Neuroinflammation drives sex-dependent effects on pain and negative affect in a murine model of repeated mild traumatic brain injury.

The Center for Disease Control and Prevention estimates that 75% of reported cases of traumatic brain injury (TBI) are mild, where chronic pain and depression are 2 of the most common symptoms. In this study, we used a murine model of repeated mild TBI to characterize the associated pain hypersensitivity and affective-like behavior and to what extent microglial reactivity contributes to these behavioral phenotypes. Male and female C57BL/6J mice underwent sham or repeated mild traumatic brain injury (rmTBI) and were tested for up to 9 weeks postinjury, where an anti-inflammatory/neuroprotective drug (minocycline) was introduced at 5 weeks postinjury in the drinking water.

Kappa Opioid Receptors Drive a Tonic Aversive Component of Chronic Pain.

Pain is a multidimensional experience and negative affect, or how much the pain is "bothersome", significantly impacts the sufferers' quality of life. It is well established that the κ opioid system contributes to depressive and dysphoric states, but whether this system contributes to the negative affect precipitated by the occurrence of chronic pain remains tenuous. Using a model of persistent pain, we show by quantitative real-time-PCR, florescence hybridization, Western blotting and GTPgS autoradiography an upregulation of expression and the function of κ opioid receptors (KORs) and its endogenous ligand dynorphin in the mesolimbic circuitry in animals with chronic pain compared with surgical controls.

Migraine and reward system-or is it aversive?

Migraine is a debilitating neurological disorder with grave consequences for both the individual and society. This review will focus on recent literature investigating how brain structures implicated in reward and aversion contribute to the genesis of migraine pain. There exist many overlapping and interacting brain regions within pain and reward circuitry that contribute to negative affect and subjective experience of pain.

The novel role of IL-7 ligation to IL-7 receptor in myeloid cells of rheumatoid arthritis and collagen-induced arthritis.

Although the role of IL-7 and IL-7R has been implicated in the pathogenesis of rheumatoid arthritis (RA), the majority of the studies have focused on the effect of IL-7/IL-7R in T cell development and function. Our novel data, however, document that patients with RA and greater disease activity have higher levels of IL-7, IL-7R, and TNF-α in RA monocytes, suggesting a feedback regulation between IL-7/IL-7R and TNF-α cascades in myeloid cells that is linked to chronic disease progression. Investigations into the involved mechanism showed that IL-7 is a novel and potent chemoattractant that attracts IL-7R(+) monocytes through activation of the PI3K/AKT1 and ERK pathways at similar concentrations of IL-7 detected in RA synovial fluid.

Role of the CCL21 and CCR7 pathways in rheumatoid arthritis angiogenesis.

Objective: To determine the role of CCL21 and its receptor CCR7 in the pathogenesis of rheumatoid arthritis (RA).

Methods: Histologic studies were performed to compare the expression of CCR7 and CCL21 in RA synovial tissue. Next, the role of CCL21 and/or CCR7 in angiogenesis was examined using in vitro chemotaxis, tube formation, and in vivo Matrigel plug assays.

Anti-CXCL5 therapy ameliorates IL-17-induced arthritis by decreasing joint vascularization.

IL-17-induced joint inflammation is associated with increased angiogenesis. However, the mechanism by which IL-17 mediates angiogenesis is undefined. Therefore, the pathologic role of CXCL1 and CXCL5 was investigated in arthritis mediated by local expression of IL-17, employing a neutralizing antibody to each chemokine.

Characterization of interleukin-7 and interleukin-7 receptor in the pathogenesis of rheumatoid arthritis.

Objective: To characterize the expression of interleukin-7 (IL-7) and IL-7 receptor (IL-7R) in rheumatoid arthritis (RA) synovial tissue and to examine their regulation and pathogenic role in macrophages, endothelial cells, and synovial tissue fibroblasts in RA.

Methods: Expression of IL-7 and IL-7R in RA and normal synovial tissue was demonstrated by immunohistochemistry. Expression and regulation of IL-7 and IL-7R in RA peripheral blood in vitro-differentiated macrophages, RA synovial tissue fibroblasts, and human microvascular endothelial cells (HMVECs) were determined by real-time reverse transcription-polymerase chain reaction and/or flow cytometry.

Local expression of interleukin-27 ameliorates collagen-induced arthritis.

Objective: To determine the mechanism of action of interleukin-27 (IL-27) against rheumatoid arthritis (RA).

Methods: Adenovirus containing IL-27 transcript was constructed and was locally delivered into the ankles of mice with collagen-induced arthritis (CIA). Progression of arthritis was determined in treated and untreated mice by measuring ankle circumference and through histologic analysis.

Characterization of CCL19 and CCL21 in rheumatoid arthritis.

Objective: To characterize the expression of CCL19 and CCL21 in rheumatoid arthritis (RA) synovial tissue (ST) and to examine their regulation and pathogenetic role in macrophages and RA ST fibroblasts.

Methods: Expression of CCL19 and CCL21 in RA and normal ST was demonstrated by immunohistochemistry analysis. CCL19 and CCL21 levels in synovial fluid (SF) from patients with osteoarthritis (OA), juvenile idiopathic arthritis, psoriatic arthritis (PsA), and RA were quantified by enzyme-linked immunosorbent assay (ELISA).

IL-17-mediated monocyte migration occurs partially through CC chemokine ligand 2/monocyte chemoattractant protein-1 induction.

Rheumatoid arthritis (RA) is a chronic inflammatory disease that is mediated, in part, by proinflammatory factors produced by RA synovial tissue (ST) fibroblasts and macrophages, resulting in monocyte migration from the blood to the ST. To characterize the potential role of IL-17 in monocyte migration, RA synovial fibroblasts and macrophages were activated with IL-17 and examined for the expression of monocyte chemokines. The two potentially important monocyte chemoattractants identified were CCL20/MIP-3alpha and CCL2/MCP-1, which were significantly induced in RA synovial fibroblasts and macrophages.

IL-17 contributes to angiogenesis in rheumatoid arthritis.

Angiogenesis is an early and a critical event in the pathogenesis of rheumatoid arthritis (RA). Neovascularization is dependent on endothelial cell activation, migration and proliferation, and inhibition of angiogenesis may provide a novel therapeutic approach in RA. In this study, we document a novel role of IL-17 in mediating angiogenesis.

IL-17 induces monocyte migration in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease which is in part mediated by the migration of monocytes from blood to RA synovial tissue, where they differentiate into macrophages and secrete inflammatory cytokines and chemokines. The T cell cytokine IL-17 is expressed in the RA synovial tissue and synovial fluid. To better understand the mechanism by which IL-17 might promote inflammation, its role in monocyte trafficking was examined.

Fatty acyl amides of endogenous tetrahydroisoquinolines are active at the recombinant human TRPV1 receptor.

The SAR of capsazepine revealed that tetrahydroisoquinoline (TIQ) moiety is a core pharmacophore of TRPV1 activity. This implied that conjugates of endogenous TIQs with fatty acids would be active at TRPV1 receptors. Six such compounds were synthesized and tested for calcium mobilization at recombinant TRPV1 receptors overexpressed in HEK293 cells.

Targeted lipidomics: discovery of new fatty acyl amides.

The discovery of endogenous fatty acyl amides such as N-arachidonoyl ethanolamide (anandamide), N-oleoyl ethanolamide (OEA), and N-arachidonoyl dopamine (NADA) as important signaling molecules in the central and peripheral nervous system has led us to pursue other unidentified signaling molecules. Until recently, technical challenges, particularly those associated with lipid purification and chemical analysis, have hindered the identification of low abundance signaling lipids. Improvements in chromatography and mass spectrometry (MS) such as miniaturization of high-performance liquid chromatography components, hybridization of multistage mass spectrometers and time-of-flight technology, the development of electrospray ionization (ESI) and of information-dependent acquisition, now permit rapid identification of novel, low abundance, signaling lipids.