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2024 Mar 06 - Curr Biol
Editor's Pick

An insular cortical circuit required for itch sensation and aversion.

Authors: Zheng J, Zhang XM, Tang W, Li Y, Wang P, Jin J, Luo Z, Fang S, Yang S, Wei Z, Song K, Huang Z, Wang Z, Zhu Z, Shi N, Xiao D, Yuan L, Shen H, Huang L, Li B
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Itch encompasses both sensory and emotional dimensions, with the two dimensions reciprocally exacerbating each other. However, whether a shared neural circuit mechanism governs both dimensions remains elusive. Here, we report that the anterior insular cortex (AIC) is activated by both histamine-dependent and -independent itch stimuli. The activation of AIC elicits aversive emotion and exacerbates pruritogen-induced itch sensation and aversion. Mechanistically, AIC excitatory neurons project to the GABAergic neurons in the dorsal bed nucleus of the stria terminalis (dBNST). Manipulating the activity of the AIC → dBNST pathway affects both itch sensation and itch-induced aversion. Our study discovers the shared neural circuit (AIC → dBNST pathway) underlying the itch sensation and aversion, highlights the critical role of the AIC as a central hub for the itch processing, and provides a framework to understand the neural mechanisms underlying the sensation and emotion interaction.

2024 Mar 05 - Nat Metab
Editor's Pick

Neuron-astrocyte metabolic coupling facilitates spinal plasticity and maintenance of inflammatory pain.

Authors: Marty-Lombardi S, Lu S, Ambroziak W, Schrenk-Siemens K, Wang J, DePaoli-Roach AA, Hagenston AM, Wende H, Tappe-Theodor A, Simonetti M, Bading H, Okun JG, Kuner R, Fleming T, Siemens J
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Long-lasting pain stimuli can trigger maladaptive changes in the spinal cord, reminiscent of plasticity associated with memory formation. Metabolic coupling between astrocytes and neurons has been implicated in neuronal plasticity and memory formation in the central nervous system, but neither its involvement in pathological pain nor in spinal plasticity has been tested. Here we report a form of neuroglia signalling involving spinal astrocytic glycogen dynamics triggered by persistent noxious stimulation via upregulation of the Protein Targeting to Glycogen (PTG) in spinal astrocytes. PTG drove glycogen build-up in astrocytes, and blunting glycogen accumulation and turnover by Ptg gene deletion reduced pain-related behaviours and promoted faster recovery by shortening pain maintenance in mice. Furthermore, mechanistic analyses revealed that glycogen dynamics is a critically required process for maintenance of pain by facilitating neuronal plasticity in spinal lamina 1 neurons. In summary, our study describes a previously unappreciated mechanism of astrocyte-neuron metabolic communication through glycogen breakdown in the spinal cord that fuels spinal neuron hyperexcitability.


2024 Mar - Sci Immunol
Editor's Pick

Recurrent infections drive persistent bladder dysfunction and pain via sensory nerve sprouting and mast cell activity.

Authors: Hayes BW, Choi HW, Rathore APS, Bao C, Shi J, Huh Y, Kim MW, Mencarelli A, Bist P, Ng LG, Shi C, Nho JH, Kim A, Yoon H, Lim D, Hannan JL, Purves JT, Hughes FM, Ji RR, Abraham SN
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Urinary tract infections (UTIs) account for almost 25% of infections in women. Many are recurrent (rUTI), with patients frequently experiencing chronic pelvic pain and urinary frequency despite clearance of bacteriuria after antibiotics. To elucidate the basis for these bacteria-independent bladder symptoms, we examined the bladders of patients with rUTI. We noticed a notable increase in neuropeptide content in the lamina propria and indications of enhanced nociceptive activity. In mice subjected to rUTI, we observed sensory nerve sprouting that was associated with nerve growth factor (NGF) produced by recruited monocytes and tissue-resident mast cells. Treatment of rUTI mice with an NGF-neutralizing antibody prevented sprouting and alleviated pelvic sensitivity, whereas instillation of native NGF into naïve mice bladders mimicked nerve sprouting and pain behavior. Nerve activation, pain, and urinary frequency were each linked to the presence of proximal mast cells, because mast cell deficiency or treatment with antagonists against receptors of several direct or indirect mast cell products was each effective therapeutically. Thus, our findings suggest that NGF-driven sensory sprouting in the bladder coupled with chronic mast cell activation represents an underlying mechanism driving bacteria-independent pain and voiding defects experienced by patients with rUTI.


2024 Mar 01 - Nat Med
Editor's Pick

A multi-ancestry genetic study of pain intensity in 598,339 veterans.

Authors: Toikumo S, Vickers-Smith R, Jinwala Z, Xu H, Saini D, Hartwell EE, Pavicic M, Sullivan KA, Xu K, Jacobson DA, Gelernter J, Rentsch CT, , Stahl E, Cheatle M, Zhou H, Waxman SG, Justice AC, Kember RL, Kranzler HR
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Chronic pain is a common problem, with more than one-fifth of adult Americans reporting pain daily or on most days. It adversely affects the quality of life and imposes substantial personal and economic costs. Efforts to treat chronic pain using opioids had a central role in precipitating the opioid crisis. Despite an estimated heritability of 25-50%, the genetic architecture of chronic pain is not well-characterized, in part because studies have largely been limited to samples of European ancestry. To help address this knowledge gap, we conducted a cross-ancestry meta-analysis of pain intensity in 598,339 participants in the Million Veteran Program, which identified 126 independent genetic loci, 69 of which are new. Pain intensity was genetically correlated with other pain phenotypes, level of substance use and substance use disorders, other psychiatric traits, education level and cognitive traits. Integration of the genome-wide association studies findings with functional genomics data shows enrichment for putatively causal genes (n = 142) and proteins (n = 14) expressed in brain tissues, specifically in GABAergic neurons. Drug repurposing analysis identified anticonvulsants, β-blockers and calcium-channel blockers, among other drug groups, as having potential analgesic effects. Our results provide insights into key molecular contributors to the experience of pain and highlight attractive drug targets.


2024 Mar 01 - Blood
Editor's Pick

Sickle cell disease iPSC-derived sensory neurons exhibit increased excitability and sensitization to patient plasma.

Authors: Allison R, Welby E, Ehlers V, Burand A, Isaeva O, Nieves Torres DD, Highland J, Brandow AM, Stucky CL, Ebert AD
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Individuals living with sickle cell disease (SCD) experience severe recurrent acute and chronic pain. Challenges to gaining mechanistic insight into pathogenic SCD pain processes include differential gene expression and function of sensory neurons between humans and mice with SCD, and extremely limited availability of neuronal tissues from SCD patients. Here we used SCD patient-derived induced pluripotent stem cells (iPSCs) differentiated into sensory neurons (SCD iSNs) to begin to overcome these challenges. We characterize key gene expression and function of SCD iSNs to establish a model to investigate intrinsic and extrinsic factors that may contribute to SCD pain. Despite similarities in receptor gene expression, SCD iSNs show pronounced excitability using patch clamp electrophysiology. Further, we find that plasma taken from SCD patients during acute pain associated with a vaso-occlusive event increases the calcium responses in SCD iSNs to the nociceptive stimulus capsaicin compared to those treated with paired SCD patient plasma at steady state baseline or healthy control plasma samples. We identified high levels of the polyamine spermine in baseline and acute pain states of SCD patient plasma, which sensitizes SCD iSNs to sub-threshold concentrations of capsaicin. Together, these data identify potential intrinsic mechanisms within SCD iSNs that may extend beyond a blood-based pathology.


2024 Feb 24 - Nat Commun
Editor's Pick

NAAA-regulated lipid signaling in monocytes controls the induction of hyperalgesic priming in mice.

Authors: Fotio Y, Mabou Tagne A, Squire E, Lee HL, Phillips CM, Chang K, Ahmed F, Greenberg AS, Villalta SA, Scarfone VM, Spadoni G, Mor M, Piomelli D
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Circulating monocytes participate in pain chronification but the molecular events that cause their deployment are unclear. Using a mouse model of hyperalgesic priming (HP), we show that monocytes enable progression to pain chronicity through a mechanism that requires transient activation of the hydrolase, N-acylethanolamine acid amidase (NAAA), and the consequent suppression of NAAA-regulated lipid signaling at peroxisome proliferator-activated receptor-α (PPAR-α). Inhibiting NAAA in the 72 hours following administration of a priming stimulus prevented HP. This effect was phenocopied by NAAA deletion and depended on PPAR-α recruitment. Mice lacking NAAA in CD11b cells – monocytes, macrophages, and neutrophils – were resistant to HP induction. Conversely, mice overexpressing NAAA or lacking PPAR-α in the same cells were constitutively primed. Depletion of monocytes, but not resident macrophages, generated mice that were refractory to HP. The results identify NAAA-regulated signaling in monocytes as a control node in the induction of HP and, potentially, the transition to pain chronicity.


2024 Feb 23 - Brain Behav Immun
Editor's Pick

PRMT6 deficiency or inhibition alleviates neuropathic pain by decreasing glycolysis and inflammation in microglia.

Authors: Hua T, Kong E, Zhang H, Lu J, Huang K, Ding R, Wang H, Li J, Han C, Yuan H
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Microglia induced chronic inflammation is the critical pathology of Neuropathic pain (NP). Metabolic reprogramming of macrophage has been intensively reported in various chronic inflammation diseases. However, the metabolic reprogramming of microglia in chronic pain remains to be elusive. Here, we reported that immuno-metabolic markers (HIF-1α, PKM2, GLUT1 and lactate) were related with increased expression of PRMT6 in the ipsilateral spinal cord dorsal horn of the chronic construction injury (CCI) mice. PRMT6 deficiency or prophylactic and therapeutic intrathecal administration of PRMT6 inhibitor (EPZ020411) ameliorated CCI-induced NP, inflammation and glycolysis in the ipsilateral spinal cord dorsal horn. PRMT6 knockout or knockdown inhibited LPS-induced inflammation, proliferation and glycolysis in microglia cells. While PRMT6 overexpression exacerbated LPS-induced inflammation, proliferation and glycolysis in BV2 cells. Recent research revealed that PRMT6 could interact with and methylate HIF-1α, which increased HIF-1α protein stability. In sum, increased expression of PRMT6 exacerbates NP progress by increasing glycolysis and neuroinflammation through interacting with and stabilizing HIF-1α in a methyltransferase manner, which outlines novel pathological mechanism and drug target for NP.


2024 Feb 13 - Lancet
Editor's Pick

Abatacept inhibits inflammation and onset of rheumatoid arthritis in individuals at high risk (ARIAA): a randomised, international, multicentre, double-blind, placebo-controlled trial.

Authors: Rech J, Tascilar K, Hagen M, Kleyer A, Manger B, Schoenau V, Hueber AJ, Kleinert S, Baraliakos X, Braun J, Kiltz U, Fleck M, Rubbert-Roth A, Kofler DM, Behrens F, Feuchtenberger M, Zaenker M, Voll R, Venhoff N, Thiel J, Glaser C, Feist E, Burmester GR, Karberg K, Strunk J, Cañete JD, Senolt L, Filkova M, Naredo E, Largo R, Krönke G, D'Agostino MA, Østergaard M, Schett G
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Individuals with anti-citrullinated protein antibodies (ACPAs) and subclinical inflammatory changes in joints are at high risk of developing rheumatoid arthritis. Treatment strategies to intercept this pre-stage clinical disease remain to be developed. We aimed to assess whether 6-month treatment with abatacept improves inflammation in preclinical rheumatoid arthritis.


2024 Feb 13 - Lancet
Editor's Pick

Abatacept in individuals at high risk of rheumatoid arthritis (APIPPRA): a randomised, double-blind, multicentre, parallel, placebo-controlled, phase 2b clinical trial.

Authors: Cope AP, Jasenecova M, Vasconcelos JC, Filer A, Raza K, Qureshi S, D'Agostino MA, McInnes IB, Isaacs JD, Pratt AG, Fisher BA, Buckley CD, Emery P, Ho P, Buch MH, Ciurtin C, van Schaardenburg D, Huizinga T, Toes R, Georgiou E, Kelly J, Murphy C, Prevost AT
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Individuals with serum antibodies to citrullinated protein antigens (ACPA), rheumatoid factor, and symptoms, such as inflammatory joint pain, are at high risk of developing rheumatoid arthritis. In the arthritis prevention in the pre-clinical phase of rheumatoid arthritis with abatacept (APIPPRA) trial, we aimed to evaluate the feasibility, efficacy, and acceptability of treating high risk individuals with the T-cell co-stimulation modulator abatacept.


2024 Jan 31 - Neuron
Editor's Pick

Anterior cingulate cortex projections to the dorsal medial striatum underlie insomnia associated with chronic pain.

Authors: Li YD, Luo YJ, Su WK, Ge J, Crowther A, Chen ZK, Wang L, Lazarus M, Liu ZL, Qu WM, Huang ZL
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Chronic pain often leads to the development of sleep disturbances. However, the precise neural circuit mechanisms responsible for sleep disorders in chronic pain have remained largely unknown. Here, we present compelling evidence that hyperactivity of pyramidal neurons (PNs) in the anterior cingulate cortex (ACC) drives insomnia in a mouse model of nerve-injury-induced chronic pain. After nerve injury, ACC PNs displayed spontaneous hyperactivity selectively in periods of insomnia. We then show that ACC PNs were both necessary for developing chronic-pain-induced insomnia and sufficient to mimic sleep loss in naive mice. Importantly, combining optogenetics and electrophysiological recordings, we found that the ACC projection to the dorsal medial striatum (DMS) underlies chronic-pain-induced insomnia through enhanced activity and plasticity of ACC-DMS dopamine D1R neuron synapses. Our findings shed light on the pivotal role of ACC PNs in developing chronic-pain-induced sleep disorders.