Receptors in Endosomes Mediate Chronic Pain Associated with Trauma and Stress: Nonopioid Targets for Pain

The sensation of pain is an evolutionarily conserved mechanism of protection that is required for the well-being and survival of an organism. Pain allows avoidance of a dangerous stimulus and the awareness of injury. The importance of pain is highlighted by the plight of individuals with congenital defects in their ability to detect painful stimuli; they cannot sense the pain from a stab wound, an open flame, or a broken bone, and consequently can suffer from life-threatening injuries. Normal, protective pain is a tightly regulated and transient sensation that does not persist when the noxious stimulus is removed. However, when dysregulated, pain becomes sustained or chronic and can persist long after removal of the noxious stimulus or healing of an injury. Chronic pain is a major cause of human suffering; it hampers recovery, disrupts quality of life, and is poorly understood. Current treatments for chronic pain are often ineffective and can have unacceptable side effects. The opioid epidemic highlights the problems of therapy for chronic pain. Opioids do not work for all people all of the time; their effectiveness wanes with continued use, which leads to a requirement for higher doses; they can be addictive, and they can cause severe constipation, respiratory depression, and death. Military personnel and Veterans suffer from disproportionate levels of chronic pain. Explosions and concussions lead to severe headache, major multiple trauma causes pain due to nerve damage, and gastrointestinal infections lead to abdominal pain. This grant application aims to understand how normal, protective pain changes to become abnormal, deleterious pain and seeks to develop new treatments for chronic pain faced by injured military personnel and Veterans. The surface of pain-sensing nerves is replete with sensors of painful stimuli. These sensors, or receptors, can detect many noxious substances that are produced by injured tissues. One strategy to inhibit pain is to develop drugs that block the function of receptors at the surface of pain-sensing nerves. However, the Initiating Principal Investigator has discovered that, during chronic pain, receptors move from the surface to sites deep within the nerves. Receptors inside nerves, rather than at the surface, are responsible for long-lasting pain. Drugs that can inhibit receptors inside nerves provide superior and long-lasting relief from pain. Conventional drugs that are unable to penetrate nerves cannot effectively inhibit these receptors, which may explain their limited effectiveness in patients. The overall goal of this application is to develop new drugs that inhibit receptors inside pain-sensing nerves and to evaluate their effectiveness in models of pain in mice that replicate features of chronic pain experienced by injured military personnel and Veterans, including headache pain, nerve injury pain, and abdominal pain. If successful, this research will identify new classes of drugs that can be further developed for evaluation of their effectiveness to treat chronic pain in injured Soldiers and Veterans. Importantly, the drugs that will be developed are not opioids and do not share the deleterious side effects of opioids. The new drugs that will be developed will reduce reliance on opioids and will provide a major benefit to society. The research has broad implications that extend beyond the military. The management of chronic pain is a major problem for the civilian population. One in five individuals suffer from chronic pain during their lives, and the opioid crisis highlights the challenges of treating chronic pain. The information derived from this research will allow development of new therapies for chronic pain in the civilian population. The implications of this research extend beyond the treatment of pain. The types of receptors that are the subject of this proposal are members of a 1,000-strong family of receptors that are found on all cells in