR) has been used clinically to reduce pain in amputees, but its underlying analgesic mechanisms remain unclear. We developed a rat below-knee amputation model to evaluate pain outcomes following immediate TMR (iTMR) in both male and female Sprague-Dawley rats. Animals were randomized to amputation-only or amputation with iTMR, and assessed for reflexive pain behaviors (von Frey, pin, and cold hypersensitivity) and spontaneous pain behaviors (guarding, flinching, and sucrose preference as a measure of anhedonia). Retrograde labeling was used to trace sensory and motor neurons and confirm nerve coaptation patterns. iTMR significantly reduced hyperalgesia and anhedonia compared to amputation-only. By four weeks, pin testing showed decreased responses in iTMR rats (25%) compared to controls (51%, p=0.01), and sucrose preference was higher in iTMR rats (76% vs. 43%, p=0.01). Cold sensitivity responses were reduced in iTMR-treated males (49% vs. 100% in amputation-only males, p<0.001), but not in females, indicating sex-specific differences. Histologic analysis demonstrated neuroma formation in amputation-only rats but not in iTMR rats. Retrograde labeling confirmed both sensory and motor axons entered the motor branch post-iTMR. These findings demonstrate that iTMR provides analgesia and prevents neuroma formation following amputation, with cold hypersensitivity responses differing by sex. This supports the utility of the hindlimb iTMR model and highlights the need for continued mechanistic investigation and sex-specific analyses in future studies.

Perspective

Using a rat hindlimb amputation model to evaluate iTMR, we demonstrate its potential to mitigate neuropathic pain and symptomatic neuroma formation and reveal sex-specific responses to cold hypersensitivity. These findings indicate the potential clinical utility of iTMR in improving pain outcomes, providing more tailored approaches to pain management in amputees.

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大鼠后肢截肢模型显示立即定向肌肉神经再支配的镇痛和性二态冷过敏。

靶向肌肉神经移植（Targeted muscle reinneuration， TMR）已在临床上用于减轻截肢者的疼痛，但其潜在的镇痛机制尚不清楚。我们建立了一个大鼠膝下截肢模型来评估雄性和雌性Sprague-Dawley大鼠即刻TMR （iTMR）后的疼痛结果。动物随机分为单纯截肢组和iTMR截肢组，并评估反射性疼痛行为（von Frey， pin和冷超敏反应）和自发疼痛行为（保护，退缩和糖偏好作为快感缺乏的衡量标准）。逆行标记用于追踪感觉和运动神经元，并确认神经适应模式。与单纯截肢相比，iTMR显著减少痛觉过敏和快感缺乏。到四周时，针试验显示iTMR大鼠的反应（25%）比对照组（51%,p=0.01）下降，iTMR大鼠对蔗糖的偏好更高（76%对43%，p=0.01）。在接受itmr治疗的男性中，冷敏感性反应降低了49%，而在只截肢的男性中，冷敏感性反应降低了100%

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Pain 医学-临床神经学

CiteScore

6.30

自引率

7.50%

发文量

441

审稿时长

42 days

期刊介绍： The Journal of Pain publishes original articles related to all aspects of pain, including clinical and basic research, patient care, education, and health policy. Articles selected for publication in the Journal are most commonly reports of original clinical research or reports of original basic research. In addition, invited critical reviews, including meta analyses of drugs for pain management, invited commentaries on reviews, and exceptional case studies are published in the Journal. The mission of the Journal is to improve the care of patients in pain by providing a forum for clinical researchers, basic scientists, clinicians, and other health professionals to publish original research.