Deep-tissue mechanosensation emerges from the interaction of external force and internal tissue state

<jats:p>Muscle sensation is often considered in terms of proprioception, but muscle pain illustrates that other types of sensory neurons are also involved. Here, we show that trigeminal neurons innervating the masseter muscle fall into three classes: Aβ low-threshold mechanoreceptors, Aδ high-threshold mechanoreceptors (Aδ-HTMRs), and peptidergic neurons (PEP). All three types are recruited by mechanical stimulation, with massage being a particularly effective stimulus. Chemogenetic activation of masseter Aδ-HTMRs and PEP neurons results in pain-like symptoms. Moreover, acute and chronic inflammation sensitize nociceptors, altering behavioral tolerance in an animal model of massage. Taken together, our results provide a framework for understanding muscle somatosensation and how massage of sore muscles may be painful yet beneficial.</jats:p>