Persistent mechanical hyperalgesia, associated with peripheral inflammation and tissue injury, impairs patient’s quality of life and daily activity. However, its molecular mechanism and treatment are yet to be deciphered. Herein, we report that Tmeme45b is expressed in a subset of unmyelinated primary sensory neurons and plays an essential role in inflammation and tissue injury-induced mechanical hyperalgesia. Our findings provide new insights into the mechanisms and the treatment of mechanical hyperalgesia.