The intersection of endocrine signaling and neuroimmune communication regulates muscle inflammation-induced nociception in neonatal mice.

Neonatal pain is a significant clinical issue but the mechanisms by which pain is produced early in life are poorly understood. Our recent work has linked the transcription factor serum response factor downstream of local growth hormone (GH) signaling to incision-related hypersensitivity in neonates. However, it remains unclear if similar mechanisms contribute to inflammatory pain in neonates.

Synaptic-like coupling of macrophages to myofibers regulates muscle repair.

Peripheral injury responses essential for muscle repair and nociception require complex interactions of target tissues, immune cells and primary sensory neurons. Nociceptors and myofibers both react robustly to signals generated from circulating immune cells, which promote repair, growth, and regeneration of muscle while simultaneously modulating peripheral sensitization. Here, we found that macrophages form a synaptic-like contact with myofibers to hasten repair after acute incision injury and to facilitate regeneration after major muscle damage.

The intersection of endocrine signaling and neuroimmune communication regulates neonatal nociception.

Neonatal pain is a significant clinical issue but the mechanisms by which pain is produced early in life are poorly understood. Our recent work has linked the transcription factor serum response factor downstream of local growth hormone (GH) signaling to incision-related hypersensitivity in neonates. However, it remains unclear if similar mechanisms contribute to inflammatory pain in neonates.

Small-molecule-induced epigenetic rejuvenation promotes SREBP condensation and overcomes barriers to CNS myelin regeneration.

Remyelination failure in diseases like multiple sclerosis (MS) was thought to involve suppressed maturation of oligodendrocyte precursors; however, oligodendrocytes are present in MS lesions yet lack myelin production. We found that oligodendrocytes in the lesions are epigenetically silenced. Developing a transgenic reporter labeling differentiated oligodendrocytes for phenotypic screening, we identified a small-molecule epigenetic-silencing-inhibitor (ESI1) that enhances myelin production and ensheathment.

Macrophage memories of early-life injury drive neonatal nociceptive priming.

The developing peripheral nervous and immune systems are functionally distinct from those of adults. These systems are vulnerable to early-life injury, which influences outcomes related to nociception following subsequent injury later in life (i.e.

Schwann cells modulate nociception in neurofibromatosis 1.

Pain of unknown etiology is frequent in individuals with the tumor predisposition syndrome neurofibromatosis 1 (NF1), even when tumors are absent. Nerve Schwann cells (SCs) were recently shown to play roles in nociceptive processing, and we find that chemogenetic activation of SCs is sufficient to induce afferent and behavioral mechanical hypersensitivity in wild-type mice. In mouse models, animals showed afferent and behavioral hypersensitivity when SCs, but not neurons, lacked Nf1.

Developmental impact of peripheral injury on neuroimmune signaling.

A peripheral injury drives neuroimmune interactions at the level of the injury and throughout the neuraxis. Understanding these systems will be beneficial in the pursuit to target persistent pain that involves both neural and immune components. In this review, we discuss the impact of injury on the development of neuroimmune signaling, along with data that suggest a possible cellular immune memory.

Sex specific role of RNA-binding protein, AUF1, on prolonged hypersensitivity after repetitive ischemia with reperfusion injury.

Repetitive ischemia with reperfusion (I/R) injury is a common cause of myalgia. I/R injuries occur in many conditions that differentially affect males and females including complex regional pain syndrome and fibromyalgia. Our preclinical studies have indicated that primary afferent sensitization and behavioral hypersensitivity due to I/R may be due to sex specific gene expression in the DRGs and distinct upregulation of growth factors and cytokines in the affected muscles.

Macrophage epigenetic memories of early life injury drive neonatal nociceptive priming.

The developing peripheral nervous and immune systems are functionally distinct from adults. These systems are vulnerable to early life injury, which influences outcomes related to nociception following subsequent injury later in life (neonatal nociceptive priming). The underpinnings of this phenomenon are largely unknown, although previous work indicates that macrophages are epigenetically trained by inflammation and injury.

Genetic and epigenetic mechanisms influencing acute to chronic postsurgical pain transitions in pediatrics: Preclinical to clinical evidence.

Background: Chronic postsurgical pain (CPSP) in children remains an important problem with no effective preventive or therapeutic strategies. Recently, genomic underpinnings explaining additional interindividual risk beyond psychological factors have been proposed.

Aims: We present a comprehensive review of current preclinical and clinical evidence for genetic and epigenetic mechanisms relevant to pediatric CPSP.

Disruption of Hyaluronic Acid in Skeletal Muscle Induces Decreased Voluntary Activity via Chemosensitive Muscle Afferent Sensitization in Male Mice.

PEGPH20, a human recombinant hyaluronidase, has been proposed as a coadjutant to pancreatic cancer chemotherapy. In early trials, patients reported increased widespread muscle pain as the main adverse reaction to PEGPH20. To understand how PEGPH20 caused musculoskeletal pain, we systemically administered PEGPH20 to male mice and measured voluntary wheel activity and pain-related behaviors.

Hyaluronan homeostasis and its role in pain and muscle stiffness.

Hyaluronan (HA) is a glycosaminoglycan that consists of single-chain polymers of disaccharide units of glucuronic acid and N-acetylglucosamine. It is a chief constituent of the extracellular matrix. About 27% of the total HA in the body is expressed in the skeleton and connective tissue, while 8% is expressed in muscles.

Identification of Key Factors Driving the Response of Muscle Sensory Neurons to Noxious Stimuli.

Nociceptive nerve endings embedded in muscle tissue transduce peripheral noxious stimuli into an electrical signal [i.e., an action potential (AP)] to initiate pain sensations.

Early Life Nociception is Influenced by Peripheral Growth Hormone Signaling.

A number of cellular systems work in concert to modulate nociceptive processing in the periphery, but the mechanisms that regulate neonatal nociception may be distinct compared with adults. Our previous work indicated a relationship between neonatal hypersensitivity and growth hormone (GH) signaling. Here, we explored the peripheral mechanisms by which GH modulated neonatal nociception under normal and injury conditions (incision) in male and female mice.

Purinergic signaling in peripheral nervous system glial cells.

To facilitate analyses of purinergic signaling in peripheral nerve glia, we review recent literature and catalog purinergic receptor mRNA expression in cultured mouse Schwann cells (SCs). Purinergic signaling can decrease developmental SC proliferation, and promote SC differentiation. The purinergic receptors P2RY2 and P2RX7 are implicated in nerve development and in the ratio of Remak SCs to myelinating SCs in differentiated peripheral nerve.

Systemic Delivery of AAV- Mitigates the Phenotypes of Mitochondrial Disorders in Mutant Mice.

Gene therapy now provides a novel approach for treating inherited monogenetic disorders, including nuclear gene mutations associated with mitochondrial diseases. In this study, we have utilized a mouse model carrying a p.Arg389Gln mutation of the mitochondrial gene () and treated them with neurotropic AAV-PHP.

Integrated analysis of the molecular pathogenesis of FDXR-associated disease.

The mitochondrial flavoprotein ferredoxin reductase (FDXR) is required for biogenesis of iron-sulfur clusters and for steroidogenesis. Iron-sulfur (Fe-S) clusters are ubiquitous cofactors essential to various cellular processes, and an increasing number of disorders are associated with disruptions in the synthesis of Fe-S clusters. Our previous studies have demonstrated that hypomorphic mutations in FDXR cause a novel mitochondriopathy and optic atrophy in humans and mice, attributed in part to reduced function of the electron transport chain (ETC) as well as elevated production of reactive oxygen species (ROS).

A dual role for peripheral GDNF signaling in nociception and cardiovascular reflexes in the mouse.

Group III/IV muscle afferents transduce nociceptive signals and modulate exercise pressor reflexes (EPRs). However, the mechanisms governing afferent responsiveness to dually modulate these processes are not well characterized. We and others have shown that ischemic injury can induce both nociception-related behaviors and exacerbated EPRs in the same mice.

Single-cell q-PCR derived expression profiles of identified sensory neurons.

Sensory neurons are chemically and functionally heterogeneous, and this heterogeneity has been examined extensively over the last several decades. These studies have employed a variety of different methodologies, including anatomical, electrophysiological, and molecular approaches. Recent studies using next-generation sequencing techniques have examined the transcriptome of single sensory neurons.

Sex differences and mechanisms of muscle pain.

Clinical conditions resulting in musculoskeletal pain show important sex differences in both prevalence and degree of functional disability. The underlying mechanisms for these distinctions in pain manifestation are not fully known. However, recent preclinical studies have shown at the primary afferent level that males and females present fundamental differences in their peripheral response properties and injury-related gene expression patterns that may underlie observed afferent sensitization.

The evolution and multi-molecular properties of NF1 cutaneous neurofibromas originating from C-fiber sensory endings and terminal Schwann cells at normal sites of sensory terminations in the skin.

In addition to large plexiform neurofibromas (pNF), NF1 patients are frequently disfigured by cutaneous neurofibromas (cNF) and are often afflicted with chronic pain and itch even from seemingly normal skin areas. Both pNFs and cNF consist primarily of benign hyperproliferating nonmyelinating Schwann cells (nSC). While pNF clearly arise within deep nerves and plexuses, the role of cutaneous innervation in the origin of cNF and in chronic itch and pain is unknown.

Systemic growth hormone deficiency causes mechanical and thermal hypersensitivity during early postnatal development.

Injury during early postnatal life causes acute alterations in afferent function and DRG gene expression, which in addition to producing short-term sensitivity has the potential to influence nociceptive responses in adulthood. We recently discovered that growth hormone (GH) is a key regulator of afferent sensitization and pain-related behaviors during developmental inflammation of the skin. Peripheral injury caused a significant reduction in cutaneous GH levels, which corresponded with the observed hypersensitivity.