Funded Projects

Cholecystokinin B receptor (CCKBR) is a molecule found in the brain that helps regulate anxiety and depression but also influences the development of tolerance to opioids. CCKBR levels are also increased in models of nerve injury-induced (neuropathic) pain. Therefore, targeting CCKBR may offer a new approach to treating neuropathic pain and the associated anxiety and depression. Researchers have developed mouse antibodies that can inactivate CCKBR. However, to be usable in humans without causing an immune response, these antibodies need to be modified to include more human sequences. This project will use a fragment of the CCKBR antibody, modify it with the addition of human antibody sequences, and then select the clones that bind most strongly and specifically to human CCKBR. These will then be tested in cell and animal models of neuropathic pain to identify the most promising candidates for further evaluation in humans.

Most opioid misuse begins during adolescence and young adulthood. Adolescence is the best time for prevention interventions in settings like school-based health centers (HCs), yet few programs focus on preventing initiation of opioid misuse. This study harnesses the power of video game interventions and incorporates components of effective substance use prevention programs to develop an evidence-informed intervention to prevent the initiation of opioid misuse in adolescents. In partnership with the national School-Based Health Alliance (SBHA), researchers will develop and test a new video game intervention, PlaySmart. It will build on our previous video game intervention that has demonstrated efficacy in improving attitudes and knowledge related to risk behaviors. The study will evaluate the game in a randomized controlled trial in 10 school-based HCs and examine strategies for implementing PlaySmart in school-based HCs nationally. This research has considerable potential for wide implementation, reach, and impact on high-risk adolescents through school-based HCs.

The parent project’s Housing First initiative can be divided into two interconnected goals: (1) to reduce the likelihood of substance misuse and the development of an opioid use disorder and (2) to provide youth with housing stability and opioid and related risk prevention services that will assist them in exiting homelessness. The proposed supplement project complements the goals of the parent grant project by exploring two additional components that are related to exiting homelessness and reducing substance misuse or the development of opioid use disorder: (1) to further investigate youth’s interactions with social service providers, via qualitative methods, with the goal of cultivating a detail understanding actionable practices as it relates to fostering successful interactions between substance using homeless youth and service providers and (2) to evaluate, via quantitative methods, the extent to which ethnic identity protects youth from the negative effects of discrimination, substance misuse, and the development of a opioid use disorder.

Disruptions in make-up of the microbiome are associated with disorders characterized by chronic pain and inflammation, such as rheumatoid arthritis and fibromyalgia. The gut microbiome has immune and metabolic effects, and human gut-derived bacteria may be a source of novel, safe, and non-addictive pain treatments. However, connections between gut and pain signals, known as the “gut–pain axis,” are still poorly understood. This study aims to identify human-gut-native bacteria that i) interact with known pain targets in lab studies, ii) test their activity and analgesic/anti-inflammatory potential in an animal model, and iii) develop a computational approach to predict microbial-genetic effects on pain signals.

The need to develop non-opioid therapeutics for chronic pain is greater than ever.  One option being explored is inhibiting the activity of calpains – enzymes that have been shown to cause pain in animal models of chronic pain.  Using an artificial intelligence (AI)-driven drug discovery platform, researchers have uncovered and validated four calpain-1 inhibitors using biochemical assays.  This study by 1910 Genetics Inc. hopes to synthesize multiple analogs of its most potent discovered calpain-1 inhibitor and determine its effectiveness against calpain-2 and certain enzymes that break down proteins.  Findings that successfully significantly inhibit calpain-1 in at least one animal model of chronic pain could lead to the first oral, central nervous system penetrating selective calpain-1 inhibitor [non-opioid therapeutic] for chronic pain.

Knee osteoarthritis is one of the leading causes of disability worldwide, particularly among older adults. Despite multiple guidelines for care, most patients do not receive adequate treatment, and about 30% are prescribed long-term opioids. This award will be used to recruit and support an early career faculty member from a group underrepresented in biomedicine. This research, part of the Pain Management Effectiveness Research Network will evaluate conservative and more aggressive treatments for knee osteoarthritis and determine which individual-level factors contribute to treatment outcomes.

Patients with severe, intractable chronic pain primarily receive treatment with opioids, and non-opioid treatment options are urgently needed. These patients may be candidates for treatment using other types of pain medications administered via intrathecal injection—that is, injection directly into the fluid-filled space between the membranes surrounding the brain and spinal cord. Intrathecal injection requires much lower medication doses than systemic administration. Centrexion Therapeutics Corporation seeks to develop CNTX-3100, a highly selective and highly potent novel small molecule that activates the nociception receptor (NOPr), for intrathecal administration using a pump approved by the U.S. Food and Drug Administration. In animal studies, such NOPr agonists had powerful analgesic effects when delivered directly to the spinal cord by intrathecal administration. CNTX-3100 has ideal properties for intrathecal delivery and in animal studies provided pain relief and a safety profile that was superior to intrathecally administered morphine. This project will scale up the drug, develop a formulation that ensures a stable product for intrathecal delivery, and conduct preclinical toxicity studies to prepare for a Phase 1 clinical trial.

Over-the-counter medicines such as non-steroidal anti-inflammatory drugs are ineffective for treating severe chronic pain and may have serious side effects from continued use, which limits treatment options. A kinase (an enzyme whose activity targets a specific molecule) called TAK1 is involved in the chronic pain process. This research will develop a molecule previously shown to be effective in a model of inflammatory pain that also inhibits TAK1. A main goal will be to determine if this inhibitor (takinib analog HS-276) can cross the blood-brain barrier and, if successful, pursue FDA  Investigative New Drug-enabling safety studies leading to a Phase I clinical trial and a potential new chronic pain treatment.

The ACT NOW Outcomes of Babies with Opioid Exposure (OBOE) Study – also called the ACT NOW Longitudinal Study – is a longitudinal cohort study to prospectively examine longitudinal outcomes from birth to 2 years of age among infants who were exposed to opioids in utero as compared to matched controls. The objectives of this study are to i) determine the impact of pre-birth opioid exposure on brain structure and connectivity over the first 2 years of life, ii) define medical, developmental, and behavioral outcomes over the first 2 years of life in infants exposed to opioids, and iii) Explore whether and how the home environment, maternal mental health, and parenting affect brain connectivity and neurodevelopment trajectories over the first 2 years of life. This research will use an innovative approach to engage a more diverse study population and thereby improve the generalizability of the research findings.

Chronic overlapping pain conditions represent up to half of all chronic pain cases and can be more debilitating than other forms of chronic pain. These conditions include but are not limited to the following: temporomandibular disorders, fibromyalgia, irritable bowel syndrome, vulvodynia, interstitial cystitis/painful bladder syndrome, painful endometriosis, chronic tension type headache, migraine headache, chronic low back pain, and chronic fatigue syndrome. Common neurobiological mechanisms have been suspected to account for the overlap between these conditions, but until recently it has been difficult to efficiently classify each condition within individual patients. A digital classification tool for clinicians has been developed for this purpose, but access to the tool remains limited. Here we propose converting this chronic overlapping pain conditions classification tool into a common web-based application format.

The NIH Back Pain Consortium (BACPAC) Research Program brings together leading centers with expertise in studying and treating chronic low back pain to advance understanding of the mechanisms that underlie the condition and to identify novel treatment strategies. BACPAC is undertaking a multisite precision medicine clinical trial taking into account patient-specific information to understand which patients with chronic low back pain respond best to various nonopioid, evidence-based treatments. The trial seeks to enroll a racially, ethnically, and socioeconomically diverse patient population to ensure that the results are applicable to all Americans with chronic low back pain. This project aims to develop comprehensive recruitment and retention plans for study sites that can recruit from historically underrepresented populations in clinical research (e.g., Black and Hispanic populations) and to provide dedicated financial resources to engage patients from these populations using tailored, culturally appropriate strategies.

Understanding municipal policies that influence implementation of effective evidence-based practices (EBPs) as well as effective strategies for working with municipal groups may inform local efforts to translate EBPs. Just as important, engaging with local stakeholders may help to facilitate the long-term sustainability of EBPs. This can only occur if diverse local actors in municipal governance are thinking about health and behavioral health in the context of municipal planning and policy. Building from research related opioid use disorder and the risk environment, built environment, and zoning, this research will work to support coalition-based approach currently implemented by the HEALing Communities Study. The research aims to develop an understanding of local policies that may affect implementation of community action plans in the HEALing Communities Study Massachusetts communities.