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Papers Of The Week
2024 Sep 06 - Pain
Editor's Pick

11th revision of the International Classification of Diseases chronic primary pain diagnoses in children and adolescents: representation of pediatric patients in the new classification system.

Authors: Rau LM, Korwisi B, Barke A, Frosch M, Zernikow B, Wager J
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Chronic pain is common among children and adolescents; however, the diagnoses in the newly developed 11th revision of the International Classification of Diseases (ICD-11) chronic pain chapter are based on adult criteria, overlooking pediatric neurodevelopmental differences. The chronic pain diagnoses have demonstrated good clinical applicability in adults, but to date, no field study has examined these diagnoses to the most specific diagnostic level in a pediatric sample. The current study aimed to explore pediatric representation within the ICD-11, with focus on chronic primary pain. Healthcare professionals (HCPs) at a specialized pediatric pain center documented the symptoms of and assigned both ICD-10 and ICD-11 diagnoses to N = 402 patients. Using criteria-based computer algorithms, specific ICD-11 pain diagnoses were allocated for each documented pain location, with residual diagnoses (ie, “unspecified”) assigned if criteria were not (fully) met. Within the ICD-11, the algorithms assigned specific pain diagnoses to most patients (73.6%). In ICD-10, HCPs could not specify a diagnosis for 5.2% of patients; the ICD-11 algorithm allocated a residual chronic primary pain diagnosis in 51.2%. Residual categories were especially prevalent among younger children, boys, patients with headaches, and those with lower pain severity. Overall, clinical utility of the ICD-11 was high, although less effective for chronic back pain and headache diagnoses. The latter also exhibited the lowest agreement between HCPs and algorithm. The current study underscores the need for evidence-based improvements to the ICD-11 diagnostic criteria in pediatrics. Developing pediatric coding notes could improve the visibility of patients internationally and improve the likelihood of receiving reimbursement for necessary treatments through accurate coding.

2024 Sep 10 - Nat Commun
Editor's Pick

A distinct neuronal ensemble of prelimbic cortex mediates spontaneous pain in rats with peripheral inflammation.

Authors: Ma L, Yue L, Liu S, Xu S, Tong J, Sun X, Su L, Cui S, Liu FY, Wan Y, Yi M
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The absence of a comprehensive understanding of the neural basis of spontaneous pain limits the development of therapeutic strategies targeting this primary complaint of patients with chronic pain. Here we report a distinct neuronal ensemble within the prelimbic cortex which processes signals related to spontaneous pain in rats with chronic inflammatory pain. This neuronal ensemble specifically encodes spontaneous pain-related behaviors, independently of other locomotive and evoked behaviors. Activation of this neuronal ensemble elicits marked spontaneous pain-like behaviors and enhances nociceptive responses, whereas prolonged silencing of its activities alleviates spontaneous pain and promotes overall recovery from inflammatory pain. Notably, afferents from the primary somatosensory cortex and infralimbic cortex bidirectionally modulate the activities of the spontaneous pain-responsive prelimbic cortex neuronal ensemble and pain behaviors. These findings reveal the cortical basis of spontaneous pain at the neuronal level, highlighting a distinct neuronal ensemble within the prelimbic cortex and its associated pain-regulatory brain networks.


2024 Sep 06 - Nat Rev Rheumatol
Editor's Pick

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

Authors: Rutter-Locher Z, Kirkham BW, Bannister K, Bennett DL, Buckley CD, Taams LS, Denk F
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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. In this Review, we discuss these novel insights from an interdisciplinary neuro-immune perspective. We outline a potential working model for the peripheral drivers of pain in RA, which includes autoantibodies, resident immune and mesenchymal cells and their interactions with different subtypes of peripheral sensory neurons. We also offer suggestions for how future collaborative research could be designed to accelerate analgesic drug development.


2024 Sep 06 - Sci Adv
Editor's Pick

Lung-innervating nociceptor sensory neurons promote pneumonic sepsis during carbapenem-resistant lung infection.

Authors: Joshi PR, Adhikari S, Onah C, Carrier C, Judd A, Mack M, Baral P
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Carbapenem-resistant (CRKP) causes Gram-negative lung infections and fatal pneumonic sepsis for which limited therapeutic options are available. The lungs are densely innervated by nociceptor sensory neurons that mediate breathing, cough, and bronchoconstriction. The role of nociceptors in defense against Gram-negative lung pathogens is unknown. Here, we found that lung-innervating nociceptors promote CRKP pneumonia and pneumonic sepsis. Ablation of nociceptors in mice increased lung CRKP clearance, suppressed trans-alveolar dissemination of CRKP, and protected mice from hypothermia and death. Furthermore, ablation of nociceptors enhanced the recruitment of neutrophils and Ly6C monocytes and cytokine induction. Depletion of Ly6C monocytes, but not of neutrophils, abrogated lung and extrapulmonary CRKP clearance in ablated mice, suggesting that Ly6C monocytes are a critical cellular population to regulate pneumonic sepsis. Further, neuropeptide calcitonin gene-related peptide suppressed the induction of reactive oxygen species in Ly6C monocytes and their CRKP-killing abilities. Targeting nociceptor signaling could be a therapeutic approach for treating multidrug-resistant Gram-negative infection and pneumonic sepsis.


2024 Sep 04 - Nature
Editor's Pick

A γδ T cell-IL-3 axis controls allergic responses through sensory neurons.

Authors: Flayer CH, Kernin IJ, Matatia PR, Zeng X, Yarmolinsky DA, Han C, Naik PR, Buttaci DR, Aderhold PA, Camire RB, Zhu X, Tirard AJ, McGuire JT, Smith NP, McKimmie CS, McAlpine CS, Swirski FK, Woolf CJ, Villani AC, Sokol CL
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In naive individuals, sensory neurons directly detect and respond to allergens, leading to both the sensation of itch and the activation of local innate immune cells, which initiate the allergic immune response. In the setting of chronic allergic inflammation, immune factors prime sensory neurons, causing pathologic itch. Although these bidirectional neuroimmune circuits drive responses to allergens, whether immune cells regulate the set-point for neuronal activation by allergens in the naive state is unknown. Here we describe a γδ T cell-IL-3 signalling axis that controls the allergen responsiveness of cutaneous sensory neurons. We define a poorly characterized epidermal γδ T cell subset, termed GD3 cells, that produces its hallmark cytokine IL-3 to promote allergic itch and the initiation of the allergic immune response. Mechanistically, IL-3 acts on Il3ra-expressing sensory neurons in a JAK2-dependent manner to lower their threshold for allergen activation without independently eliciting itch. This γδ T cell-IL-3 signalling axis further acts by means of STAT5 to promote neuropeptide production and the initiation of allergic immunity. These results reveal an endogenous immune rheostat that sits upstream of and governs sensory neuronal responses to allergens on first exposure. This pathway may explain individual differences in allergic susceptibility and opens new therapeutic avenues for treating allergic diseases.

 

Come discuss this paper over at Pain Researcher!


2024 Aug 31 - Nat Commun
Editor's Pick

Highly efficient modeling and optimization of neural fiber responses to electrical stimulation.

Authors: Hussain MA, Grill WM, Pelot NA
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Peripheral neuromodulation has emerged as a powerful modality for controlling physiological functions and treating a variety of medical conditions including chronic pain and organ dysfunction. The underlying complexity of the nonlinear responses to electrical stimulation make it challenging to design precise and effective neuromodulation protocols. Computational models have thus become indispensable in advancing our understanding and control of neural responses to electrical stimulation. However, existing approaches suffer from computational bottlenecks, rendering them unsuitable for real-time applications, large-scale parameter sweeps, or sophisticated optimization. In this work, we introduce an approach for massively parallel estimation and optimization of neural fiber responses to electrical stimulation using machine learning techniques. By leveraging advances in high-performance computing and parallel programming, we present a surrogate fiber model that generates spatiotemporal responses to a wide variety of cuff-based electrical peripheral nerve stimulation protocols. We used our surrogate fiber model to design stimulation parameters for selective stimulation of pig and human vagus nerves. Our approach yields a several-orders-of-magnitude improvement in computational efficiency while retaining generality and high predictive accuracy, demonstrating its robustness and potential to enhance the design and optimization of peripheral neuromodulation therapies.


2024 Aug 30 - Science
Editor's Pick

Morphine-responsive neurons that regulate mechanical antinociception.

Authors: Fatt MP, Zhang MD, Kupari J, Altınkök M, Yang Y, Hu Y, Svenningsson P, Ernfors P
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Opioids are widely used, effective analgesics to manage severe acute and chronic pain, although they have recently come under scrutiny because of epidemic levels of abuse. While these compounds act on numerous central and peripheral pain pathways, the neuroanatomical substrate for opioid analgesia is not fully understood. By means of single-cell transcriptomics and manipulation of morphine-responsive neurons, we have identified an ensemble of neurons in the rostral ventromedial medulla (RVM) that regulates mechanical nociception in mice. Among these, forced activation or silencing of excitatory RVM projection neurons mimicked or completely reversed morphine-induced mechanical antinociception, respectively, via a brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB)-dependent mechanism and activation of inhibitory spinal galanin-positive neurons. Our results reveal a specific RVM-spinal circuit that scales mechanical nociception whose function confers the antinociceptive properties of morphine.


2024 Aug 24 - Brain Behav Immun
Editor's Pick

Linking severe traumatic brain injury to pulmonary Infections: Translocation of intestinal bacteria mediated by nociceptor neurons.

Authors: You X, Niu L, Song X, Fu J, Miao Y, Diao F, Wu C, Zhuang P, Zhang Y
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The prevalence of bacterial infections significantly increases among patients with severe traumatic brain injury (STBI), leading to a notable rise in mortality rates. While immune dysfunctions are linked to the incidence of pneumonia, our observations indicate that endogenous pathogens manifest in the lungs post-STBI due to the migration of gut commensal bacteria. This translocation involves gut-innervating nociceptor sensory neurons, which are crucial for host defense. Following STBI, the expression of transient receptor potential vanilloid 1 (TRPV1) in dorsal root ganglion (DRG) neurons significantly decreases, despite an initial brief increase. The timing of TRPV1 defects coincides with the occurrence of pulmonary infections post-STBI. This alteration in TRPV1 neurons diminishes their ability to signal bacterial injuries, weakens defense mechanisms against intestinal bacteria, and increases susceptibility to pulmonary infections via bacterial translocation. Experimental evidence demonstrates that pulmonary infections can be successfully replicated through the chemical ablation and gene interference of TRPV1 nociceptors, and that these infections can be mitigated by TRPV1 activation, thereby confirming the crucial role of nociceptor neurons in controlling intestinal bacterial migration. Furthermore, TRPV1 nociceptors regulate the immune response of microfold cells by releasing calcitonin gene-related peptide (CGRP), thereby influencing the translocation of gut bacteria to the lungs. Our study elucidates how changes in nociceptive neurons post-STBI impact intestinal pathogen defense. This new understanding of endogenous risk factors within STBI pathology offers novel insights for preventing and treating pulmonary infections.

Come discuss this paper over at Pain Researcher!


2024 Aug 27 - J Clin Invest
Editor's Pick

Proton-Activated Chloride Channel Increases Endplate Porosity and Pain in a Mouse Spinal Degeneration Model.

Authors: Xue P, Zhang W, Shen M, Yang J, Chu J, Wang S, Wan M, Zheng J, Qiu Z, Cao X
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Chronic low back pain (LBP) can severely affect daily physical activity. Aberrant osteoclast-mediated resorption leads to porous endplates for the sensory innervation to cause LBP. Here, we report that the expression of proton-activated chloride (PAC) channel is induced during osteoclast differentiation in the porous endplates via a RANKL-NFATc1 signaling pathway. Extracellular acidosis evokes robust PAC currents in osteoclasts. An acidic environment of porous endplates and elevated PAC activation-enhanced osteoclast fusion provoke LBP. Further, we find that genetic knockout of PAC gene Pacc1 significantly reduces endplate porosity and spinal pain in a mouse LBP model, but it does not affect bone development or homeostasis of bone mass in adult mice. Moreover, both osteoclast bone resorptive compartment environment and PAC traffic from the plasma membrane to endosomes to form an intracellular organelle Cl channel have low pH around 5.0. The low pH environment activates PAC channel to increase sialyltransferase St3gal1 expression and sialylation of TLR2 in initiation of osteoclast fusion. Aberrant osteoclast-mediated resorption is also found in most skeletal disorders, including osteoarthritis, ankylosing spondylitis, rheumatoid arthritis, heterotopic ossification, enthesopathy. Thus, elevated Pacc1 expression and PAC activity could be a potential therapeutic target for LBP and osteoclast-associated pain.


2024 Aug 23 - Sci Immunol
Editor's Pick

Mast cell-derived BH4 and serotonin are critical mediators of postoperative pain.

Authors: Starkl P, Jonsson G, Artner T, Turnes BL, Gail LM, Oliveira T, Jain A, Serhan N, Stejskal K, Lakovits K, Hladik A, An M, Channon KM, Kim H, Köcher T, Weninger W, Stary G, Knapp S, Klang V, Gaudenzio N, Woolf CJ, Tikoo S, Jain R, Penninger JM, Cronin SJF
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Postoperative pain affects most patients after major surgery and can transition to chronic pain. The considerable side effects and limited efficacy of current treatments underline the need for new therapeutic options. We observed increased amounts of the metabolites BH4 and serotonin after skin injury. Mast cells were primary postoperative sources of Gch1, the rate-limiting enzyme in BH4 synthesis, itself an obligate cofactor in serotonin production by tryptophan hydroxylase (Tph1). Mice deficient in mast cells or in mast cell-specific Gch1 or Tph1 showed drastically decreased postoperative pain. We found that injury induced the nociceptive neuropeptide substance P, mast cell degranulation, and granule nerve colocalization. Substance P triggered serotonin release in mouse and human mast cells, and substance P receptor blockade substantially ameliorated pain hypersensitivity. Our findings highlight the importance of mast cells at the neuroimmune interface and substance P-driven mast cell BH4 and serotonin production as a therapeutic target for postoperative pain treatment.

Come discuss this paper over at Pain Researcher!


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