Analgesic Effects of Topical Amitriptyline in Patients With Chemotherapy-Induced Peripheral Neuropathy: Mechanistic Insights From Studies in Mice

JOURNAL OF PAIN

卷:22

Article

Genevois, Anne-Laure¹  Ruel, Jerome²  Penalba, Virginie²  Hatton, Severine¹  Petitfils, Camille³  Ducrocq, Myriam²  Principe, Paola⁴  Dietrich, Gilles³  Greco, Celine^1,5  Delmas, Patrick² 

[1] Necker Hosp Sick Children, AP HP, Dept Pain & Palliat Care Unit, 149 Rue Sevres, F-75015 Paris, France

[2] Aix Marseille Univ, Cognit Neurosci Lab, CNRS, UMR 7291, Marseille, France

[3] Toulouse Univ, IRSD, INSERM, INRA,ENVT,UPS, Toulouse, France

[4] AlgoTherapeutix, Suresnes, France

[5] Paris Saclay Univ, INSERM, UMR S935, Villejuif, France

关键词: Amitriptyline;    chemotherapy-induced peripheral neuropathy;    analgesics;    topical administration;    voltage-gated sodium channels;    nociceptive sensory neurons;    transient receptor potential ankyrin 1;    nociceptors;    Nav1.8;    Nav1.7 and Nav1.9 isoforms;   

DOI  :  10.1016/j.jpain.2020.11.002

来源: Elsevier

【 摘 要 】

Oral amitriptyline hydrochloride (amitriptyline) is ineffective against some forms of chronic pain and is often associated with dose-limiting adverse events. We evaluated the potential effectiveness of high-dose topical amitriptyline in a preliminary case series of chemotherapy-induced peripheral neuropathy patients and investigated whether local or systemic adverse events associated with the use of amitriptyline were present in these patients. We also investigated the mechanism of action of topically administered amitriptyline in mice. Our case series suggested that topical 10% amitriptyline treatment was associated with pain relief in chemotherapy-induced peripheral neuropathy patients, without the side effects associated with systemic absorption. Topical amitriptyline significantly increased mechanical withdrawal thresholds when applied to the hind paw of mice, and inhibited the firing responses of C-, Ab- and Ad-type peripheral nerve fibers in ex vivo skin-saphenous nerve preparations. Whole-cell patch-clamp recordings on cultured sensory neurons revealed that amitriptyline was a potent inhibitor of the main voltage-gated sodium channels (Nav1.7, Nav1.8, and Nav1.9) found in nociceptors. Calcium imaging showed that amitriptyline activated the transient receptor potential cation channel, TRPA1. Our case series indicated that high-dose 10% topical amitriptyline could alleviate neuropathic pain without adverse local or systemic effects. This analgesic action appeared to be mediated through local inhibition of voltage-gated sodium channels. Perspective: Our preliminary case series suggested that topical amitriptyline could provide effective pain relief for chemotherapy-induced peripheral neuropathy patients without any systemic or local adverse events. Investigation of the mechanism of this analgesic action in mice revealed that this activity was mediated through local inhibition of nociceptor Nav channels. (C) 2020 The Author(s). Published by Elsevier Inc. on behalf of United States Association for the Study of Pain, Inc.

【 授权许可】

Free