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Background <p>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.</p> Methods <p>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.</p> Results <p>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.</p> Conclusions <p>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.</p>

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

  • 期刊论文

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  • 发表日期：

    2026年4月15日

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

摘要

Background

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.

Methods

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.

Results

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.

Conclusions

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.