 Pain after surgery is a common and important problem. And much research has focused on understanding the underlying mechanisms responsible for this complication. Now, a new study published in the journal Anesthesiology sheds light on the cause of this pain when surgical wounds reach deep muscle tissue. When an incision is made during surgery, reactive oxygen species are produced as a way to fight infection and aid in healing. One of these, hydrogen peroxide, is known to activate the pain-related ion channel, TRIP-A1. But few studies have investigated the role of this molecule as a pain mediator in deep muscle tissue. To investigate this, a team of researchers at the University of Iowa evaluated the actions of hydrogen peroxide on pain-related signals of deep muscle tissue in rats and mice. They found that when hydrogen peroxide solution was injected into this tissue, the animal spent a considerable amount of time exhibiting pain-like behaviors, such as flinching, lifting, and licking their legs, and developed an aversion to the environment associated with this injection. Additionally, these deep muscle injections caused sustained activity of spinal cord neurons that process sensory input. When administered just under the skin, however, these behaviors were insignificant. To test if these pain-related behaviors are mediated via TRIP-A1, the team evaluated the effect of TRIP-A1 antagonists, which block this ion channel before hydrogen peroxide injections. The animals that received these antagonists showed fewer pain-related behaviors. Genetically modified mice containing a disrupted TRIP-A1 gene also showed significantly less pain-related behavior after hydrogen peroxide injection. The greater sensitivity of muscle tissue to the injections may help explain why incisions that include deep muscle are more troublesome to patients than those that include only superficial skin tissue. These findings provide important insights into the underlying mechanisms responsible for postoperative pain and highlight novel targets for improved treatment of patients undergoing surgery or suffering major trauma.