Developing Non-Opiate GPCR Signaling-Biased Agents for Pain Management
Abstract
Chronic pain is a common medical complaint that arises in over a quarter of healthcare visits, costs over 600 billion dollars a year in lost productivity and pain-related treatment, and disproportionally affects active-duty and retired military personnel. Chronic pain has become the number one reason to see a doctor, and when it is persistent and unrelieved contributes to depression, anxiety, decreased quality of life, poor sleep patterns, and may lead to suicidal ideation, and substance use disorders. To this day, opioids are the best medication to relieve chronic pain. They have become a mainstay pain therapy for all classes of patients, and their use doubled in the decade from 2000-2010 to include more than 20% of office visits. Commonly approved prescription medications that are opioids include codeine, hydrocodone, morphine, oxycodone, and fentanyl; and abused opioids associated with illegal use include heroin and heroin/fentanyl combinations. Opioid drugs work by binding opioid receptors, but chronic exposure of these receptors to either legally prescribed or illegally acquired opioid drugs is invariably associated with the development of opioid dependence, and this has become a leading cause of death from accidental overdoses. There are currently no satisfactory medications that can effectively and safely prevent the development of opioid dependence; thus, there is an urgent need to develop non-opioid drugs for pain management therapies that either replace opioids or substantially lessen their use/dependence. Neurotensin is a natural peptide hormone found in the gastrointestinal tract (GI) tract and brain that binds to non-opioid receptors that have been shown in animal models to alleviate pain. However, neurotensin is not druggable because of its fast degradation and moreover, it has a limiting side effect profile because it induces life-threatening hypotension and hypothermia. In our investigations of neurotensin receptors, we have discovered a druggable molecule, SBI-553, that binds to neurotensin receptors and improves the binding of neurotensin to them as well, while simultaneously blocking the limiting side effects of neurotensin. SBI-553, when tested in a mouse model investigating opioid drugs, not only antagonizes the addictive/rewarding behavior associated with the opioid remifentanil, but it also appears effective against neuropathic pain. Our preliminary electrophysiology data in spinal cord slices in mice indicates that SBI-553 blocks spontaneous excitatory nerve currents responsible for pain. In our proposed study, we will test in mice whether SBI-553 can effectively block various categories of chronic pain. Moreover, since SBI-553 can essentially block the rewarding/addictive effects of opioids, it may be possible to combine both SBI-553 and opioids to obtain even a more effective paradigm for chronic pain management. This proposal addresses the topic area Non-Opioid Therapy for Pain Management including the development of non-opioid and anti-addictive pain management therapies. Specifically, our research team, with respective expertise in G-protein coupled receptor (GPCR) signaling and pain research, aims to develop a novel therapeutic based on the biased signaling of the neurotensin receptor 1 (NTSR1) for treating acute and chronic pain. We will test our hypothesis that SBI-553 and its Investigational New Drug (IND)-ready analogs SBI-810 can effectively attenuate neuropathic pain and surgical pain in mouse and rat pain models through the following four specific aims. Aim 1 and Aim 2 (Initiating Principal Investigator PI): Determine selectivity and efficacy of SBI-553 and IND lead compounds (Aim 1) and determine pharmacokinetic properties and acute toxicity of lead compounds in mice (Aim 2). Aim 3 and Aim 4 (Partnering PI): Test the analgesic effects of lead compounds in mouse models of acute pain and chronic pain and a rat model of neuropathic pain (Aim 3) and determine th
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210266
Entities
People
- Lawrence S Barak
Organizations
- Duke University
- United States Army