Funded Projects

This project will use a variety of technologies to create a comprehensive, 3D map of how sensory neurons activate knee joints in both mice and humans. The research will use imaging techniques and molecular approaches that measure gene expression. The findings will help create a comprehensive gene expression profile map of individual cells in the nerve fibers leading to the knee, as well as describe how nerve cells and joint cells interact at the most fundamental level. This research will generate a rich anatomical and molecular resource to understand the molecular basis of joint pain and guide the development of novel pain-relieving strategies.

The study team developed an mHealth pain self-management intervention for the perioperative period (SurgeryPal) to target psychosocial risk factors and teach pain self-management skills. The goal of this proposal is to establish the effectiveness of the SurgeryPal psychosocial intervention to improve clinically meaningful outcomes in adolescents undergoing major musculoskeletal surgery, and to identify the optimal timing of intervention delivery. The study team will plan for the efficient implementation of a multisite randomized clinical trial at 25 centers in 500 youth ages 12–18 years undergoing spinal fusion surgery and their parents. Participants will be randomized to receive SurgeryPal or attention control condition during the preoperative and postoperative phases. Self-reported pain severity and interference and secondary outcomes will be assessed at baseline, 3-, and 6-months. If effective, this scalable, low cost intervention will allow broad implementation to prevent chronic postsurgical pain in youth.

Some chemotherapy treatments damage nerves outside the brain and spinal cord. This condition, chemotherapy-induced peripheral neuropathy, involves tingling, burning, weakness, or numbness in hands and/or feet and affects nearly 70% of cancer patients receiving chemotherapy. Common pain medications, including opioids, can relieve pain for short intervals but are not suitable for long-term therapy. This project will develop and test a new type of treatment (reduced size cyclic analogs) for this condition. The research will evaluate the ability of this therapy to reduce inflammation and pain, as well as to repair nerve damage.

More than half of children and adolescents diagnosed with a type of cancer called bone sarcoma experience pain that interferes with daily life. This project will adapt an evidence-based cognitive behavioral therapy mobile app for use with Black and Hispanic adolescents who disproportionately experience pain from this cancer, putting them at risk for opioid misuse. Once fully adapted, this therapy will be paired with a remotely delivered brain stimulation treatment (transcranial direct current stimulation). This research will also examine the impact of patient-reported conditions such as depression, anxiety, and sleep problems, as well as of various social determinants of health, on pain.

Neuropathic pain conditions are exceedingly difficult to treat, and novel non-opioid analgesics are desperately needed. Receptomic and unbiased transcriptomic approaches recently identified the orphan G-protein coupled receptor (oGPCR), GPR160, as a major oGPCR whose transcript is significantly increased in the dorsal horn of the spinal cord (DH-SC) ipsilateral to nerve injury, in a model of traumatic nerve-injury induced neuropathic pain caused by constriction of the sciatic nerve in rats (CCI). De-orphanization of GPR160 led to the identification of cocaine- and amphetamine-regulated transcript peptide (CARTp) as a ligand which activates pathways crucial to persistent pain sensitization. This project will test the hypothesis that CARTp/GPR160 signaling in the spinal cord is essential for the development and maintenance of neuropathic pain states. It will also validate GPR160 as a non-opioid receptor target for therapeutic intervention in neuropathic pain, and characterize GPR160 coupling and downstream molecular signaling pathways underlying chronic neuropathic pain.

Up to 5 percent of adolescents suffer from high-impact chronic musculoskeletal (MSK) pain, and only about 50 percent with chronic MSK pain who present for treatment recover. Current treatments for chronic MSK pain are suboptimal and have been tied to the opioid crisis. Discovery of robust markers of the recovery versus persistence of pain and disability is essential to develop more resourceful and patient-specific treatment strategies, requiring measurements across multiple dimensions in the same patient cohort in combination with a suitable computational analysis pipeline. Preliminary data has implicated novel candidates for neuroimaging, immune, quantitative sensory, and psychological markers for discovery. In addition, a standardized specimen collection, processing, storage, and distribution system is in place, along with expertise in machine learning approaches to extract reliable and prognostic bio-signatures from a large and complex data set. This project will facilitate risk stratification and a resourceful selection of patients who are likely to respond to current multidisciplinary pain treatment approaches.

The research team has developed ultrasonic drug uncaging for neuroscience, in which neuromodulatory agents are uncaged from ultrasound-sensitive biocompatible and biodegradable drug-loaded nanocarriers. This project will clinically translate ultrasonic ketamine uncaging for chronic pain therapy. In the UG3 phase, the research team will scale our nanoparticle production processes to human scales and adapt them to pharmaceutical standards. In the UH3 phase, they will complete a first-in-human evaluation of the safety and efficacy of ultrasonic ketamine uncaging by quantifying how much ketamine is released relative to the ultrasound dose and assessing whether the uncaged ketamine can modulate the sensitivity and affective response to pain, in patients suffering from chronic osteoarthritic pain. This project aims to yield a novel, noninvasive, non-opioid therapy for chronic pain that maximizes the therapeutic efficacy of ketamine over its side effects, by targeting its action to a critical hub of pain processing.

Multidisciplinary chronic pain treatments show incomplete recovery at the population level because of significant heterogeneity on the individual level in the high impact chronic pain population. Subgroups of individuals either completely respond, do not change, or even worsen following pain management. Therefore, diagnostic biomarker signatures are needed to differentiate high impact chronic pain from low impact chronic pain. This study aims to develop prognostic biomarkers to predict the disease trajectory for individuals with musculoskeletal high-impact chronic pain. These biomarker signatures will integrate central nervous system (CNS), multi-?omic?, sensory, functional, psychosocial, and demographic domains into detection algorithms. Biomarker signatures from the proposed research are intended to facilitate risk and treatment stratification for clinical trial design and to facilitate treatment decisions in clinical practice for patients with musculoskeletal chronic pain.

Most of the 200k Americans who undergo thoracotomy each year receive opiates to reduce postoperative pain because clinicians have few non-addictive, cost-effective choices to control the severe pain patients often experience in the first two weeks after surgery. Managing pain post-thoracotomy is critical to enable patients to take deep breaths and remove (via coughing) lung secretions that otherwise significantly increase risk of pneumonia and collapsed lung, hospital re-admission and morbidity. The most severe pain associated with thoracotomy is transmitted along the intercostal nerves, but no long-term analgesic or nerve block device exists that can provide safe and effective long-term reduction of pain. A reversible, patient-controlled, non- addictive, intercostal nerve block device would reduce suffering due to thoracotomy, broken ribs and herpes zoster. In this Phase I project, the team will develop a minimally invasive thermal nerve block device that can control nerve conduction by gently warming and cooling a short nerve segment between room temperature and warm water temperature. This novel approach is based on the discovery that warm and cool temperature mechanisms of nerve block are different and additive, enabling moderate-temperature nerve block by cycling neural tissues slightly above and below body temperature. Reversible thermal nerve blocks represent a completely new approach to managing pain.  

Postoperative pain is a major contributor to the current opioid epidemic. Novel objective measures capable of personalizing pain care will enhance medical precision in prevention and treatment of postoperative pain. This project seeks to discover and validate a novel biosignature of the human pain experience, based on underlying IL-1 family cytokine activity and associated brain endogenous opioid function, that is readily quantifiable and clinically translatable to prevention and treatment of postoperative pain states. Specific aims will assess whether the novel biosignature will predict 1) experimentally induced pain during an experimental nociceptive pain challenge; 2) postoperative pain states with accuracy >75%, accounting for a wide range of variance in the human pain experience; and 3) postoperative pain states in an expanded clinically enriched sample.

Neuropathic corneal pain (NCP) causes patients to have severe discomfort and a compromised quality of life (QoL). The lack of signs observed by standard examination has resulted in misdiagnosis as dry eye disease (DED). An optical biopsy using laser in vivo confocal microscopy (IVCM) revealed that microneuromas (bulbs at the ends of severed nerves caused by buildup of molecular constituents) are present in NCP but not DED and may serve as a biomarker for NCP. The aims are to (1) use a database of more than 2,000 DED/NCP subjects and more than 500,000 IVCM images to confirm that the presence of microneuromas is an appropriate biomarker for NCP, (2) provide biological validation of microneuromas, (3) develop a validated artificial intelligence (AI) program for automated identification of microneuromas, and (4) establish the clinical utility of microneuromas observed by IVCM as a biomarker for NCP in a prospective, multicenter study.

A substantial proportion of Americans seeking emergency care after traumatic stress exposure (TSE) are at a high risk of chronic pain and opioid use/misuse. Physiologic systems involved in the stress response could possibly play a critical role in the development of chronic pain after TSE. FK506-binding protein 51 (FKBP51) is an intracellular protein known to affect glucocorticoid negative feedback inhibition and component of stress response, provides an important non-opioid therapeutic target for such chronic pain. This project will test the hypothesis that functional inhibition of FKBP51 prevents or reduces enduring stress-induced hyperalgesia in a timing, dose, and duration-dependent manner in animal models of single prolonged stress alone and in combination with surgery. This project will also test if FKBP51 inhibition enhances recovery following TSE via reduction in pro-inflammatory responses in peripheral and central tissues. It will also test whether FKBP51 inhibition effects cardiotoxicity or addiction. Completion of these studies will increase understanding of FKBP51 as a novel therapeutic target for the prevention of chronic pain and opioid use/misuse resulting from TSE.