The local molecular signature of human peripheral neuropathic pain.

Focal nerve injuries are often associated with neuropathic pain. Preclinical research suggests altered neuroimmune signalling underlies such neuropathic pain; however, its cause remains poorly understood in humans. In this multicentre cohort study, we describe the local cellular and molecular signature of neuropathic pain at the lesion site, using Morton's neuroma as a human model system of neuropathic pain (n = 22; 18 women) compared with nerves from participants without nerve injury (n = 11; 4 women).

Modeling neuropathic pain in a dish.

The study of pain mechanisms has advanced significantly with the development of innovative in vitro models. This chapter explores those already used in or potentially useful for neuropathic pain research, emphasizing the complementary roles of animal and human cellular models to enhance translational success. Traditional animal models have provided foundational insights into the neurobiology of pain and remain invaluable for understanding complex pain pathways.

An interdisciplinary perspective on peripheral drivers of pain in rheumatoid arthritis.

Pain is one of the most debilitating symptoms of rheumatoid arthritis (RA), and yet remains poorly understood, especially when pain occurs in the absence of synovitis. Without active inflammation, experts most often attribute joint pain to central nervous system dysfunction. However, advances in the past 5 years in both immunology and neuroscience research suggest that chronic pain in RA is also driven by a variety of abnormal interactions between peripheral neurons and mediators produced by resident cells in the local joint environment.

A randomised controlled trial of the effect of intra-articular lidocaine on pain scores in inflammatory arthritis.

Chronic pain in inflammatory arthritis (IA) reflects a complex interplay between active disease in a peripheral joint and central pronociceptive mechanisms. Because intra-articular lidocaine may be used to abolish joint-specific peripheral input to the central nervous system, we aimed to validate its use as a clinical tool to identify those patients with IA whose pain likely incorporates centrally mediated mechanisms. We began by investigating whether there was a placebo response of intra-articular injection in patients with IA 1:1 randomised to receive intra-articular lidocaine or control (0.

Deep sequencing of Phox2a nuclei reveals five classes of anterolateral system neurons.

The anterolateral system (ALS) is a major ascending pathway from the spinal cord that projects to multiple brain areas and underlies the perception of pain, itch, and skin temperature. Despite its importance, our understanding of this system has been hampered by the considerable functional and molecular diversity of its constituent cells. Here, we use fluorescence-activated cell sorting to isolate ALS neurons belonging to the Phox2a-lineage for single-nucleus RNA sequencing.

Cerebrospinal fluid immune cells appear similar across neuropathic and non-neuropathic pain conditions.

Background: Microglia have been implicated in the pathophysiology of neuropathic pain. Here, we sought to investigate whether cerebrospinal fluid (CSF) might be used as a proxy-measure of microglial activation in human participants.

Methods: We preformed fluorescence-activated cell sorting (FACS) of CSF immune cell populations derived from individuals who experienced pain with neuropathic features.

calcium imaging shows that satellite glial cells have increased activity in painful states.

Satellite glial cells are important for proper neuronal function of primary sensory neurons for which they provide homeostatic support. Most research on satellite glial cell function has been performed with studies, but recent advances in calcium imaging and transgenic mouse models have enabled this first study of single-cell satellite glial cell function in mouse models of inflammation and neuropathic pain. We found that in naïve conditions, satellite glial cells do not respond in a time-locked fashion to neuronal firing.

Assessing spontaneous sensory neuron activity using in vivo calcium imaging.

Heightened spontaneous activity in sensory neurons is often reported in individuals living with chronic pain. It is possible to study this activity in rodents using electrophysiology, but these experiments require great skill and can be prone to bias. Here, we have examined whether in vivo calcium imaging with GCaMP6s can be used as an alternative approach.

Spontaneous activity in peripheral sensory nerves: a systematic review.

In the peripheral nervous system, spontaneous activity in sensory neurons is considered to be one of the 2 main drivers of chronic pain states, alongside neuronal sensitization. Despite this, the precise nature and timing of this spontaneous activity in neuropathic pain is not well-established. Here, we have performed a systematic search and data extraction of existing electrophysiological literature to shed light on which fibre types have been shown to maintain spontaneous activity and over what time frame.

Practical approaches to improving translatability and reproducibility in preclinical pain research.

Pain research continues to face the challenge of poor translatability of pre-clinical studies. In this short primer, we are summarizing the possible causes, with an emphasis on practical and constructive solutions. In particular, we stress the importance of increased heterogeneity in animal studies; formal or informal pre-registration to combat publication bias; and increased statistical training in order to help pre-clinical scientists appreciate the usefulness of available experimental design and reporting guidelines.

Deep sequencing of Phox2a nuclei reveals five classes of anterolateral system neurons.

The anterolateral system (ALS) is a major ascending pathway from the spinal cord that projects to multiple brain areas and underlies the perception of pain, itch and skin temperature. Despite its importance, our understanding of this system has been hampered by the considerable functional and molecular diversity of its constituent cells. Here we use fluorescence-activated cell sorting to isolate ALS neurons belonging to the Phox2a-lineage for single-nucleus RNA sequencing.

Comparative transcriptional analysis of satellite glial cell injury response.

Satellite glial cells (SGCs) tightly surround and support primary sensory neurons in the peripheral nervous system and are increasingly recognized for their involvement in the development of neuropathic pain following nerve injury. SGCs are difficult to investigate due to their flattened shape and tight physical connection to neurons and their rapid changes in phenotype and protein expression when cultured . Consequently, several aspects of SGC function under normal conditions as well as after a nerve injury remain to be explored.

Early life inflammation is associated with spinal cord excitability and nociceptive sensitivity in human infants.

Immune function and sensitivity to pain are closely related, but the association between early life inflammation and sensory nervous system development is poorly understood-especially in humans. Here, in term-born infants, we measure brain activity and reflex withdrawal activity (using EEG and EMG) and behavioural and physiological activity (using the PIPP-R score) to assess the impact of suspected early-onset neonatal infection on tactile- and noxious-evoked responses. We present evidence that neonatal inflammation (assessed by measuring C-reactive protein levels) is associated with increased spinal cord excitability and evoked brain activity following both tactile and noxious stimulation.

Fibroblasts: the neglected cell type in peripheral sensitisation and chronic pain? A review based on a systematic search of the literature.

Unlabelled: Chronic pain and its underlying biological mechanisms have been studied for many decades, with a myriad of molecules, receptors and cell types known to contribute to abnormal pain sensations. Besides an obvious role for neurons, immune cells like microglia, macrophages and T cells are also important drivers of persistent pain. While neuroinflammation has therefore been widely studied in pain research, there is one cell type that appears to be rather neglected in this context: the humble fibroblast.

Examination of the contribution of Nav1.7 to axonal propagation in nociceptors.

Nav1.7 is a promising drug target for the treatment of pain. However, there is a mismatch between the analgesia produced by Nav1.

TRPC5 and the path towards analgesic drug development.

A recent study by Sadler et al. highlights transient receptor potential canonical 5 (TRPC5) as a potential target for treating pain conditions. This article discusses their findings in the context of analgesic drug development, an urgent pursuit required to combat the opioid crisis and help millions of people with chronic pain.

Probing the peripheral immune response in mouse models of oxaliplatin-induced peripheral neuropathy highlights their limited translatability.

Chemotherapy-induced peripheral neuropathy (CIPN) is a disabling side effect of various chemotherapeutic agents, including oxaliplatin. It is highly prevalent amongst cancer patients, causing sensory abnormalities and pain. Unfortunately, as the underlying mechanisms remain poorly understood, effective therapeutics are lacking.

The impact of bone cancer on the peripheral encoding of mechanical pressure stimuli.

Skeletal metastases are frequently accompanied by chronic pain that is mechanoceptive in nature. Mechanistically, cancer-induced bone pain (CIBP) is mediated by peripheral sensory neurons innervating the cancerous site, the cell bodies of which are housed in the dorsal root ganglia (DRG). How these somatosensory neurons encode sensory information in CIBP remains only partly explained.

A transcriptional toolbox for exploring peripheral neuroimmune interactions.

Correct communication between immune cells and peripheral neurons is crucial for the protection of our bodies. Its breakdown is observed in many common, often painful conditions, including arthritis, neuropathies, and inflammatory bowel or bladder disease. Here, we have characterised the immune response in a mouse model of neuropathic pain using flow cytometry and cell-type-specific RNA sequencing (RNA-seq).

Sensitization of knee-innervating sensory neurons by tumor necrosis factor-α-activated fibroblast-like synoviocytes: an in vitro, coculture model of inflammatory pain.

Pain is a principal contributor to the global burden of arthritis with peripheral sensitization being a major cause of arthritis-related pain. Within the knee joint, distal endings of dorsal root ganglion neurons (knee neurons) interact with fibroblast-like synoviocytes (FLS) and the inflammatory mediators they secrete, which are thought to promote peripheral sensitization. Correspondingly, RNA sequencing has demonstrated detectable levels of proinflammatory genes in FLS derived from arthritis patients.