Exercise improves load bearing bone structural properties in female secreted protein acidic and rich in cysteine (SPARC) null mice but not in males.

Secreted protein acidic and rich in cysteine (SPARC) is the most abundant glycoprotein in bone and is thought to play a critical role in bone remodeling and homeostasis. However, the effect of SPARC in relation to gender and exercise on bone quality is not well understood. The purpose of this study was to quantify differences in the structural and biomechanical properties between calvarial and femoral bone from male and female wild-type (WT) and SPARC null (SPARC) mice as well as the ability of exercise to rescue bone health.

Stiffness and axial pain are associated with the progression of calcification in a mouse model of diffuse idiopathic skeletal hyperostosis.

Background: Diffuse idiopathic skeletal hyperostosis (DISH) is characterized by progressive calcification of spinal tissues; however, the impact of calcification on pain and function is poorly understood. This study examined the association between progressive ectopic spine calcification in mice lacking equilibrative nucleoside transporter 1 (ENT1), a preclinical model of DISH, and behavioral indicators of pain.

Methods: A longitudinal study design was used to assess radiating pain, axial discomfort, and physical function in wild-type and ENT1 mice at 2, 4, and 6 months.

Genetic evidence of the function of Phox2a-expressing anterolateral system neurons in the transmission of chronic pain.

The development of the chronic neuropathic pain state often originates at the level of peripheral sensory neurons, whose abnormal function elicits central sensitization and maladaptive plasticity in the nociceptive circuits of the spinal dorsal horn. These changes eventually reach supraspinal areas bringing about cognitive and affective co-morbidities of chronic pain such as anxiety and depression. This transmission presumably relies on the function of spinal projection neurons at the origin of the anterolateral system (AS).

Sex-specific effects of neuropathic pain on long-term pain behavior and mortality in mice.

Human epidemiological studies suggest that chronic pain can increase mortality risk. We investigated whether this was true in mice so that underlying mechanisms might be identified. At 10 weeks of age, C57BL/6 mice of both sexes received sham or spared nerve injury (SNI) surgery producing neuropathic pain.

TAK-242 treatment and its effect on mechanical properties and gene expression associated with IVD degeneration in SPARC-null mice.

Purpose: Intervertebral disc (IVD) degeneration is accompanied by mechanical and gene expression changes to IVDs. SPARC-null mice display accelerated IVD degeneration, and treatment with (toll-like receptor 4 (TLR4) inhibitor) TAK-242 decreases proinflammatory cytokines and pain. This study examined if chronic TAK-242 treatment impacts mechanical properties and gene expression associated with IVD degeneration in SPARC-null mice.

Effect of voluntary running activity on mRNA expression of extracellular matrix genes in a mouse model of intervertebral disc degeneration.

Introduction: Low back pain (LBP), a leading cause of global disability, is often associated with intervertebral disc degeneration (IDD). Exercise therapy is recommended for chronic LBP management and affects many tissues and organ systems. However, the ability of exercise to repair the extracellular matrix (ECM) in degenerating discs is unclear.

The methyl donor S-adenosyl methionine reverses the DNA methylation signature of chronic neuropathic pain in mouse frontal cortex.

Unlabelled: Chronic pain is associated with persistent but reversible structural and functional changes in the prefrontal cortex (PFC). This stable yet malleable plasticity implicates epigenetic mechanisms, including DNA methylation, as a potential mediator of chronic pain-induced cortical pathology. We previously demonstrated that chronic oral administration of the methyl donor S-adenosyl methionine (SAM) attenuates long-term peripheral neuropathic pain and alters global frontal cortical DNA methylation.

Disc degeneration spreads: long-term behavioural, histologic and radiologic consequences of a single-level disc injury in active and sedentary mice.

Study Design: A multi-cohort, case-control rodent study.

Purpose: Investigate the long-term behavioural, histologic and radiologic consequences on the complete lumbar spine of L4/5 intervertebral disc (IVD) injury in mice and determine if increased physical activity mitigates the observed changes.

Methods: Cohorts of 2-month-old CD1 female mice underwent a single ventral puncture of the L4/5 IVD.

Exercise attenuates low back pain and alters epigenetic regulation in intervertebral discs in a mouse model.

Background Context: Chronic low back pain (LBP) is a multifactorial disorder with complex underlying mechanisms, including associations with intervertebral disc (IVD) degeneration in some individuals. It has been demonstrated that epigenetic processes are involved in the pathology of IVD degeneration. Epigenetics refers to several mechanisms, including DNA methylation, that have the ability to change gene expression without inducing any change in the underlying DNA sequence.

Multifidus Muscle Fiber Type Distribution is Changed in Mouse Models of Chronic Intervertebral Disc Degeneration, but is not Attenuated by Whole Body Physical Activity.

Study Design: Case-controlled animal study.

Objective: The aim of this study was to investigate whether multifidus muscle fiber type distribution changes in models of interverbal disc (IVD) degeneration and whether this is resolved by physical activity (PA).

Summary Of Background Data: The loss of slow type I muscle fibers in the multifidus muscle in people with low back pain is contentious.

Diet-induced obesity leads to behavioral indicators of pain preceding structural joint damage in wild-type mice.

Introduction: Obesity is one of the largest modifiable risk factors for the development of musculoskeletal diseases, including intervertebral disc (IVD) degeneration and back pain. Despite the clinical association, no studies have directly assessed whether diet-induced obesity accelerates IVD degeneration, back pain, or investigated the biological mediators underlying this association. In this study, we examine the effects of chronic consumption of a high-fat or high-fat/high-sugar (western) diet on the IVD, knee joint, and pain-associated outcomes.

Mechanical Consequence of Induced Intervertebral Disc Degeneration in the SPARC-Null Mouse.

Intervertebral disc (IVD) degeneration is associated with low back pain (LBP) and accompanied by mechanical changes to the spine. Secreted protein acidic and rich in cysteine (SPARC) is a protein that contributes to the functioning and maintenance of the extracellular matrix. SPARC-null mice display accelerated IVD degeneration and pain-associated behaviors.

The transition from acute to chronic pain: dynamic epigenetic reprogramming of the mouse prefrontal cortex up to 1 year after nerve injury.

Chronic pain is associated with persistent structural and functional changes throughout the neuroaxis, including in the prefrontal cortex (PFC). The PFC is important in the integration of sensory, cognitive, and emotional information and in conditioned pain modulation. We previously reported widespread epigenetic reprogramming in the PFC many months after nerve injury in rodents.

The geriatric pain experience in mice: intact cutaneous thresholds but altered responses to tonic and chronic pain.

Older individuals have an elevated risk for chronic pain as half of all individuals over 65 years old have at least one chronic pain condition. Unfortunately, relevant assessment tools and recommendations for chronic pain management targeting older adults are lacking. This study explores changes in response to pain between young (2-3 months old) and geriatric (20-24 months old) ages using mice.

Long-term histological analysis of innervation and macrophage infiltration in a mouse model of intervertebral disc injury-induced low back pain.

Low back pain (LBP) is a leading cause of global disability. Multiple anatomical, cellular, and molecular factors are implicated in LBP, including the degeneration of lumbar intervertebral discs (IVDs). We previously described a mouse model that displays behavioral symptoms of chronic LBP.

Interleukin-8 as a therapeutic target for chronic low back pain: Upregulation in human cerebrospinal fluid and pre-clinical validation with chronic reparixin in the SPARC-null mouse model.

Background: Low back pain (LBP) is the leading global cause of disability and is associated with intervertebral disc degeneration (DD) in some individuals. However, many adults have DD without LBP. Understanding why DD is painful in some and not others may unmask novel therapies for chronic LBP.

Dysregulation of the Inflammatory Mediators in the Multifidus Muscle After Spontaneous Intervertebral Disc Degeneration SPARC-null Mice is Ameliorated by Physical Activity.

Study Design: A longitudinal case-control animal model.

Objective: The aim of this study was to investigate the inflammatory pathways active in the multifidus muscle after spontaneous intervertebral disc degeneration (IDD), and whether these IDD-related muscle changes can be ameliorated by exercise.

Summary Of Background Data: A pro-inflammatory response is present in the multifidus muscle after an intervertebral disc lesion and has been proposed to drive the structural alterations present during low back pain.

Anti-nerve growth factor therapy attenuates cutaneous hypersensitivity and musculoskeletal discomfort in mice with osteoporosis.

Introduction: The prevalence of osteoporosis is increasing with the aging population and is associated with increased risk of fracture and chronic pain. Osteoporosis is currently treated with bisphosphonate therapy to attenuate bone loss. We previously reported that improvement in bone mineral density is not sufficient to reduce osteoporosis-related pain in an ovariectomy (OVX)-induced mouse model of osteoporosis, highlighting the need for new treatments.

Low back pain and disc degeneration are decreased following chronic toll-like receptor 4 inhibition in a mouse model.

Objective: Intervertebral disc degeneration is a leading cause of chronic low back pain (LBP) but current treatment is limited. Toll-like receptors (TLRs) on disc cells are activated by endogenous extracellular matrix (ECM) fragments and modulate degeneration in vitro. This study investigated whether inhibiting TLR4 slows disc degeneration and reduces behavioral signs of LBP in vivo.

Delayed onset of persistent discogenic axial and radiating pain after a single-level lumbar intervertebral disc injury in mice.

Low back pain (LBP) is associated with both axial discomfort and radiating leg pain. Although intervertebral discs are suspected as the source of pain in some individuals, the relationship between disc degeneration and back pain remains controversial. The goals of this study were to investigate the long-term impact of L4/L5 disc puncture on disc degeneration and the subsequent emergence, persistence, and underlying mechanisms of axial and radiating LBP in mice.

Chronic Osteoporotic Pain in Mice: Cutaneous and Deep Musculoskeletal Pain Are Partially Independent of Bone Resorption and Differentially Sensitive to Pharmacological Interventions.

Although the pathological changes in osteoporotic bones are well established, the characterization of the osteoporotic pain and its appropriate treatment are not fully elucidated. We investigated the behavioral signs of cutaneous and deep musculoskeletal pain and physical function; time-dependent changes in bone mineral density (BMD) and the emergence of the behavioral phenotype; and the effects of pharmacological interventions having different mechanisms of action (chronic intraperitoneal administration of pamidronate [0.25 mg/kg, 5x/week for 5 weeks] versus acute treatment with intraperitoneal morphine [10 mg/kg] and pregabalin [100 mg/kg]) in a mouse model of ovariectomized or sham-operated mice 6 months following surgery.

Therapeutic benefits of the methyl donor S-adenosylmethionine on nerve injury-induced mechanical hypersensitivity and cognitive impairment in mice.

Despite considerable advances in understanding mechanisms involved in chronic pain, effective treatment remains elusive. Comorbid conditions including anxiety, depression, and cognitive impairment further impact quality of life. Chronic pain is associated with reversible changes in brain anatomy and function and with long-term changes in gene expression.

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.

Behavioral signs of axial low back pain and motor impairment correlate with the severity of intervertebral disc degeneration in a mouse model.

Background Context: Chronic low back pain is debilitating and difficult to treat. Depending on the etiology, responses to treatments vary widely. Although chronic low back pain is frequently related to intervertebral disc degeneration, the relationship between disc degeneration severity and clinical symptoms are still poorly understood.

Dual allosteric modulation of opioid antinociceptive potency by α2A-adrenoceptors.

Opioid and α2-adrenoceptor (AR) agonists are analgesic when administered in the spinal cord and show a clinically beneficial synergistic interaction when co-administered. However, α2-AR antagonists can also inhibit opioid antinociception, suggesting a complex interaction between the two systems. The α2A-AR subtype is necessary for spinal adrenergic analgesia and synergy with opioids for most agonist combinations.