CAREER: Alternative Non-Opioid Therapies for Low Back Pain

University Of Nebraska-Lincoln, Lincoln NE

Investigators

Abstract

While the majority of the population will experience low back pain during their lifetime, over 25% of these people will go on to suffer from chronic unresolved low back pain. Pain medicine is a common treatment for chronic low back pain patients and often results in addiction, which is a huge problem in the United States. This problem can be reduced by creating treatments that target pain directly at its source and thus reduce the need for the systemic pain medicines. Chronic low back pain can arise from the discs in the spine. Nerves can grow into these discs and be a source of pain. The hypothesis of this project is that local delivery of treatments can reduce low back pain by causing existing nerves to retract and by preventing re-growth of new nerves. As such, the research goal of this project is to understand undesired nerve growth and to engineer treatments for local delivery to prevent and reverse nerve growth. The project will identify and test compounds that cause retraction of and prevent regrowth of nerve fibers. In parallel with the research goal, the major education goal is to present this new back pain research to both scientific and public audiences and to train students to communicate with varied audiences. Therefore, this project will train students and peer faculty in the communication of science and educate the local community over the age of 50 about low back pain. Taken together, the completion of this project will provide the foundation for the principal investigator's career in low back pain research while preparing the next group of engineers and increasing knowledge among the general public about low back pain and treatments. The principal investigator's long-term career research goal is to develop novel biomaterial-based treatments for musculoskeletal pain. Toward this goal, this project will engineer targeted biomaterials that will prevent and reverse the sprouting of painful (nociceptive) sensory nerve fibers into the previously nerve-free nucleus pulposus (NP) core of intervertebral discs (IVD), which is one of the major causes of chronic low back pain (LBP). The project's overarching hypothesis is that local delivery of therapeutic biomaterials and compounds can alleviate pain and prevent chronicity by causing existing nerves to retract or dieback and prevent re-growth of painful nerve fibers. The Research Plan is organized under three objectives. The FIRST OBJECTIVE is to identify and test compounds that cause dieback of undesired sensory nerve fibers and characterize mechanisms of dieback. Studies will be performed in 3D cell cultures in which neurite extensions have been grown from trimmed dorsal root ganglion (DRG) harvested from rat pups. Myelin associated glycoprotein (MAG) and Resiniferatoxin (RTX), two compounds associated with dieback after spinal cord injury and in cell culture studies, will be added to the culture medium and dieback of neurite extensions will be assessed. Studies are designed to determine ideal concentrations of MAG and RTX to cause dieback of sensory neurons in vitro, to assess cell health of DRGs and NP cells with dieback compounds and to differentially assess how MAG and/or RTX impact gene expression of pain-associated ion channels in sensory neurite subsets, and therefore downstream pain. The SECOND OBJECTIVE is to develop novel materials to prevent undesired nerve growth. Studies will be performed in 3D gel cocultures consisting of a human derived NP core surrounded by a gel containing rat derived DRGs and matrix support for the NP core. Various compositions of microparticles containing methacrylated chondroitin sulfate A and C (MA-CS-A and MA-CS-C), which are known to be neuro-inhibitory, will be incorporated into the NP core and their ability to prevent nerve ingrowth will be assessed. Studies are designed to develop a neurological 3D in vitro mimic of NP with tunable composition for long term culture of NP cells and DRGs, to determine CS concentration and type effects on DRG growth in vitro, to verify mechanism of inhibition and to fabricate microparticles for injectable delivery of neuro-inhibitors, enabling in vivo delivery. The THIRD OBJECTIVE is to test efficacy of identified materials and compounds to prevent and reverse LBP in an animal model. Studies will be performed in a rat lumber disc puncture model that has been used extensively as a model of disc degeneration. Ten weeks after puncture, animals will be divided into 5 treatment groups depending on results obtained in objectives 1 and 2: MAG or RTX dieback compounds, MA-CS-A or MA-CS-C microparticles, dieback compound and microparticles, type I collagen control or sham surgical control. The degree and resolution of pain will be assessed using a novel rodent gait analysis. Studies are designed to identify novel biomaterial and compound combinations that alleviate pain and stabilize the disc in an animal model of LBP and to increase understanding of the effects of biomaterials/compounds on neurites in the NP. Determining the effectiveness of these therapeutics to directly treat LBP without the use of addictive pain medications has the potential to lead to new treatments that will greatly benefit patients and society. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.