{"doi":"10.1101/2024.06.19.599732","title":"Mouse models of non-dystrophic and dystrophic myotonia exhibit nociplastic pain-like behaviors","abstract":"Abstract Pain is a prominent and debilitating symptom in myotonic disorders, including myotonia congenita and myotonic dystrophy type 1 (DM1). Although patients frequently report chronic pain, its underlying mechanisms remain poorly defined. In both disorders, impaired chloride conductance through voltage-gated CLC-1 chloride channels in skeletal muscle disrupts membrane repolarization, leading to delayed relaxation and persistent muscle hyperexcitability. Here, we investigated the pathophysiology of pain in mouse models of acute and chronic myotonia. In the acute model, a single intraperitoneal injection of anthracene-9-carboxylic acid (9-AC, 30 mg/kg), a selective ClC-1 antagonist, induced transient muscle stiffness, cramping, and gait abnormalities, followed by prolonged pain-like behavior, including static and dynamic mechanical allodynia, thermal hyperalgesia, and cold hypersensitivity for up to 48 hours. Whole-cell patch-clamp recordings from dorsal root ganglion neurons demonstrated increased action potential firing in small diameter sensory neurons, consistent with enhanced peripheral excitability of putative nociceptors. Compound action potentials from isolated sciatic nerves revealed that 9-AC impaired A-fiber recruitment and stimulus-response gain without affecting conduction velocity, suggesting a reduction in non-nociceptive fiber input that may disinhibit central nociceptive processing. To assess central mechanisms of sensitization, we performed in vivo fiber photometry of the parabrachial nucleus (PBN), a key supraspinal hub for pain signaling. Mice treated with 9-AC exhibited exaggerated PBN responses to normally innocuous mechanical and cold stimuli, indicative of enhanced central nociceptive transmission. Having established that acute myotonia can evoke both peripheral and central sensitization, we next examined whether chronic myotonic activity in a disease-relevant genetic model produces similar pathophysiological changes. To model chronic myotonia, we evaluated HSA LR20b mice, a transgenic model of DM1 carrying a skeletal muscle-specific CTG repeat expansion. These mice displayed persistent mechanical and thermal hypersensitivity, along with elevated dorsal root ganglia neuron excitability, supporting sustained peripheral sensitization in a genetic model of myotonic disease. Together, these findings establish robust preclinical models of myotonic pain and demonstrate that myotonia drives a prolonged nociplastic pain state through combined peripheral and central mechanisms. These results provide a foundation for future studies aimed at identifying and validating therapeutic targets for pain associated with myotonic disorders.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":498702,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9621,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":964288,"name":"Aida Calderón‐Rivera","orcid":"0000-0002-0129-2848","position":1,"is_corresponding":false},{"id":863583,"name":"Heather N. Allen","orcid":"0000-0003-0771-1959","position":2,"is_corresponding":false},{"id":401586,"name":"Emanuel Loeza‐Alcocer","orcid":"0000-0002-3655-0376","position":3,"is_corresponding":false},{"id":693439,"name":"Jorge Baruch Pineda-Farías","orcid":"0000-0002-4734-5909","position":4,"is_corresponding":false},{"id":1345306,"name":"Narges Pachenari","orcid":"0000-0001-5528-6008","position":5,"is_corresponding":false},{"id":254848,"name":"Kimberly Gómez","orcid":"0000-0003-1867-5041","position":6,"is_corresponding":false},{"id":964287,"name":"Santiago Loya‐López","orcid":"0000-0001-6207-8370","position":7,"is_corresponding":false},{"id":1040610,"name":"Erick J. Rodríguez‐Palma","orcid":"0000-0002-9940-363X","position":8,"is_corresponding":false},{"id":880662,"name":"Paz Duran","orcid":"0000-0001-8729-8636","position":9,"is_corresponding":false},{"id":401588,"name":"Michael S. Gold","orcid":"0000-0002-2083-6206","position":10,"is_corresponding":false},{"id":254857,"name":"Rajesh Khanna","orcid":"0000-0002-9066-2969","position":11,"is_corresponding":false},{"id":325506,"name":"Tyler S. Nelson","orcid":"0000-0002-6675-4820","position":0,"is_corresponding":true}],"reference_count":111,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:09:42.181447Z","pmid":"38948724","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}