Accepted

To investigate the impact of having headaches prior to traumatic brain injury (TBI) on headache features and long-term patient health outcomes.

Development of chronic pain is related to aberrant neuroimmune signaling. Small extracellular vesicles (sEVs) are 30-150nm size particles of endosomal origin. They play an important role in neuroimmune crosstalk facilitating transfer of biomolecular cargo between cells. Our studies show that sEVs from RAW 264.7 macrophage cells can be therapeutic or prophylactic in mouse model of inflammatory pain. We investigated the mechanistic basis of how sEVs from lipopolysaccharide (LPS) stimulated (Exo+) and unstimulated (Exo-) cells impact primary glial cells, dendritic cells (DCs) and adaptive immune cells such as CD4 T cells. We hypothesize that macrophage derived sEVs can potentiate T cell activation directly, or indirectly by the upregulation of major histocompatibility complex-II (MHC-II) and co-stimulatory molecules on DCs, attenuating pain hypersensitivity. We will also test if sEVs confer protection to glial cells in the context of inflammation.

This article comprehensively covers 3 major novel technologies and techniques in the management of chronic lower back pain. The first 2 procedures, percutaneous interspinous spacer implantation, and minimally invasive lumbar decompression have shown significant impact in the management of lumbar spinal stenosis (LSS), especially in patients who are not great surgical candidates or are otherwise not amenable to open spinal surgery. The wealth of data for these procedures continues to increase, with up to 4 to 6-year follow-up data recently being made available. A novel solution for vertebrogenic back pain is also discussed as follow-up data emphasizes the safety and sustainability of the procedure. This article also establishes a framework for evaluating novel technologies in interventional pain management.

Phospholipase C β (PLCβ) plays an important role in cardiovascular diseases and opioid analgesia. PLCβ catalyzes the hydrolysis of the inner membrane lipid phosphatidylinositol-4,5-bisphosphate (PIP ) to inositol-1,4,5-triphosphate (IP ) and diacylglycerol (DAG). IP and DAG are crucial secondary messengers that activate multiple signaling pathways and modulate gene expression to control responses to extracellular signals. PLCβ is a downstream effector of G-protein coupled receptors (GPCRs) and is activated by both the Gα and Gβγ subunits. Activation by Gα requires a unique 400 amino acid C-terminal region of the lipase, which is subdivided into the proximal and distal C-terminal domains (CTDs). These domains are required for allosteric activation by Gα and for membrane binding. Our lab and others have reported that PLCβ is more flexible in solution, as compared to crystal structures of the protein. In small angle X-ray scattering (SAXS) experiments, the solution structure of PLCβ had additional density that cannot be accounted by the crystal structure. Additionally, crosslinking the PH and EF hand domains decreased this density and the maximum particle diameter. We propose that this additional density corresponds to an open conformation, wherein the PH and EF hand domains are extended from the core of the lipase, and that this conformation of PLCβ represents an autoinhibited state. To test this hypothesis, we mutated residues in PLCβ3 at the interface between the PH and EF hand domains to disrupt their interaction, and then measured changes in PLCβ basal activity and Gβγ-stimulated activity. These mutations had no significant impact on basal activity, however in many of these mutants, there was a decrease in apparent Gβγ activation. Since these mutations should stabilize an open conformation of PLCβ, this suggests the open conformation has less ability to bind to or be activated by Gβγ. We are currently working to solve the structure of PLCβ3 in solution using single particle cryo-electron microscopy (cryo-EM), which will allow us to determine a solution structure of PLCβ to a higher resolution than SAXS studies. We hypothesize that PLCβ3 will exist in the open, autoinhibited conformation, and will also shed light on possible allosteric interactions between the distal CTD and the core.

Opioids are commonly prescribed for the treatment of neuropathic pain; however, their high rates of physical dependency and addiction raise concern. Given their adverse side effects, there is a need for new therapeutics that target non-opioid receptors. GPR183 (Epstein-Barr induced gene 2, EBI2) is a G-protein coupled receptor (GPCR) that plays a role in the transduction of neuropathic pain. SAE-14 is a novel molecule that is able to antagonize, or inhibit GPR183; thus, preventing the transmission of pain. To gain a better understanding of which substituents improve the binding between SAE-14 and GPR-183, it is necessary to synthesize several analogs of the molecule. We have developed a structure-activity-relationship for GPR183 antagonism and the results from this gives a better understanding of the functional groups that are necessary for GPR183 antagonism and improve to the compound's potential therapeutic for neuropathic pain treatment.

This article provides a detailed description of peripheral joint radiofrequency ablation and its contemporary use in the treatment of chronic knee, hip, and shoulder pain. Special attention is given to anatomy and innervation of the joints discussed, technical approach, selection criteria, contraindications, and patient outcomes.