Peripheral Inflammation is accompanied by Cerebral Hypoperfusion in Mice.

Introduction: Chronic pain is a disabling condition that is accompanied by neuropsychiatric comorbidities such as anxiety, depression, and cognitive decline. While the peripheral alterations are well-studied, we lack an understanding of how these peripheral changes can result in long-lasting brain alterations and the ensuing behavioral phenotypes. This study aims to quantify changes in cerebral blood perfusion using laser speckle contrast imaging (LSCI) in the murine Complete Freund's adjuvant (CFA) model of unilateral peripheral inflammation.

Acute restraint stress regulates brain DNMT3a and promotes defensive behaviors in male rats.

Depending on its duration and severity, stress may contribute to neuropsychiatric diseases such as depression and anxiety. Studies have shown that stress impacts the hypothalamic-pituitary-adrenal (HPA) axis, but its downstream molecular, behavioral, and nociceptive effects remain unclear. We hypothesized that a 2-hour single exposure to acute restraint stress (ARS) activates the HPA axis and changes DNA methylation, a molecular mechanism involved in the machinery of stress regulation.

Persistent inflammatory pain is linked with anxiety-like behaviors, increased blood corticosterone, and reduced global DNA methylation in the rat amygdala.

Chronic pain increases the risk of developing anxiety, with limbic areas being likely neurological substrates. Despite high clinical relevance, little is known about the precise behavioral, hormonal, and brain neuroplastic correlates of anxiety in the context of persistent pain. Previous studies have shown that decreased nociceptive thresholds in chronic pain models are paralleled by anxiety-like behavior in rats, but there are conflicting ideas regarding its effects on the stress response and circulating corticosterone levels.

Is there hemispheric specialization in the chronic pain brain?

Organismal bilateral symmetry is associated with near-identical halves of the central nervous system, with certain functions displaying specialization through one brain hemisphere. The processing of pain in the brain as well as brain plasticity in the context of painful injuries have garnered much attention in recent decades. Noninvasive brain imaging studies in pain-free human subjects have identified multiple brain regions that are linked to the sensory and affective components of pain.

Garments and Footwear for Chronic Pain.

In most human societies, wearing clothing and shoes, particularly in public settings, is commonplace and may even be legally required. Consequently, there is an abundance of clothing and footwear options for individuals of different ages, genders, body shapes and catering to different needs such as workwear and active-wear. However, many of the available options may not be viable for the millions and pain sufferers worldwide, indicating a need for adaptive apparel for the pain patient.

Complex regional pain syndrome patient immunoglobulin M has pronociceptive effects in the skin and spinal cord of tibia fracture mice.

It has been proposed that complex regional pain syndrome (CRPS) is a post-traumatic autoimmune disease. Previously, we observed that B cells are required for the full expression of CRPS-like changes in a mouse tibia fracture model and that serum immunoglobulin M (IgM) antibodies from fracture mice have pronociceptive effects in muMT fracture mice lacking B cells. The current study evaluated the pronociceptive effects of injecting CRPS patient serum or antibodies into muMT fracture mice by measuring hind paw allodynia and unweighting changes.

Differential olfactory bulb methylation and hydroxymethylation are linked to odor location memory bias in injured mice.

Chronic pain is often linked to comorbidities such as anxiety and cognitive dysfunction, alterations that are reflected in brain plasticity in regions such as the prefrontal cortex and the limbic area. Despite the growing interest in pain-related cognitive deficits, little is known about the relationship between the emotional valence of the stimulus and the salience of its memory following painful injuries. We used the tibia fracture model of chronic pain in mice to determine whether pleasant and unpleasant odor location memories differ in their salience seven weeks following the onset of the painful injury.

Spinal matrix metalloproteinase 8 regulates pain after peripheral trauma.

It is well documented that pain chronification requires a host of plastic mechanisms at the spinal cord (SC) level, including alterations in neuronal and glial structure and function. Such cellular plasticity necessitates the existence of a plastic extracellular matrix (ECM). Here, we describe a key role for ECM remodeling in the regulation of chronic pain following peripheral injury.

The hippocampal extracellular matrix regulates pain and memory after injury.

Chronic pain poses a heavy burden for the individual and society, comprising personal suffering, comorbid psychiatric symptoms, cognitive decline, and disability. Treatment options are poor due in large part to pain centralization, where an initial injury can result in lasting CNS maladaptations. Hippocampal cellular plasticity in chronic pain has become a focus of study due to its roles in cognition, memory, and the experience of pain itself.

Autoinflammatory and autoimmune contributions to complex regional pain syndrome.

Complex regional pain syndrome (CRPS) is a highly enigmatic syndrome typically developing after injury or surgery to a limb. Severe pain and disability are common among those with chronic forms of this condition. Accumulating evidence suggests that CRPS may involve both autoinflammatory and autoimmune components.

Nociceptive and Cognitive Changes in a Murine Model of Polytrauma.

Polytrauma commonly involves concussion (mild traumatic brain injury [mTBI]) and peripheral trauma including limb fractures. Interactions between mTBI and peripheral injuries are poorly understood, both leading to chronic pain and neurobehavioral impairments. To elucidate these interactions, a murine polytrauma model was developed.

Nonpharmacological Interventions in Targeting Pain-Related Brain Plasticity.

Chronic pain is a highly prevalent and debilitating condition that is frequently associated with multiple comorbid psychiatric conditions and functional, biochemical, and anatomical alterations in various brain centers. Due to its widespread and diverse manifestations, chronic pain is often resistant to classical pharmacological treatment paradigms, prompting the search for alternative treatment approaches that are safe and efficacious. The current review will focus on the following themes: attentional and cognitive interventions, the role of global environmental factors, and the effects of exercise and physical rehabilitation in both chronic pain patients and preclinical pain models.

Identification of KRT16 as a target of an autoantibody response in complex regional pain syndrome.

Objective: Using a mouse model of complex regional pain syndrome (CRPS), our goal was to identify autoantigens in the skin of the affected limb.

Methods: A CRPS-like state was induced using the tibia fracture/cast immobilization model. Three weeks after fracture, hindpaw skin was homogenized, run on 2-d gels, and probed by sera from fracture and control mice.

Overlapping signatures of chronic pain in the DNA methylation landscape of prefrontal cortex and peripheral T cells.

We tested the hypothesis that epigenetic mechanisms in the brain and the immune system are associated with chronic pain. Genome-wide DNA methylation assessed in 9 months post nerve-injury (SNI) and Sham rats, in the prefrontal cortex (PFC) as well as in T cells revealed a vast difference in the DNA methylation landscape in the brain between the groups and a remarkable overlap (72%) between differentially methylated probes in T cells and prefrontal cortex. DNA methylation states in the PFC showed robust correlation with pain score of animals in several genes involved in pain.

New Concepts in Complex Regional Pain Syndrome.

Despite the severe pain and disability associated with complex regional pain syndrome (CRPS), the lack of understanding of the pathophysiological mechanisms supporting this enigmatic condition prevents the rational design of new therapies, a situation that is frustrating to both the physician and the patient. The review highlights some of the mechanisms thought to be involved in the pathophysiology of CRPS in preclinical models and CRPS patients, with the ultimate goal that understanding these mechanisms will lead to the design of efficacious, mechanism-based treatments available to the clinic.

Differential Efficacy of Ketamine in the Acute versus Chronic Stages of Complex Regional Pain Syndrome in Mice.

Background: Complex regional pain syndrome (CRPS) is a painful, disabling, and often chronic condition, where many patients transition from an acute phase with prominent peripheral neurogenic inflammation to a chronic phase with evident central nervous system changes. Ketamine is a centrally acting agent believed to work through blockade of N-methyl-D- aspartate receptors and is being increasingly used for the treatment of refractory CRPS, although the basis for the drug's effects and efficacy at different stages of the syndrome remains unclear.

Methods: The authors used a mouse model of CRPS (n = 8 to 12/group) involving tibia fracture/cast immobilization to test the efficacy of ketamine (2 mg kg day; 7 days) or vehicle infusion during acute (3 weeks after fracture) and chronic (7 weeks after fracture) stages.

Novel cytogenic and neurovascular niches due to blood-brain barrier compromise in the chronic pain brain.

Background: The mechanisms by which painful injuries are linked to the multitude of pain-related comorbidities and neuroplastic changes in the brain remain poorly understood. Here we propose a model that relies on epi-neuronal communication through the vascular system to effect various brain structures. Specifically, we hypothesize that the differential vulnerability of the blood-brain barrier (BBB) in different brain regions is associated with region-specific neuroplastic and neurovascular changes that are in turn associated with particular pain-related comorbidities.

Sex differences in a Murine Model of Complex Regional Pain Syndrome.

Complex Regional Pain Syndrome (CRPS) is a major cause of chronic pain after surgery or trauma to the limbs. Despite evidence showing that the prevalence and severity of many forms of chronic pain, including CRPS, differ between males and females, laboratory studies on sex-related differences in animal models of CRPS are not available, and the impact of sex on the transition from acute to chronic CRPS pain and disability are unexplored. Here we make use of a tibia fracture/cast mouse model that recapitulates the nociceptive, functional, vascular, trophic, inflammatory and immune aspects of CRPS.

An epigenetic hypothesis for the genomic memory of pain.

Chronic pain is accompanied with long-term sensory, affective and cognitive disturbances. What are the mechanisms that mediate the long-term consequences of painful experiences and embed them in the genome? We hypothesize that alterations in DNA methylation, an enzymatic covalent modification of cytosine bases in DNA, serve as a "genomic" memory of pain in the adult cortex. DNA methylation is an epigenetic mechanism for long-term regulation of gene expression.

Brain neuroplastic changes accompany anxiety and memory deficits in a model of complex regional pain syndrome.

Background: Complex regional pain syndrome (CRPS) is a painful condition with approximately 50,000 annual new cases in the United States. It is a major cause of work-related disability, chronic pain after limb fractures, and persistent pain after extremity surgery. Additionally, CRPS patients often experience cognitive changes, anxiety, and depression.

Acute and chronic phases of complex regional pain syndrome in mice are accompanied by distinct transcriptional changes in the spinal cord.

Background: CRPS is a painful, debilitating, and often-chronic condition characterized by various sensory, motor, and vascular disturbances. Despite many years of study, current treatments are limited by our understanding of the underlying mechanisms. Little is known on the molecular level concerning changes in gene expression supporting the nociceptive sensitization commonly observed in CRPS limbs, or how those changes might evolve over time.

Peripheral nerve injury is accompanied by chronic transcriptome-wide changes in the mouse prefrontal cortex.

Background: Peripheral nerve injury can have long-term consequences including pain-related manifestations, such as hypersensitivity to cutaneous stimuli, as well as affective and cognitive disturbances, suggesting the involvement of supraspinal mechanisms. Changes in brain structure and cortical function associated with many chronic pain conditions have been reported in the prefrontal cortex (PFC). The PFC is implicated in pain-related co-morbidities such as depression, anxiety and impaired emotional decision-making ability.

Peripheral nerve injury is associated with chronic, reversible changes in global DNA methylation in the mouse prefrontal cortex.

Changes in brain structure and cortical function are associated with many chronic pain conditions including low back pain and fibromyalgia. The magnitude of these changes correlates with the duration and/or the intensity of chronic pain. Most studies report changes in common areas involved in pain modulation, including the prefrontal cortex (PFC), and pain-related pathological changes in the PFC can be reversed with effective treatment.