Paclitaxel-induced neuroinflammation after systemic administration in male and female mice.

Peripheral neuropathy is one of the most prevalent neurotoxic, dose-limiting side effects of paclitaxel, a chemotherapy agent used widely in solid cancers. The mechanism of paclitaxel-induced peripheral neuropathy (PIPN) is poorly understood, and thus there are no approved treatments currently. Notably, neuroinflammation has been described as a cardinal component in the pathogenesis of PIPN.

12/15-lipoxygenases mediate toll-like receptor 4-dependent nociplastic pain hypersensitivity in female mice.

Chronic nociplastic pain syndromes are characterized by sensitization of peripheral and central nervous systems and exhibit increased incidence in women. However, nonsteroidal anti-inflammatory drugs are ineffective in mitigating nociplastic pain, and current prescription treatments, such as opioids, anticonvulsants, and antidepressants, provide limited therapeutic benefit for these indications. In the current work, we extended previous studies in rats of central Toll-like receptor 4-dependent pain hypersensitivity to male and female C57BL/6N mice, uncovering an unexpected hyperalgesic phenotype in female mice following intrathecal (IT) lipopolysaccharide (LPS).

Intravenous Streptozotocin Induces Variants in Painful Diabetic Peripheral Neuropathy in Female Mice.

Purpose: At least half of the 34 million diabetic patients in the US develop painful diabetic peripheral neuropathy (DPN). Recent evidence suggests that there are sex differences in the prevalence and mechanisms underlying pathological pain states. However, due to technical limitations in murine models, there is a dearth of the use of females in diabetic neuropathy research.

Intravenous streptozotocin induces variants in painful diabetic peripheral neuropathy in female mice.

Purpose: At least half of the 34 million diabetic patients in the U.S. develop painful diabetic peripheral neuropathy (DPN).

Systems neuroimmunology: current bottlenecks, research priorities and future directions.

Strategies to advance the field of neuroimmunology by embracing its complexity via inclusion of its multidisciplinary properties were discussed at a meeting in Cold Spring Harbor. Attendees proposed fostering of open communications and funding of collaborations across disciplines, and the recognition that our understanding of the neuroimmune system requires interdisciplinary science.

Sensory neuron LKB1 mediates ovarian and reproductive function.

Treatments for reproductive disorders in women consist of hormone replacement therapy, which have negative side effects that impact health, spurring the need to understand new mechanisms to employ new therapeutic strategies. Bidirectional communication between sensory neurons and the organs they innervate is an emerging area of interest in tissue physiology with a relevance in reproductive disorders. We hypothesized that the metabolic activity of sensory neurons has a profound effect on reproductive phenotypes.

B-cell and plasma cell activation in a mouse model of chronic muscle pain.

Fibromyalgia (FM) is a complex chronic musculoskeletal pain disorder with an elusive pathogenesis, with a strong implication of immune interactions. We recently found that IL-5 and the adaptive immune system mediates pain outcomes in fibromyalgia (FM) patients and preclinical models of FM-like chronic widespread pain (CWP). However, there is an active debate if FM/CWP has an autoimmune etiology.

The influence of sex on neuroimmune communication, pain, and physiology.

With the National Institutes of Health's mandate to consider sex as a biological variable (SABV), there has been a significant increase of studies utilizing both sexes. Historically, we have known that biological sex and hormones influence immunological processes and now studies focusing on interactions between the immune, endocrine, and nervous systems are revealing sex differences that influence pain behavior and various molecular and biochemical processes. Neuroendocrine-immune interactions represent a key integrative discipline that will reveal critical processes in each field as it pertains to novel mechanisms in sex differences and necessary therapeutics.

Spinal cord microglia drive sex differences in ethanol-mediated PGE2-induced allodynia.

The mechanisms of how long-term alcohol use can lead to persistent pain pathology are unclear. Understanding how earlier events of short-term alcohol use can lower the threshold of non-painful stimuli, described as allodynia could prove prudent to understand important initiating mechanisms. Previously, we observed that short-term low-dose alcohol intake induced female-specific allodynia and increased microglial activation in the spinal cord dorsal horn.

A programmable microfluidic platform to monitor calcium dynamics in microglia during inflammation.

Neuroinflammation is characterized by the elevation of cytokines and adenosine triphosphate (ATP), which in turn activates microglia. These immunoregulatory molecules typically form gradients in vivo, which significantly influence microglial behaviors such as increasing calcium signaling, migration, phagocytosis, and cytokine secretion. Quantifying microglial calcium signaling in the context of inflammation holds the potential for developing precise therapeutic strategies for neurological diseases.

Transcriptome Analysis of Rheumatoid Arthritis Uncovers Genes Linked to Inflammation-Induced Pain.

Autoimmune diseases such as rheumatoid arthritis (RA) can promote states of chronic Inflammation with accompanying tissue destruction and pain. RA can cause inflammatory synovitis in peripheral joints, particularly within the hands and feet, but can also sometimes trigger temporomandibular joint (TMJ) arthralgia. To better understand the effects of ongoing Inflammation-induced pain signaling, dorsal root ganglia (DRGs) were acquired from individuals with RA for transcriptomic study.

Anti-hyperalgesic and anti-inflammatory effects of 4R-tobacco cembranoid in a mouse model of inflammatory pain.

4R is a tobacco cembranoid that binds to and modulates cholinergic receptors and exhibits neuroprotective and anti-inflammatory activity. Given the established function of the cholinergic system in pain and inflammation, we propose that 4R is also analgesic. Here, we tested the hypothesis that systemic 4R treatment decreases pain-related behaviors and peripheral inflammation via modulation of the alpha 7 nicotinic acetylcholine receptors (α7 nAChRs) in a mouse model of inflammatory pain.

A Programmable Microfluidic Platform to Monitor Calcium Dynamics in Microglia during Inflammation.

Calcium dynamics significantly influence microglial cell immune responses, regulating activation, migration, phagocytosis, and cytokine release. Understanding microglial calcium signaling is vital for insights into central nervous system immune responses and their impact on neuroinflammation. We introduce a calcium monitoring micro-total analysis system (CAM-μTAS) for quantifying calcium dynamics in microglia (BV2 cells) within defined cytokine microenvironments.

Pain and aging: A unique challenge in neuroinflammation and behavior.

Chronic pain is one of the most common, costly, and potentially debilitating health issues facing older adults, with attributable costs exceeding $600 billion annually. The prevalence of pain in humans increases with advancing age. Yet, the contributions of sex differences, age-related chronic inflammation, and changes in neuroplasticity to the overall experience of pain are less clear, given that opposing processes in aging interact.

Sensory neuron LKB1 mediates ovarian and reproductive function.

Treatments for reproductive disorders in women primarily consist of hormone replacement therapy, which can have negative health impacts. Bidirectional communication between sensory neurons and innervated organs is an emerging area of interest in tissue physiology with potential relevance for reproductive disorders. Indeed, the metabolic activity of sensory neurons can have profound effects on reproductive phenotypes.

Inducible co-stimulatory molecule (ICOS) alleviates paclitaxel-induced neuropathic pain via an IL-10-mediated mechanism in female mice.

Chemotherapy-induced peripheral neuropathy (CIPN) is a primary dose-limiting side effect caused by antineoplastic agents, such as paclitaxel. A primary symptom of this neuropathy is pain. Currently, there are no effective treatments for CIPN, which can lead to long-term morbidity in cancer patients and survivors.

Age and sex drive differential behavioral and neuroimmune phenotypes during postoperative pain.

Surgical procedures in the geriatric population are steadily increasing, driven by improved healthcare technologies and longer lifespans. However, effective postoperative pain treatments are lacking, and this diminishes quality of life and recovery. Here we present one of the first preclinical studies to pursue sex- and age-specific differences in postoperative neuroimmune phenotypes and pain.

Sex-specific differences in alcohol-induced pain sensitization.

Pain sensitization is a phenomenon that occurs to protect tissues from damage and recent studies have shown how a variety of non-noxious stimuli included in our everyday lives can lead to pain sensitization. Consumption of large amounts of alcohol over a long period of time invokes alcohol use disorder (AUD), a complex pathological state that has many manifestations, including alcohol peripheral neuropathy (neuropathic pain). We asked if 'non-pathological' alcohol consumption can cause pain sensitization in the absence of other pathology? Studies have pointed to glia and other immune cells and their role in pain sensitization that results in cell and sex-specific responses.

C781, a β-Arrestin Biased Antagonist at Protease-Activated Receptor-2 (PAR2), Displays in vivo Efficacy Against Protease-Induced Pain in Mice.

Given the limited options and often harmful side effects of current analgesics and the suffering caused by the opioid crisis, new classes of pain therapeutics are needed. Protease-activated receptors (PARs), particularly PAR2, are implicated in a variety of pathologies, including pain. Since the discovery of the role of PAR2 in pain, development of potent and specific antagonists has been slow.

High-fat diet causes mechanical allodynia in the absence of injury or diabetic pathology.

Understanding the interactions between diet, obesity, and diabetes is important to tease out mechanisms in painful pathology. Western diet is rich in fats, producing high amounts of circulating bioactive metabolites. However, no research has assessed how a high-fat diet (HFD) alone may sensitize an individual to non-painful stimuli in the absence of obesity or diabetic pathology.

RNA profiling of human dorsal root ganglia reveals sex differences in mechanisms promoting neuropathic pain.

Neuropathic pain is a leading cause of high-impact pain, is often disabling and is poorly managed by current therapeutics. Here we focused on a unique group of neuropathic pain patients undergoing thoracic vertebrectomy where the dorsal root ganglia is removed as part of the surgery allowing for molecular characterization and identification of mechanistic drivers of neuropathic pain independently of preclinical models. Our goal was to quantify whole transcriptome RNA abundances using RNA-seq in pain-associated human dorsal root ganglia from these patients, allowing comprehensive identification of molecular changes in these samples by contrasting them with non-pain-associated dorsal root ganglia.

Regulatory T-cells and IL-5 mediate pain outcomes in a preclinical model of chronic muscle pain.

Fibromyalgia (FM) is a chronic musculoskeletal pain disorder primarily diagnosed in women. Historically, clinical literature focusing on cytokines and immune cells has been inconsistent. However, recent key studies show several layers of immune system dysfunction in FM.

Preoperative Polypharmacy in Geriatric Patients Is Associated with Increased 90-Day All-Cause Hospital Readmission After Surgery for Adult Spinal Deformity Patients.

Objective: We sought to investigate the effect of preoperative polypharmacy (PP) on the 90-day all-cause readmission rate in older adults undergoing corrective surgery for adult spinal deformity.

Methods: Older adults with a diagnosis of adult spinal deformity undergoing spinal surgery at a quaternary medical center from January 2016 to March 2019 were enrolled in this study. Patients were dichotomized into 2 groups stratified by the number of preoperative prescription medications, with PP defined as 5 or more prescription medications.