Intrinsic adaptive plasticity in mouse and human sensory neurons.

In response to changes in activity induced by environmental cues, neurons in the central nervous system undergo homeostatic plasticity to sustain overall network function during abrupt changes in synaptic strengths. Homeostatic plasticity involves changes in synaptic scaling and regulation of intrinsic excitability. Increases in spontaneous firing and excitability of sensory neurons are evident in some forms of chronic pain in animal models and human patients.

Exploring the role of peripheral nerves in trauma-induced heterotopic ossification.

Recent studies have linked pain and the resultant nociception-induced neural inflammation (NINI) to trauma-induced heterotopic ossification (THO). It is postulated that nociception at the injury site stimulates the transient receptor potential vanilloid-1 (the transient receptor potential cation channel subfamily V member 1) receptors on sensory nerves within the injured tissues resulting in the expression of neuroinflammatory peptides, substance P (SP), and calcitonin gene-related peptide (CGRP). Additionally, BMP-2 released from fractured bones and soft tissue injury also selectively activates TRVP1 receptors, resulting in the release of SP and CGRP and causing neuroinflammation and degranulation of mast cells causing the breakdown the blood-nerve barrier (BNB), leading to release of neural crest derived progenitor cells (NCDPCs) into the injured tissue.

Increased keratinocyte activity and PIEZO1 signaling contribute to paclitaxel-induced mechanical hypersensitivity.

Recent work demonstrates that epidermal keratinocytes are critical for normal touch sensation. However, it is unknown whether keratinocytes contribute to touch-evoked pain and hypersensitivity after tissue injury. Here, we used a mouse model of paclitaxel treatment to determine the extent to which keratinocyte activity contributes to the severe neuropathic pain that accompanies chemotherapy.

Meningeal KATP channels contribute to behavioral responses in preclinical migraine models.

Human experimental studies have shown that levcromakalim, an ATP-sensitive potassium (KATP) channel opener, induces migraine attacks in people with migraine but not in healthy volunteers. However, the exact site of action for KATP channels in migraine pathophysiology remains unclear. This study investigates the role of these channels in the meninges in eliciting behavioral hypersensitivity responses in mice.

Clinical phenotype and management of sound-induced pain: Insights from adults with pain hyperacusis.

Pain hyperacusis, also known as noxacusis, causes physical pain in response to sounds that do not bother most people. How sound causes excruciating pain that can last for weeks or months is not well understood, resulting in a lack of effective treatments. To gain insight into the underlying mechanisms of the condition, 32 adults attended a virtual focus group to describe their sound-induced pain.

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.

Spatial, transcriptomic, and epigenomic analyses link dorsal horn neurons to chronic pain genetic predisposition.

Key mechanisms underlying chronic pain occur within the dorsal horn. Genome-wide association studies (GWASs) have identified genetic variants predisposed to chronic pain. However, most of these variants lie within regulatory non-coding regions that have not been linked to spinal cord biology.

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.

Transcriptomic and histological characterization of telocytes in the human dorsal root ganglion.

Telocytes are interstitial cells with long processes that cover distances in tissues and likely coordinate interacts with other cell types. Though present in central and peripheral neuronal tissues, their role remains unclear. Dorsal root ganglia (DRG) house pseudounipolar afferent neurons responsible for signals such as temperature, proprioception and nociception.

The role and treatment potential of the complement pathway in chronic pain.

The role of the complement system in pain syndromes has garnered attention on the back of preclinical and clinical evidence supporting its potential as a target for new analgesic pharmacotherapies. Of the components that make up the complement system, component 5a (C5a) and component 3a (C3a) are most strongly and consistently associated with pain. Receptors for C5a are widely found in immune resident cells (microglia, astrocytes, sensory neuron-associated macrophages (sNAMs)) in the central nervous system (CNS) as well as hematogenous immune cells (mast cells, macrophages, T-lymphocytes, etc.

B cells drive neuropathic pain-related behaviors in mice through IgG-Fc gamma receptor signaling.

Neuroimmune interactions are essential for the development of neuropathic pain, yet the contributions of distinct immune cell populations have not been fully unraveled. Here, we demonstrate the critical role of B cells in promoting mechanical hypersensitivity (allodynia) after peripheral nerve injury in male and female mice. Depletion of B cells with a single injection of anti-CD20 monoclonal antibody at the time of injury prevented the development of allodynia.

The conotoxin Contulakin-G reverses hypersensitivity observed in rodent models of cancer-induced bone pain without inducing tolerance or motor disturbance.

As the incidence and survival rates of patients with cancer continues to grow, an increasing number of people are living with comorbidities, which often manifests as cancer-induced bone pain (CIBP). The majority of patients with CIBP report poor pain control from currently available analgesics. A conotoxin, Contulakin-G (CGX), has been demonstrated to be an antinociceptive agent in postsurgical and neuropathic pain states via a neurotensin receptor 2 (NTSR2)-mediated pathway.

A role for leucine-rich, glioma inactivated 1 in regulating pain sensitivity.

Neuronal hyperexcitability is a key driver of persistent pain states including neuropathic pain. Leucine-rich, glioma inactivated 1 (LGI1), is a secreted protein known to regulate excitability within the nervous system and is the target of autoantibodies from neuropathic pain patients. Therapies that block or reduce antibody levels are effective at relieving pain in these patients, suggesting that LGI1 has an important role in clinical pain.

Microbiome contributions to pain: a review of the preclinical literature.

Over the past 2 decades, the microbiome has received increasing attention for the role that it plays in health and disease. Historically, the gut microbiome was of particular interest to pain scientists studying nociplastic visceral pain conditions given the anatomical juxtaposition of these microorganisms and the neuroimmune networks that drive pain in such diseases. More recently, microbiomes both inside and across the surface of the body have been recognized for driving sensory symptoms in a broader set of diseases.

Nageotte nodules in human DRG reveal neurodegeneration in painful diabetic neuropathy.

Diabetic neuropathy is frequently accompanied by pain and loss of sensation attributed to axonal dieback. We recovered dorsal root ganglia (DRGs) from 90 organ donors, 19 of whom had medical indices for diabetic painful neuropathy (DPN). Nageotte nodules, dead sensory neurons engulfed by non-neuronal cells, were abundant in DPN DRGs and accounted for 25% of all neurons.

Glucocorticoid signaling mediates stress-induced migraine-like behaviors in a preclinical mouse model.

Background: Stress is one of the most common precipitating factors in migraine and is identified as a trigger in nearly 70% of patients. Responses to stress include release of glucocorticoids as an adaptive mechanism, but this may also contribute to migraine attacks. Here, we investigated the role of glucocorticoids on stress-induced migraine-like behaviors.

Neural mechanisms responsible for vagus nerve stimulation-dependent enhancement of somatosensory recovery.

Impairments in somatosensory function are a common and often debilitating consequence of neurological injury, with few effective interventions. Building on success in rehabilitation for motor dysfunction, the delivery of vagus nerve stimulation (VNS) combined with tactile rehabilitation has emerged as a potential approach to enhance recovery of somatosensation. In order to maximize the effectiveness of VNS therapy and promote translation to clinical implementation, we sought to optimize the stimulation paradigm and identify neural mechanisms that underlie VNS-dependent recovery.

Interleukin-6 induces nascent protein synthesis in human dorsal root ganglion nociceptors primarily via MNK-eIF4E signaling.

Plasticity of dorsal root ganglion (DRG) nociceptors in the peripheral nervous system requires new protein synthesis. This plasticity is believed to be responsible for the physiological changes seen in DRG nociceptors in animal models of chronic pain. Experiments in human DRG (hDRG) neurons also support this hypothesis, but a direct observation of nascent protein synthesis in response to a pain promoting substance, like interleukin-6 (IL-6), has not been measured in these neurons.