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

Abstract

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: A{beta} low-threshold mechanoreceptors, A{delta} high-threshold mechanoreceptors (A{delta}-HTMRs), and peptidergic neurons (PEP). All three types are recruited by mechanical stimulation, with massage being a particularly effective stimulus. Chemogenetic activation of masseter A{delta}-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. SignificanceMuscle sensation is usually most prominent when something goes wrong: after overuse, injury, or inflammation, even ordinary pressure or movement can become painful. Yet how mechanical force is detected in muscle, and when a stimulus becomes painful, remain poorly understood. Here, we identify a simple cellular organization for muscle mechanosensation in which three sensory-neuron classes encode force through graded population recruitment. Massage effectively recruited all three classes, including the two nociceptive populations. We further show that these nociceptive neurons are sensitized by acute and chronic inflammation, leading to enhanced recruitment during massage. These findings show that the representation of mechanical force in muscle can be shaped by tissue state and provide a foundation for understanding muscle soreness, pain, and therapeutic touch.