Spontaneous and Bite-Evoked Muscle Pain Are Mediated by a Common Nociceptive Pathway With Differential Contribution by TRPV1

J Pain. 2017 Nov;18(11):1333-1345. doi: 10.1016/j.jpain.2017.06.005. Epub 2017 Jun 29.


Spontaneous pain and function-associated pain are prevalent symptoms of multiple acute and chronic muscle pathologies. We established mouse models for evaluating spontaneous pain and bite-evoked pain from masseter muscle, and determined the roles of transient receptor potential cation channel subfamily V member 1 (TRPV1) and the contribution of TRPV1- or neurokinin 1 (NK1)-dependent nociceptive pathways. Masseter muscle inflammation increased Mouse Grimace Scale scores and face-wiping behavior, which were attenuated by pharmacological or genetic inhibition of TRPV1. Masseter inflammation led to a significant reduction in bite force. Inhibition of TRPV1 only marginally relieved the inflammation-induced reduction of bite force. These results suggest a differential extent of contribution of TRPV1 to the 2 types of muscle pain. However, chemical ablation of TRPV1-expressing nociceptors or chemogenetic silencing of TRPV1-lineage nerve terminals in masseter muscle attenuated inflammation-induced changes in Mouse Grimace Scale scores as well as bite force. Furthermore, ablation of neurons expressing NK1 receptor in trigeminal subnucleus caudalis also prevented both types of muscle pain. Our results suggest that TRPV1 differentially contributes to spontaneous pain and bite-evoked muscle pain, but TRPV1-expressing afferents and NK1-expressing second-order neurons commonly mediate both types of muscle pain. Therefore, manipulation of the nociceptive circuit may provide a novel approach for management of acute or chronic craniofacial muscle pain.

Perspective: We report the profound contribution of TRPV1 to spontaneous muscle pain but not to bite-evoked muscle pain. These 2 types of muscle pain are transmitted through a common nociceptive pathway. These results may help to develop new strategies to manage multiple modes of muscle pain simultaneously by manipulating pain circuits.

Keywords: Muscle pain; dorsal horn; inflammation; nociceptors; orofacial pain; transient receptor potential vanilloid 1; vanilloids.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Bite Force
  • Disease Models, Animal
  • Facial Pain / etiology
  • Facial Pain / metabolism*
  • Facial Pain / pathology
  • Freund's Adjuvant
  • Inflammation / metabolism
  • Male
  • Masseter Muscle / metabolism
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Myalgia / etiology
  • Myalgia / metabolism*
  • Myalgia / pathology
  • Neurons / metabolism
  • Neurons / pathology
  • Nociceptive Pain / etiology
  • Nociceptive Pain / metabolism*
  • Nociceptive Pain / pathology
  • Pressure
  • Random Allocation
  • Receptors, Neurokinin-1 / metabolism
  • TRPV Cation Channels / genetics
  • TRPV Cation Channels / metabolism*
  • Trigeminal Nuclei / metabolism
  • Trigeminal Nuclei / pathology


  • Receptors, Neurokinin-1
  • TRPV Cation Channels
  • TRPV1 protein, mouse
  • Freund's Adjuvant