1. A new clinically-relevant rat model of letrozole-induced chronic nociceptive disorders
- Author
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Damien Richard, Alain Eschalier, Raalib Amode, Julie Vein, Bruno Pereira, Yohann Wittrant, Aurore Collin, Christelle Guillet, David Balayssac, Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Unité de Nutrition Humaine (UNH), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Clermont Auvergne (UCA), Direction de la recherche clinique et de l’innovation [CHU Clermont-Ferrand] (DRCI), CHU Clermont-Ferrand, University of East Anglia [Norwich] (UEA), Centre de Recherche en Nutrition Humaine Auvergne [CHU Clermont-Ferrand] (CRNH A), and CHU Clermont-Ferrand-CHU Clermont-Ferrand
- Subjects
0301 basic medicine ,myalgia ,Nociception ,medicine.medical_specialty ,medicine.drug_class ,Ovariectomy ,Motor Activity ,Toxicology ,Rats, Sprague-Dawley ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Ganglia, Spinal ,medicine ,Animals ,Aromatase ,Pharmacology ,biology ,business.industry ,Aromatase Inhibitors ,Letrozole ,Body Weight ,Myalgia ,Arthralgia ,Pathophysiology ,3. Good health ,Rats ,Disease Models, Animal ,030104 developmental biology ,Endocrinology ,Gene Expression Regulation ,Estrogen ,030220 oncology & carcinogenesis ,TRPA1 Rat ,Chronic Disease ,biology.protein ,Ovariectomized rat ,[SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology ,Female ,Animal studies ,medicine.symptom ,business ,medicine.drug - Abstract
International audience; Among postmenopausal women with estrogen receptor-positive breast cancer, more than 80% receive hormone therapy including aromatase inhibitors (AIs). Half of them develop chronic arthralgia - characterized by symmetric articular pain, carpal tunnel syndrome, morning stiffness, myalgia and a decrease in grip strength - which is associated with treatment discontinuation. Only a few animal studies have linked AI treatment to nociception, and none to arthralgia. Thus, we developed a new chronic AI-induced nociceptive disorder model mimicking clinical symptoms induced by AIs, using subcutaneous letrozole pellets in ovariectomized (OVX) rats. Following plasma letrozole dosage at the end of the experiment (day 73), only rats with at least 90 ng/ml of letrozole were considered significantly exposed to letrozole (OVX + high LTZ group), whereas treated animals with less than 90 ng/ml were pooled in the OVX + low LTZ group. Chronic nociceptive disorder set in rapidly and was maintained for more than 70 days in the OVX + high LTZ group. Furthermore, OVX + high LTZ rats saw no alteration in locomotion, myalgia or experimental anxiety during this period. Bone parameters of the femora were significantly altered in all OVX rats compared to Sham+vehicle pellet. A mechanistic analysis focused on TRPA1, receptor suspected to mediate AI-evoked pain, and showed no modification in its expression in the DRG. This new long-lasting chronic rat model, efficiently reproduces the symptoms of AI-induced nociceptive disorder affecting patients' daily activities and quality-of-life. It should help to study the pathophysiology of this disorder and to promote the development of new therapeutic strategies.
- Published
- 2020
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