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Trends in Immunology Jan 2017Nociceptor sensory neurons protect organisms from danger by eliciting pain and driving avoidance. Pain also accompanies many types of inflammation and injury. It is... (Review)
Review
Nociceptor sensory neurons protect organisms from danger by eliciting pain and driving avoidance. Pain also accompanies many types of inflammation and injury. It is increasingly clear that active crosstalk occurs between nociceptor neurons and the immune system to regulate pain, host defense, and inflammatory diseases. Immune cells at peripheral nerve terminals and within the spinal cord release mediators that modulate mechanical and thermal sensitivity. In turn, nociceptor neurons release neuropeptides and neurotransmitters from nerve terminals that regulate vascular, innate, and adaptive immune cell responses. Therefore, the dialog between nociceptor neurons and the immune system is a fundamental aspect of inflammation, both acute and chronic. A better understanding of these interactions could produce approaches to treat chronic pain and inflammatory diseases.
Topics: Adaptive Immunity; Animals; Humans; Immune System; Immunity, Innate; Inflammation; Neuroimmunomodulation; Neuropeptides; Neurotransmitter Agents; Nociceptors; Pain; Sensory Receptor Cells
PubMed: 27793571
DOI: 10.1016/j.it.2016.10.001 -
The Journal of Clinical Investigation Nov 2010Specialized peripheral sensory neurons known as nociceptors alert us to potentially damaging stimuli at the skin by detecting extremes in temperature and pressure and... (Review)
Review
Specialized peripheral sensory neurons known as nociceptors alert us to potentially damaging stimuli at the skin by detecting extremes in temperature and pressure and injury-related chemicals, and transducing these stimuli into long-ranging electrical signals that are relayed to higher brain centers. The activation of functionally distinct cutaneous nociceptor populations and the processing of information they convey provide a rich diversity of pain qualities. Current work in this field is providing researchers with a more thorough understanding of nociceptor cell biology at molecular and systems levels and insight that will allow the targeted design of novel pain therapeutics.
Topics: Animals; Hot Temperature; Humans; Ion Channels; Mechanotransduction, Cellular; Nervous System; Nociceptors; Pain; Pain Threshold; Sensation; Signal Transduction; Skin
PubMed: 21041958
DOI: 10.1172/JCI42843 -
Cell Oct 2022Neuroepithelial crosstalk is critical for gut physiology. However, the mechanisms by which sensory neurons communicate with epithelial cells to mediate gut barrier...
Neuroepithelial crosstalk is critical for gut physiology. However, the mechanisms by which sensory neurons communicate with epithelial cells to mediate gut barrier protection at homeostasis and during inflammation are not well understood. Here, we find that Nav1.8CGRP nociceptor neurons are juxtaposed with and signal to intestinal goblet cells to drive mucus secretion and gut protection. Nociceptor ablation led to decreased mucus thickness and dysbiosis, while chemogenetic nociceptor activation or capsaicin treatment induced mucus growth. Mouse and human goblet cells expressed Ramp1, receptor for the neuropeptide CGRP. Nociceptors signal via the CGRP-Ramp1 pathway to induce rapid goblet cell emptying and mucus secretion. Notably, commensal microbes activated nociceptors to control homeostatic CGRP release. In the absence of nociceptors or epithelial Ramp1, mice showed increased epithelial stress and susceptibility to colitis. Conversely, CGRP administration protected nociceptor-ablated mice against colitis. Our findings demonstrate a neuron-goblet cell axis that orchestrates gut mucosal barrier protection.
Topics: Mice; Humans; Animals; Goblet Cells; Nociceptors; Calcitonin Gene-Related Peptide; Colitis; Mucus; Receptor Activity-Modifying Protein 1
PubMed: 36243004
DOI: 10.1016/j.cell.2022.09.024 -
Veterinary Journal (London, England :... Jul 2018The mechanisms by which noxious stimuli produce the sensation of pain in animals are complex. Noxious stimuli are transduced at the periphery and transmitted to the CNS,... (Review)
Review
The mechanisms by which noxious stimuli produce the sensation of pain in animals are complex. Noxious stimuli are transduced at the periphery and transmitted to the CNS, where this information is subject to considerable modulation. Finally, the information is projected to the brain where it is perceived as pain. Additionally, plasticity can develop in the pain pathway and hyperalgesia and allodynia may develop through sensitisation both peripherally and centrally. A large number of different ion channels, receptors, and cell types are involved in pain perception, and it is hoped that through a better understanding of these, new and refined treatments for pain will result.
Topics: Acute Pain; Animals; Hyperalgesia; Neural Pathways; Nociceptors; Pain Measurement; Sensation; Signal Transduction; Spinal Cord
PubMed: 30089546
DOI: 10.1016/j.tvjl.2018.05.004 -
Brain : a Journal of Neurology Jun 2021Chronic pain affects one in five of the general population and is the third most important cause of disability-adjusted life-years globally. Unfortunately, treatment... (Review)
Review
Chronic pain affects one in five of the general population and is the third most important cause of disability-adjusted life-years globally. Unfortunately, treatment remains inadequate due to poor efficacy and tolerability. There has been a failure in translating promising preclinical drug targets into clinic use. This reflects challenges across the whole drug development pathway, from preclinical models to trial design. Nociceptors remain an attractive therapeutic target: their sensitization makes an important contribution to many chronic pain states, they are located outside the blood-brain barrier, and they are relatively specific. The past decade has seen significant advances in the techniques available to study human nociceptors, including: the use of corneal confocal microscopy and biopsy samples to observe nociceptor morphology, the culture of human nociceptors (either from surgical or post-mortem tissue or using human induced pluripotent stem cell derived nociceptors), the application of high throughput technologies such as transcriptomics, the in vitro and in vivo electrophysiological characterization through microneurography, and the correlation with pain percepts provided by quantitative sensory testing. Genome editing in human induced pluripotent stem cell-derived nociceptors enables the interrogation of the causal role of genes in the regulation of nociceptor function. Both human and rodent nociceptors are more heterogeneous at a molecular level than previously appreciated, and while we find that there are broad similarities between human and rodent nociceptors there are also important differences involving ion channel function, expression, and cellular excitability. These technological advances have emphasized the maladaptive plastic changes occurring in human nociceptors following injury that contribute to chronic pain. Studying human nociceptors has revealed new therapeutic targets for the suppression of chronic pain and enhanced repair. Cellular models of human nociceptors have enabled the screening of small molecule and gene therapy approaches on nociceptor function, and in some cases have enabled correlation with clinical outcomes. Undoubtedly, challenges remain. Many of these techniques are difficult to implement at scale, current induced pluripotent stem cell differentiation protocols do not generate the full diversity of nociceptor populations, and we still have a relatively poor understanding of inter-individual variation in nociceptors due to factors such as age, sex, or ethnicity. We hope our ability to directly investigate human nociceptors will not only aid our understanding of the fundamental neurobiology underlying acute and chronic pain but also help bridge the translational gap.
Topics: Animals; Chronic Pain; Humans; Nociceptors; Translational Research, Biomedical
PubMed: 34128530
DOI: 10.1093/brain/awab048 -
Nature Reviews. Immunology Jul 2019Pain is a hallmark of tissue injury, inflammatory diseases, pathogen invasion and neuropathy. It is mediated by nociceptor sensory neurons that innervate the skin,... (Review)
Review
Pain is a hallmark of tissue injury, inflammatory diseases, pathogen invasion and neuropathy. It is mediated by nociceptor sensory neurons that innervate the skin, joints, bones, muscles and mucosal tissues and protects organisms from noxious stimuli. Nociceptors are sensitized by inflammatory mediators produced by the immune system, including cytokines, lipid mediators and growth factors, and can also directly detect pathogens and their secreted products to produce pain during infection. Upon activation, nociceptors release neuropeptides from their terminals that potently shape the function of innate and adaptive immune cells. For some pathogens, neuron-immune interactions enhance host protection from infection, but for other pathogens, neuron-immune signalling pathways can be exploited to facilitate pathogen survival. Here, we discuss the role of nociceptor interactions with the immune system in pain and infection and how understanding these pathways could produce new approaches to treat infectious diseases and chronic pain.
Topics: Animals; Cytokines; Humans; Immune System; Immunity; Infections; Lymphocytes; Macrophages; Nociceptors; Pain
PubMed: 30874629
DOI: 10.1038/s41577-019-0147-2 -
Current Molecular Pharmacology 2021Pain is often flammable, sharp and sometimes described as an electrical shock. It can be categorized in three different ways as nociceptive, neuropathic and... (Review)
Review
BACKGROUND
Pain is often flammable, sharp and sometimes described as an electrical shock. It can be categorized in three different ways as nociceptive, neuropathic and inflammatory. Nociceptive pain always originates in specific situations such as in trauma. Neuropathic pain results in nerve damage. In inflammatory pain, inflammatory mediators are involved in the sensitization of nociceptors. It is important to control the pain as it affects the individual physically, mentally, and socially.
OBJECTIVE
Recognizing pain physiopathology and pain pathways, defining the relationship between receptor and transmitter is critical in developing new treatment strategies. In this review, current information on the definitions, classifications, and physiological and chemical mechanisms involved in pain are reviewed.
METHODS
Various search engines were used to gather related articles/information. Only peer-reviewed journals were considered. Additional, books/chapters of standard publishers were also included in the article.
RESULTS
With a better understanding of the physiological and chemical mechanisms that play a role in pain, significant improvements have been made in pain treatment. Various oral or intravenous drugs, local injection treatments, physical and occupational therapy, electrical stimulation, alternative medicine applications, psychological support, and surgical applications are routinely performed in the treatment, dependent upon the type, severity and cause of the pain.
CONCLUSION
Improved understanding of pain physiopathology will serve as the basis for future improvements in the delivery of efficacious and reliable treatments, and is likely to rely on novel technological innovations.
Topics: Humans; Nociceptors; Pain; Pain Perception
PubMed: 32525788
DOI: 10.2174/1874467213666200611142438 -
Cell Oct 2022Nociceptive pain is a hallmark of many chronic inflammatory conditions including inflammatory bowel diseases (IBDs); however, whether pain-sensing neurons influence...
Nociceptive pain is a hallmark of many chronic inflammatory conditions including inflammatory bowel diseases (IBDs); however, whether pain-sensing neurons influence intestinal inflammation remains poorly defined. Employing chemogenetic silencing, adenoviral-mediated colon-specific silencing, and pharmacological ablation of TRPV1 nociceptors, we observed more severe inflammation and defective tissue-protective reparative processes in a murine model of intestinal damage and inflammation. Disrupted nociception led to significant alterations in the intestinal microbiota and a transmissible dysbiosis, while mono-colonization of germ-free mice with GramClostridium spp. promoted intestinal tissue protection through a nociceptor-dependent pathway. Mechanistically, disruption of nociception resulted in decreased levels of substance P, and therapeutic delivery of substance P promoted tissue-protective effects exerted by TRPV1 nociceptors in a microbiota-dependent manner. Finally, dysregulated nociceptor gene expression was observed in intestinal biopsies from IBD patients. Collectively, these findings indicate an evolutionarily conserved functional link between nociception, the intestinal microbiota, and the restoration of intestinal homeostasis.
Topics: Mice; Animals; Gastrointestinal Microbiome; Nociceptors; Substance P; Dysbiosis; Inflammatory Bowel Diseases; Inflammation
PubMed: 36240781
DOI: 10.1016/j.cell.2022.09.008 -
Spatial transcriptomics of dorsal root ganglia identifies molecular signatures of human nociceptors.Science Translational Medicine Feb 2022Nociceptors are specialized sensory neurons that detect damaging or potentially damaging stimuli and are found in the dorsal root ganglia (DRG) and trigeminal ganglia....
Nociceptors are specialized sensory neurons that detect damaging or potentially damaging stimuli and are found in the dorsal root ganglia (DRG) and trigeminal ganglia. These neurons are critical for the generation of neuronal signals that ultimately create the perception of pain. Nociceptors are also primary targets for treating acute and chronic pain. Single-cell transcriptomics on mouse nociceptors has transformed our understanding of pain mechanisms. We sought to generate equivalent information for human nociceptors with the goal of identifying transcriptomic signatures of nociceptors, identifying species differences and potential drug targets. We used spatial transcriptomics to molecularly characterize transcriptomes of single DRG neurons from eight organ donors. We identified 12 clusters of human sensory neurons, 5 of which are C nociceptors, as well as 1 C low-threshold mechanoreceptors (LTMRs), 1 Aβ nociceptor, 2 Aδ, 2 Aβ, and 1 proprioceptor subtypes. By focusing on expression profiles for ion channels, G protein-coupled receptors (GPCRs), and other pharmacological targets, we provided a rich map of potential drug targets in the human DRG with direct comparison to mouse sensory neuron transcriptomes. We also compared human DRG neuronal subtypes to nonhuman primates showing conserved patterns of gene expression among many cell types but divergence among specific nociceptor subsets. Last, we identified sex differences in human DRG subpopulation transcriptomes, including a marked increase in calcitonin-related polypeptide alpha () expression in female pruritogen receptor-enriched nociceptors. This comprehensive spatial characterization of human nociceptors might open the door to development of better treatments for acute and chronic pain disorders.
Topics: Animals; Chronic Pain; Female; Ganglia, Spinal; Humans; Male; Mice; Nociceptors; Sensory Receptor Cells; Transcriptome
PubMed: 35171654
DOI: 10.1126/scitranslmed.abj8186 -
Cell Jan 2021Barrier tissue immune responses are regulated in part by nociceptors. Nociceptor ablation alters local immune responses at peripheral sites and within draining lymph...
Barrier tissue immune responses are regulated in part by nociceptors. Nociceptor ablation alters local immune responses at peripheral sites and within draining lymph nodes (LNs). The mechanisms and significance of nociceptor-dependent modulation of LN function are unknown. Using high-resolution imaging, viral tracing, single-cell transcriptomics, and optogenetics, we identified and functionally tested a sensory neuro-immune circuit that is responsive to lymph-borne inflammatory signals. Transcriptomics profiling revealed that multiple sensory neuron subsets, predominantly peptidergic nociceptors, innervate LNs, distinct from those innervating surrounding skin. To uncover LN-resident cells that may interact with LN-innervating sensory neurons, we generated a LN single-cell transcriptomics atlas and nominated nociceptor target populations and interaction modalities. Optogenetic stimulation of LN-innervating sensory fibers triggered rapid transcriptional changes in the predicted interacting cell types, particularly endothelium, stromal cells, and innate leukocytes. Thus, a unique population of sensory neurons monitors peripheral LNs and may locally regulate gene expression.
Topics: Action Potentials; Animals; Immunomodulation; Inflammation; Lymph Nodes; Mice; Nociceptors; Optogenetics; Peptides; Sensory Receptor Cells; Skin; Sympathetic Nervous System; Toll-Like Receptors
PubMed: 33333021
DOI: 10.1016/j.cell.2020.11.028