Funded Projects

NOFO Title: Notice of Special Interest for HEAL Initiative: Request for Administrative Supplements to Existing Grants for Identification and Validation of New Pain and Opioid Use Disorder Targets within the Understudied Druggable Genome
NOFO Number: NOT-TR-20-008
Summary:

G-protein coupled receptor 3 (GPR3) is an orphan receptor present in the central nervous system (CNS) that plays important role in many normal physiological functions and is involved in a variety of pathological conditions. Although the brain chemical that activates this receptor has not been identified, work with GPR3 knockout mice has identified GPR3 as a novel drug target for several Central Nervous System (CNS) mediated diseases including neuropathic pain. However, despite the emerging behavioral implications of the GPR3 system, little is known about how GPR3 affects behavior due to the lack of potent and selective chemical probes that allow scientists to examine functioning of the receptor. Recently, two cannabinoid chemicals present in the cannabis plant were discovered as affecting GPR3. This study will modify the chemical structure of these compounds to increase their potency and selectivity so that they may be used as pharmacological tools to investigate the role of GPR3 in modulating pain. In addition, this project focuses on identifying new compounds that show promise for development into therapeutics for the treatment of pain.

NOFO Title: Notice of Special Interest to Encourage Eligible NIH HEAL Initiative Awardees to Apply for Administrative Supplements to Promote Training in Clinical Research on Pain (Admin Supp ? Clinical Trial Not Allowed)
NOFO Number: NOT-NS-20-044
Summary:

Chronic low back pain is difficult to diagnose and treat effectively in part, because of the interplay of biophysical and psychosocial influences that complicate the relationship between impairment, disability, and pain. Psychological factors such as fear of movement and catastrophyzing can lead to compensatory movement patterns that affect movement biomechanics and paraspinal structure and function, driving further impairment, disrupting the balance between passive and active spine stabilizers, and reinforcing the patient?s perceived disability status. This study will support research to determine how psychological factors, spinal pathology, and perception of pain severity and disability status influence compensatory movement strategies, how movement biomechanics, psychological factors, and pain mechanisms relate to paraspinal muscle quality, and their relative changes during treatment. The supplement will provide training opportunities for skills in clinical pain management research.

NOFO Title: Notice of Special Interest: HEAL Supplements to Improve the Treatment and Management of Common Co-occurring Conditions and Suicide Risk in People Affected by the Opioid Crisis
NOFO Number: NOT-MH-20-025
Summary:

People with opioid use disorders (OUD) have high rates of co-occurring alcohol, stimulant and other drug disorders, as well as mental disorders. Traditionally, treatment for OUD has been ?siloed? even though these high rates of co-occurring conditions emphasize the need for comprehensive treatment to address holistic needs. As the opioid crisis continues, attention to the whole person and access to comprehensive mental health and substance use treatment as well as primary care is needed. This study aims to better understand co-occurring mental health disorders, alcohol use disorders, and/or other substance use disorders among people with OUD, in the context of innovative integrated care networks for people with OUD. This study examines how innovative OUD treatment models work for individuals with co-occurring mental health and substance use by 1) assessing mental health treatment quality measures and outcomes; 2) testing how these innovative treatment models compare to other OUD treatment for people who have OUD and other substance use disorders; and 3) considering the ways people with OUD access co-occurring disorder care. The findings from this study will provide needed information to improve mental health, alcohol, and other substance use treatment for individuals with OUD, whether or not they are in OUD treatment and may provide information to help move the system from siloed efforts to truly integrated care

NOFO Title: Discovery and Validation of Novel Targets for Safe and Effective Pain Treatment (R01 Clinical Trial Not Allowed)
NOFO Number: RFA-NS-18-043
Summary:

This project aims to validate Peptidase Inhibitor 16 (PI16) as a novel target for the treatment of chronic pain using mouse models and tissues of human patients with neuropathy. PI16 was identified as a novel regulator of chronic pain in preclinical bench studies. PI16 is a small molecule that has not been studied in the context of pain. Mice that are deficient for PI16 function are protected against mechanical allodynia (tactile pain from light touch) in spared nerve injury (SNI) and paclitaxel models of neuropathic pain. PI16 is only detectable in fibroblasts around peripheral nerves (perineurium), and in the meninges of dorsal root ganglia (DRG), spinal cord, and brain, but not in neurons, glia or leukocytes. PI16 levels in perineurial and DRG meningeal fibroblasts increase during neuropathic pain. Increased PI16 secretion by DRG meningeal and perineurial fibroblasts may promote chronic pain by increasing blood nerve barrier (BNB) permeability and leukocyte trafficking into nerve and DRG.

NOFO Title: HEAL Initiative: Pragmatic and Implementation Studies for the Management of Pain to Reduce Opioid Prescribing (PRISM) (UG3/UH3, Clinical Trials Optional)
NOFO Number: RFA-AT-20-004
Summary:

Back pain is the most common chronic pain diagnosis and the most common diagnosis for which opioids are prescribed. Clinical practice guidelines make it clear that nonpharmacologic treatments are preferable to opioids for patients with back pain. Despite clear evidence, over-prescribing of opioids to individuals with back pain continues. Providers of nonpharmacologic care are often absent or unreachable from rural and low-income communities and patients with limited financial resources. Many rural and low-income communities are served by Federally Qualified Health Centers (FQHCs) that are at the forefront of the opioid crisis, but often lack adequate options to provide accessible nonpharmacologic treatments. This pragmatic clinical trial will compare the effectiveness of different telehealth strategies to provide effective nonpharmacologic interventions to overcome the barriers specific to serving rural and low-income communities. The trial will evaluate two strategies, one providing both a brief pain teleconsult with phone-based physical therapy, the other uses an adaptive strategy ? providing the brief pain teleconsult first, followed by phone-based physical therapy to those who need additional treatment. The study will also evaluate outcomes related to the efforts to implement strategies in FQHC clinics. This research will provide a toolkit for future efforts to make nonpharmacological interventions for back pain available in other low resource health care settings.

NOFO Title: Notice of Special Interest for HEAL Initiative: Request for Administrative Supplements to Existing Grants for Identification and Validation of New Pain and Opioid Use Disorder Targets within the Understudied Druggable Genome
NOFO Number: NOT-TR-20-008
Summary:

The cannabis plant contains many active compounds known collectively as cannabinoids that have been shown to possess analgesic and anti-inflammatory properties. These compounds exert their biological activity, in part, through the cannabinoid receptor. The cannabinoid receptor is a member of a class of proteins known as G-protein coupled receptors (GPCRs). This study will test whether a GPCR with unknown biological function, called Gpr149, has a role in the activity of cannabinoids. The study will identify and characterize Gpr149 expression in mouse cells, and deeply characterize the action of minor cannabinoids, endocannabinoids and products of inflammation to modulate Gpr149. This research will provide insight into the analgesic and anti-inflammatory action of minor cannabinoids and into the role of Gpr149 in nociception and the sensitization of nociceptors to inflammatory mediators.

NOFO Title: HEAL Initiative: Notice of Special Interest (NOSI) regarding the Availability of Administrative Supplements to Support Strategies to Reduce Stigma in Pain Management and Opioid Use Disorder (OUD) and Treatment
NOFO Number: NOT-OD-20-101
Summary:

While advances in cancer treatment have increased survival rates, these patients often suffer from chronic cancer pain. Prescription opioids are often prescribed during active cancer treatment, but their long-term use for chronic cancer pain is associated with risk for opioid use disorder and risk for stigmatization associated with emotional distress, suboptimal health behaviors and coping strategies, and difficult patient-provider communication. This study aims to conduct qualitative interviews exploring prescription opioid and chronic pain stigma in cancer survivors with moderate-to-severe pain, caregivers, and clinicians who treat patients with chronic cancer pain, including oncologists, primary care providers, pain management specialists, and palliative care physicians. An analysis of potential contributors to stigma in cancer survivors will be completed to support development of multi-level behavioral interventions to reduce stigma and explore long-term health outcomes from such interventions.

NOFO Title: Notice of Special Interest: HEAL Supplements to Improve the Treatment and Management of Common Co-occurring Conditions and Suicide Risk in People Affected by the Opioid Crisis
NOFO Number: NOT-MH-20-025
Summary:

This study will evaluate the implementation of the Zero Suicide framework across six health systems serving over nine million people in collaboration with the Mental Health Research Network. The project will incorporate the voice of the patient and provider stakeholders as part of the implementation of the Zero Suicide framework in three health settings from the NIMH-funded parent award as well as the Southcentral Foundation which is an Alaska Native-owned, nonprofit health care organization serving nearly 65,000 American Indian/Alaskan Native people living in and around Anchorage, Alaska. The team will first systematically engage patients, providers, national consumer advocacy groups, and MHRN scientists in formulating research questions to address the prevention of opioid-related overdoses in people with Opioid Use Disorders (OUD) or people without diagnosed OUD who are using opioids for pain management. Next, the team will utilize semi-structured interviews to determine how people with OUD or people without diagnosed OUD who are using opioids for pain management are experiencing the implementation of the Zero Suicide framework in four diverse health systems. Experiences will be recorded using 80 semi-structured phone interviews in a diverse sample of patients who have survived an opioid-related overdose (50% intentional; 50% unintentional), as well as 20 Addiction Medicine, Primary Care, and/or Specialty Pain Medicine providers.

NOFO Title: Discovery and Validation of Novel Targets for Safe and Effective Pain Treatment (R01 Clinical Trial Not Allowed)
NOFO Number: RFA-NS-18-043
Summary:

Chemotherapy-induced painful peripheral neuropathy (CIPN) is the most common toxicity associated with widely used chemotherapeutics. CIPN accounts for significant dose reductions and/or discontinuation of these life-saving treatments. Unfortunately CIPN can also persist in cancer-survivors, adversely affecting their quality of life. CIPN is not well-managed with existing pain therapeutics. Recent preliminary findings suggest that the transcription factor hypoxia-inducible factor alpha (HIF1A) is the target for the chemotherapeutic bortezomib, a proteasome inhibitor. This project will test the hypothesis that bortezomib chemotherapy-induced expression of HIF1A, PDHK1 and LDHA constitute an altered metabolic state known as aerobic glycolysis (AG) that leads to the initiation and maintenance of peripheral neuropathy and pain using a novel tumor-bearing animal model of CIPN. This project aims to validate HIF1A as a therapeutic target for the prevention of CIPN, as well as validate PDHK1 and LDHA as non-opioid therapeutic targets for chronic or established CIPN in animal models.

NOFO Title: Development of Medications to Prevent and Treat Opioid Use Disorders and Overdose (UG3/UH3) (Clinical Trial Optional)
NOFO Number: RFA-DA-19-002
Summary:

Medication-based treatment for opioid use disorder OUD aids in reducing mortality, opioid withdrawal, intake and opioid-seeking behaviors, however there is a clear need to increase the armamentarium of therapeutics for OUD. The ?non-classical? NOcicePtin receptor (NOPr) binds the endogenous neuropeptide nociceptin/orphanin FQ (N/OFQ) and is a promising target based on the evidence for its function in the regulation of the rewarding and motivational effects of opioids and alcohol. This study plans to assess the ability of the novel and selective NOPr antagonist BTRX-246040 to block oxycodone intake without abuse liability, and to suppress oxycodone withdrawal and relapse-like behaviors in rats. The study will also determine Drug Metabolism and Pharmacokinetics interactions (DMPK) between oxycodone and BTRX-246040 and brain penetrability in male and female rats. If successful, these preclinical studies will be followed by a Phase 1 clinical trial in non-treatment seeking OUD participants. These investigations will advance the prospects of validating a novel medication for OUD.

NOFO Title: Notice of Special Interest for HEAL Initiative: Request for Administrative Supplements to Existing Grants for Identification and Validation of New Pain and Opioid Use Disorder Targets within the Understudied Druggable Genome
NOFO Number: NOT-TR-20-008
Summary:

There is an urgent unmet need for more efficacious analgesics that act via a non-opioid pathway. Mitogen Activated Protein Kinase-interacting kinase 2 (MNK2) is an enzyme that has been implicated in pain signaling, and there is compelling evidence that inhibiting MNK2 has significant pain-reducing effects with few side-effects. Since MNK2 selective inhibitors have not yet been identified, selective inhibition of MNK2 with a small molecule has not been possible. The development of such compounds will enable studies that will illuminate key differences between MNK2 and MNK1. More importantly, from a therapeutic standpoint, highly selective MNK2 inhibitors may prove to have enhanced efficacy and a more favorable side-effect profile than molecules that inhibit both MNK2 and MNK1. This project will support the design and synthesis of at least one MNK2 inhibitor, with >100-fold selectivity over MNK1, that may be developed into a lead compound for treating neuropathic pain.

NOFO Title: Notice of Special Interest to Encourage Eligible NIH HEAL Initiative Awardees to Apply for Administrative Supplements to Promote Training in Clinical Research on Pain (Admin Supp ? Clinical Trial Not Allowed)
NOFO Number: NOT-NS-20-044
Summary:

Multiple factors, including inflammation contribute to chronic low back pain. Inflammation is mediated by numerous genes. The study aims to determine how variations in the genes encoding key inflammatory mediators impact the response of patients with chronic low back pain to physical therapy treatment. Gene variations that are known to be linked to inflammation and pain will be tested against their possible association on physical therapy treatment outcomes, to inform clinical decisions on optimal care. This study will support training in clinical research on pain within the context of the HEAL BACPAC Mechanistic Research Center. It will provide resources for a research project relevant to the parent grant and the career development of an individual in the field of pain research. The ability to identify a set of genetic variations and classify patients according to treatment response might enable use of DNA testing as a screening tool for targeted treatments for patients with CLBP.

NOFO Title: Notice of Special Interest: HEAL Supplements to Improve the Treatment and Management of Common Co-occurring Conditions and Suicide Risk in People Affected by the Opioid Crisis
NOFO Number: NOT-MH-20-025
Summary:

Homeless youth have high rates of alcohol and drug use, comorbid mental health conditions, and are at high risk for suicide. However, few preventive interventions have been proven for reducing substance use or addressing suicide among homeless youth. Resolution of youth homelessness through housing and prevention services, often referred to as ?Housing First? (HF), will be tested in the HOME (Housing, Opportunities, Motivation and Engagement) study, which aims to reduce opioid use and progression to opioid use disorder (OUD). This study will include suicide screening, treatment, education and prevention (STEP) to the model to examine whether HF provides secondary benefits for reducing suicidal ideation and behaviors among high risk homeless youth. STEP includes ongoing suicide screening procedures and Cognitive Therapy for Suicide Prevention (CTSP) for those at high risk for suicide. Youth (N=240) will be randomly assigned to receive HF + STEP + opioid and related risk prevention services (strengths-based outreach and advocacy; HIV Prevention; and motivational Interviewing) or to receive STEP + opioid and related risk prevention services, alone. Results from this study will inform the design and implementation of other national models of HF to address prevention of substance use and suicidal ideation and behaviors among homeless youth.