Masticatory myalgia to headache-like secondary hypersensitivity induces gene plasticity at dura mater

Patients with myofascial pain in the head and neck region often report widespread, referred pain or secondary hypersensitivity, including headache-like. Secondary hypersensitivity originating from masticatory myalgia may result from myalgia-induced plasticity within the central nervous system, affecting referred site sensitization. The main aims of this study were to develop animal models that mimic secondary hypersensitivity and to investigate whether stimulated myalgia induces gene expression plasticity at referred sites, which may contribute to the secondary hypersensitivity phenomenon. A majority of experiments were conducted in male and female mice. Masticatory myalgia was assessed as mechanical hypersensitivity in the region over the masseter muscle (MM). Secondary hypersensitivity was evaluated by measuring mechanical hypersensitivity at sites anatomically distinct from the stimulated muscle: periorbital and MM areas. Stimulated myalgia was achieved by either a single high-dose collagenase type-II (10U; Col) or repeated low-dose Col (0.2–0.5U) injections into the MM or the temporal muscle (TM), repetitive gentle vibration applied over the MM, a single forceful mouth opening (FMO), or repeated FMO. Statistical analyses were one-way or two-way ANOVA followed by Bonferroni post-hoc tests. Stimulation of the MM, whether by single, repeated Col injections or FMO, produced inconsistent and short-lasting (1–2 days) referred pain at a periorbital area in both males and females. In contrast, stimulation of the TM using multiple paradigms reliably induced mechanical secondary hypersensitivity in two referred sites: MM and periorbital areas. MM stimulation did not exhibit sex-dependent mechanical hypersensitivity in the MM area. In contrast, TM-induced secondary hypersensitivity at both the MM and periorbital areas was sex-dependent. Secondary hypersensitivity in the MM and periorbital regions following TM stimulation was accompanied by significant gene expression plasticity in both tissues. Notably, transcriptional changes in the MM after Col injection into the TM closely resembled those observed following direct Col injection into the MM. The presented data suggest that secondary hypersensitivity from masticatory myalgia can be effectively modeled in mice through stimulation of the TM. Importantly, TM stimulation-induced transcriptomic changes at MM and dura mater may generate nociceptive signaling from these sites, thereby contributing to an input network underlying secondary hypersensitivity.

Authors

Institutions

Publication Details

Journal
The Journal of Headache and Pain
Published
2026-04-15
DOI
https://doi.org/10.1186/s10194-026-02361-8
Primary Topic
Temporomandibular Joint Disorders
Type
article
Field-Weighted Citation Impact
0.00

Funders

Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

Masticatory myalgia to headache-like secondary hypersensitivity induces gene plasticity at dura mater

Michael J. Iadarola, Tristan Maerz, Yona Levites, Malin Ernberg et al.
The Journal of Headache and Pain
Temporomandibular Joint Disorders
article

Masticatory myalgia to headache-like secondary hypersensitivity induces gene plasticity at dura mater

Michael J. Iadarola, Tristan Maerz, Yona Levites, Malin Ernberg, Spencer Fullam, Lindsey J. Macpherson, Kevin Otto, Racel Cela, Sienna Perry, Brian A. Goolsby, Merissa Olmer, Dawen Cai, M. Danilo Boada, Janak Gaire, Stacey Greene, Alexus Roberts, E. Wang, M.Franklin Dolwick, M. E. Martone, Wei Guo, Dongjun Ren, Folly Patterson, Joshua J. Emrick, Jyl Boline, Jun Li, Joost Wagenaar, Alexei V. Tumanov, Elizabeth Ronan, Jiansen Yan, Bruna Balbino de Paula, Jennifer Mecklenburg, Joshua D. Wythe, Zixue Jin, Zelong Dou, Yangjin Bae, Sudhish Jayachandran, Jessica Aldape, Ibdanelo Cortez, Ke Ren, Lai Wang, Jiale Yang, Abbas Muhammad, Marlena Pela, Jacqueline Boccanfuso, Mairobys Soccorro Gonzalez, Kaitlin M. Southern, Airam Vivanco‐Estela, Benjamin Arenkiel, Azeez Ishola, Margarete Ribeiro Dasilva, Michael Strinden, Hernan Prieto, Kim Worley, Brendan Lee, Martin Lotz, Alia Obeidat, Sue Tappan, Miguel Otero, Rachel Miller, Dana Orange, Frank Ko, Chris Donnelly, Luis Miguel Trujillo Sánchez, Shingo Ishihara, Basak Ayaz, Priya Kulkarni, Yi Zou, Zhao Lai, Akash Gandhi, Robert Caudle, Oscar Ruiz, Dellina Lane Carpio, Rui Chen, Russell Ray, Armen N. Akopian, Anahit H. Hovhannisyan, Yenisel Cruz-Almeida, Michael Newton, Yufang Jin, Joshua Stover, Richard Miller, Kyle Allen, Bella Mehta, Camilla Majano, Jessie Alfaro, Nele Haelterman, M. Danilo. Boada, Alejandro Almarza, Anita Bandrowski, Brian Constantinescu, Shad Smith, Yong Chen, Shane Priester, Hannah Swahn, Danielle Freburg-Hoffmeister, Theodore Price
article en

Abstract

Patients with myofascial pain in the head and neck region often report widespread, referred pain or secondary hypersensitivity, including headache-like. Secondary hypersensitivity originating from masticatory myalgia may result from myalgia-induced plasticity within the central nervous system, affecting referred site sensitization. The main aims of this study were to develop animal models that mimic secondary hypersensitivity and to investigate whether stimulated myalgia induces gene expression plasticity at referred sites, which may contribute to the secondary hypersensitivity phenomenon. A majority of experiments were conducted in male and female mice. Masticatory myalgia was assessed as mechanical hypersensitivity in the region over the masseter muscle (MM). Secondary hypersensitivity was evaluated by measuring mechanical hypersensitivity at sites anatomically distinct from the stimulated muscle: periorbital and MM areas. Stimulated myalgia was achieved by either a single high-dose collagenase type-II (10U; Col) or repeated low-dose Col (0.2–0.5U) injections into the MM or the temporal muscle (TM), repetitive gentle vibration applied over the MM, a single forceful mouth opening (FMO), or repeated FMO. Statistical analyses were one-way or two-way ANOVA followed by Bonferroni post-hoc tests. Stimulation of the MM, whether by single, repeated Col injections or FMO, produced inconsistent and short-lasting (1–2 days) referred pain at a periorbital area in both males and females. In contrast, stimulation of the TM using multiple paradigms reliably induced mechanical secondary hypersensitivity in two referred sites: MM and periorbital areas. MM stimulation did not exhibit sex-dependent mechanical hypersensitivity in the MM area. In contrast, TM-induced secondary hypersensitivity at both the MM and periorbital areas was sex-dependent. Secondary hypersensitivity in the MM and periorbital regions following TM stimulation was accompanied by significant gene expression plasticity in both tissues. Notably, transcriptional changes in the MM after Col injection into the TM closely resembled those observed following direct Col injection into the MM. The presented data suggest that secondary hypersensitivity from masticatory myalgia can be effectively modeled in mice through stimulation of the TM. Importantly, TM stimulation-induced transcriptomic changes at MM and dura mater may generate nociceptive signaling from these sites, thereby contributing to an input network underlying secondary hypersensitivity.

The Journal of Headache and PainVol. 27(1)
University of Maryland, Baltimore (US), The University of Texas at San Antonio Health Science Center (US), Karolinska Institutet (SE), Children's Cancer Center (US), Wake Forest University (US)
University of Texas at Dallas, National Institutes of Health, University of Texas Health Science Center at San Antonio, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institute of Dental and Craniofacial Research
Good health and well-being
Openalex Percentile: Top 21%
Temporomandibular Joint Disorders
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.