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2023 Dec 06 - Sci Transl Med
Editor's Pick

Intervertebral disc human nucleus pulposus cells associated with back pain trigger neurite outgrowth in vitro and pain behaviors in rats.

Authors: Jiang W, Glaeser JD, Kaneda G, Sheyn J, Wechsler JT, Stephan S, Salehi K, Chan JL, Tawackoli W, Avalos P, Johnson C, Castaneda C, Kanim LEA, Tanasansomboon T, Burda JE, Shelest O, Yameen H, Perry TG, Kropf M, Cuellar JM, Seliktar D, Bae HW, Stone LS, Sheyn D
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Low back pain (LBP) is often associated with the degeneration of human intervertebral discs (IVDs). However, the pain-inducing mechanism in degenerating discs remains to be elucidated. Here, we identified a subtype of locally residing human nucleus pulposus cells (NPCs), generated by certain conditions in degenerating discs, that was associated with the onset of discogenic back pain. Single-cell transcriptomic analysis of human tissues showed a strong correlation between a specific cell subtype and the pain condition associated with the human degenerated disc, suggesting that they are pain-triggering. The application of IVD degeneration-associated exogenous stimuli to healthy NPCs in vitro recreated a pain-associated phenotype. These stimulated NPCs activated functional human iPSC-derived sensory neuron responses in an in vitro organ-chip model. Injection of stimulated NPCs into the healthy rat IVD induced local inflammatory responses and increased cold sensitivity and mechanical hypersensitivity. Our findings reveal a previously uncharacterized pain-inducing mechanism mediated by NPCs in degenerating IVDs. These findings could aid in the development of NPC-targeted therapeutic strategies for the clinically unmet need to attenuate discogenic LBP.

2023 Dec 06 - Nat Commun
Editor's Pick

Docking for EP4R antagonists active against inflammatory pain.

Authors: Gahbauer S, DeLeon C, Braz JM, Craik V, Kang HJ, Wan X, Huang XP, Billesbølle CB, Liu Y, Che T, Deshpande I, Jewell M, Fink EA, Kondratov IS, Moroz YS, Irwin JJ, Basbaum AI, Roth BL, Shoichet BK
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The lipid prostaglandin E (PGE) mediates inflammatory pain by activating G protein-coupled receptors, including the prostaglandin E2 receptor 4 (EP4R). Nonsteroidal anti-inflammatory drugs (NSAIDs) reduce nociception by inhibiting prostaglandin synthesis, however, the disruption of upstream prostanoid biosynthesis can lead to pleiotropic effects including gastrointestinal bleeding and cardiac complications. In contrast, by acting downstream, EP4R antagonists may act specifically as anti-inflammatory agents and, to date, no selective EP4R antagonists have been approved for human use. In this work, seeking to diversify EP4R antagonist scaffolds, we computationally dock over 400 million compounds against an EP4R crystal structure and experimentally validate 71 highly ranked, de novo synthesized molecules. Further, we show how structure-based optimization of initial docking hits identifies a potent and selective antagonist with 16 nanomolar potency. Finally, we demonstrate favorable pharmacokinetics for the discovered compound as well as anti-allodynic and anti-inflammatory activity in several preclinical pain models in mice.

2023 Dec 03 - Cell Rep
Editor's Pick

Single-cell RNA sequencing uncovers the cell type-dependent transcriptomic changes in the retrosplenial cortex after peripheral nerve injury.

Authors: Wang JH, Wu C, Lian YN, Cao XW, Wang ZY, Dong JJ, Wu Q, Liu L, Sun L, Chen W, Chen WJ, Zhang Z, Zhuo M, Li XY
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The retrosplenial cortex (RSC) is a vital area for storing remote memory and has recently been found to undergo broad changes after peripheral nerve injury. However, little is known about the role of RSC in pain regulation. Here, we examine the involvement of RSC in the pain of mice with nerve injury. Notably, reducing the activities of calcium-/calmodulin-dependent protein kinase type II-positive splenial neurons chemogenetically increases paw withdrawal threshold and extends thermal withdrawal latency in mice with nerve injury. The single-cell or single-nucleus RNA-sequencing results predict enhanced excitatory synaptic transmissions in RSC induced by nerve injury. Local infusion of 1-naphthyl acetyl spermine into RSC to decrease the excitatory synaptic transmissions relieves pain and induces conditioned place preference. Our data indicate that RSC is critical for regulating physiological and neuropathic pain. The cell type-dependent transcriptomic information would help understand the molecular basis of neuropathic pain.

2023 Nov 30 - Transl Res
Editor's Pick

Crosstalk between GABA receptors in astrocytes and neurons triggered by general anesthetic drugs.

Authors: Wang DS, Ju L, Pinguelo AG, Kaneshwaran K, Haffey SC, Lecker I, Gohil H, Wheeler MB, Kaustov L, Ariza A, Yu M, Volchuk A, Steinberg BE, Goldenberg NM, Orser BA
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General anesthetic drugs cause cognitive deficits that persist after the drugs have been eliminated. Astrocytes may contribute to such cognition-impairing effects through the release of one or more paracrine factors that increase a tonic inhibitory conductance generated by extrasynaptic γ-aminobutyric acid type A (GABA) receptors in hippocampal neurons. The mechanisms underlying this astrocyte-to-neuron crosstalk remain unknown. Interestingly, astrocytes express anesthetic-sensitive GABA receptors. Here, we tested the hypothesis that anesthetic drugs activate astrocytic GABA receptors to initiate crosstalk leading to a persistent increase in extrasynaptic GABA receptor function in neurons. We also investigated the signaling pathways in neurons and aimed to identify the paracrine factors released from astrocytes. Astrocytes and neurons from mice were grown in primary cell cultures and studied using in vitro electrophysiological and biochemical assays. We discovered that the commonly used anesthetics etomidate (injectable) and sevoflurane (inhaled) stimulated astrocytic GABA receptors to release paracrine factors, which increased the tonic current in neurons via a p38 MAPK-dependent signaling pathway. The increase in tonic current was mimicked by exogenous IL-1β and abolished by blocking IL-1 receptors; however, unexpectedly, IL-1β and other cytokines were not detected in astrocyte-conditioned media. In summary, we have identified a novel form of crosstalk between GABA receptors in astrocytes and neurons that engages a p38 MAPK-dependent pathway.

2023 Dec 01 - Exp Mol Med
Editor's Pick

IgSF11 deficiency alleviates osteoarthritis in mice by suppressing early subchondral bone changes.

Authors: Kim GM, Kim J, Lee JY, Park MC, Lee SY
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Osteoarthritis (OA) is a degenerative joint disease. While it is classically characterized by articular cartilage destruction, OA affects all tissues in the joints and is thus also accompanied by local inflammation, subchondral bone changes, and persistent pain. However, our understanding of the underlying subchondral bone dynamics during OA progression is poor. Here, we demonstrate the contribution of immunoglobulin superfamily 11 (IgSF11) to OA subchondral bone remodeling by using a murine model. In particular, IgSF11 was quickly expressed by differentiating osteoclasts and upregulated in subchondral bone soon after destabilization-of-the-medial-meniscus (DMM)-induced OA. In mice, IgSF11 deficiency not only suppressed subchondral bone changes in OA but also blocked cartilage destruction. The IgSF11-expressing cells in OA subchondral bone were found to be involved in osteoclast maturation and bone resorption and colocalized with receptor-activator of nuclear-factor κ-B (RANK), the key osteoclast differentiation factor. Thus, our study shows that blocking early subchondral bone changes in OA can ameliorate articular cartilage destruction in OA.

2023 Nov 29 - Adv Mater
Editor's Pick

A Biomimetic Nociceptor Using Centrosymmetric Crystals for Machine Intelligence.

Authors: Wang W, Wang Y, Xiang L, Chen L, Yu L, Pan A, Tan J, Yuan Q
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Pain sensation is a crucial aspect of perception in the body. Force-activated nociceptors encode electrochemical signals and yield multilevel information of pain, thus enabling smart feedback. Inspired by the natural template, multi-dimensional mechano-sensing materials provide promising approaches for biomimetic nociceptors in intelligent terminals. However, the reliance on non-centrosymmetric crystals has narrowed the range of these materials. Here we report centrosymmetric crystal Cr -doped zinc gallogermanate (ZGGO:Cr) with multi-dimensional mechano-sensing, eliminating the limitation of crystal structure. Under forces, ZGGO:Cr generates electrical signals imitating those of neuronal systems, and produces luminescence for spatial mapping of mechanical stimuli, suggesting a path toward bionic pain perception. On that basis, we developed a wireless biomimetic nociceptor system and achieved a smart pain reflex in a robotic hand and robot-assisted biopsy surgery of rat and dog. This article is protected by copyright. All rights reserved.

2023 Nov 28 - Pain
Editor's Pick

Whole-genome methylation profiling reveals regions associated with painful temporomandibular disorders and active recovery processes.

Authors: Ao X, Parisien M, Fillingim RB, Ohrbach R, Slade GD, Diatchenko L, Smith SB
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Temporomandibular disorders (TMDs), collectively representing one of the most common chronic pain conditions, have a substantial genetic component, but genetic variation alone has not fully explained the heritability of TMD risk. Reasoning that the unexplained heritability may be because of DNA methylation, an epigenetic phenomenon, we measured genome-wide DNA methylation using the Illumina MethylationEPIC platform with blood samples from participants in the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) study. Associations with chronic TMD used methylation data from 496 chronic painful TMD cases and 452 TMD-free controls. Changes in methylation between enrollment and a 6-month follow-up visit were determined for a separate sample of 62 people with recent-onset painful TMD. More than 750,000 individual CpG sites were examined for association with chronic painful TMD. Six differentially methylated regions were significantly (P < 5 × 10-8) associated with chronic painful TMD, including loci near genes involved in the regulation of inflammatory and neuronal response. A majority of loci were similarly differentially methylated in acute TMD consistent with observed transience or persistence of symptoms at follow-up. Functional characterization of the identified regions found relationships between methylation at these loci and nearby genetic variation contributing to chronic painful TMD and with gene expression of proximal genes. These findings reveal epigenetic contributions to chronic painful TMD through methylation of the genes FMOD, PM20D1, ZNF718, ZFP57, and RNF39, following the development of acute painful TMD. Epigenetic regulation of these genes likely contributes to the trajectory of transcriptional events in affected tissues leading to resolution or chronicity of pain.

2023 Nov 22 - Cell
Editor's Pick

S. aureus drives itch and scratch-induced skin damage through a V8 protease-PAR1 axis.

Authors: Deng L, Costa F, Blake KJ, Choi S, Chandrabalan A, Yousuf MS, Shiers S, Dubreuil D, Vega-Mendoza D, Rolland C, Deraison C, Voisin T, Bagood MD, Wesemann L, Frey AM, Palumbo JS, Wainger BJ, Gallo RL, Leyva-Castillo JM, Vergnolle N, Price TJ, Ramachandran R, Horswill AR, Chiu IM
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Itch is an unpleasant sensation that evokes a desire to scratch. The skin barrier is constantly exposed to microbes and their products. However, the role of microbes in itch generation is unknown. Here, we show that Staphylococcus aureus, a bacterial pathogen associated with itchy skin diseases, directly activates pruriceptor sensory neurons to drive itch. Epicutaneous S. aureus exposure causes robust itch and scratch-induced damage. By testing multiple isogenic bacterial mutants for virulence factors, we identify the S. aureus serine protease V8 as a critical mediator in evoking spontaneous itch and alloknesis. V8 cleaves proteinase-activated receptor 1 (PAR1) on mouse and human sensory neurons. Targeting PAR1 through genetic deficiency, small interfering RNA (siRNA) knockdown, or pharmacological blockade decreases itch and skin damage caused by V8 and S. aureus exposure. Thus, we identify a mechanism of action for a pruritogenic bacterial factor and demonstrate the potential of inhibiting V8-PAR1 signaling to treat itch.

2023 Nov 20 - J Neurosci
Editor's Pick

Chronic morphine induces adaptations in opioid receptor signaling in a thalamo-striatal circuit that are location-dependent, sex-specific and regulated by mu opioid receptor phosphorylation.

Authors: Jaeckel ER, Herrera YN, Schulz S, Birdsong WT
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Chronic opioid exposure induces tolerance to the pain-relieving effects of opioids but sensitization to some other effects. While the occurrence of these adaptations is well-understood, the underlying cellular mechanisms are less clear. This study aimed to determine how chronic treatment with morphine, a prototypical opioid agonist, induced adaptations to subsequent morphine signaling in different subcellular contexts. Opioids acutely inhibit glutamatergic transmission from medial thalamic (MThal) inputs to the dorsomedial striatum (DMS) via activity at μ-opioid receptors (MORs). MORs are present in somatic and presynaptic compartments of MThal neurons terminating in the DMS. We investigated the effects of chronic morphine treatment on subsequent morphine signaling at MThal-DMS synapses and MThal cell bodies in male and female mice. Surprisingly, chronic morphine treatment increased subsequent morphine inhibition of MThal-DMS synaptic transmission (morphine facilitation) in male, but not female, mice. At MThal cell bodies, chronic morphine treatment decreased subsequent morphine activation of potassium conductance (morphine tolerance) in both male and female mice. In knockin mice expressing phosphorylation-deficient MORs, chronic morphine treatment resulted in tolerance to, rather than facilitation of, subsequent morphine signaling at MThal-DMS terminals, suggesting phosphorylation-deficiency unmasks adaptations that counter the facilitation observed at presynaptic terminals in wild-type mice. The results of this study suggest that the effects of chronic morphine exposure are not ubiquitous; rather adaptations in MOR function may be determined by multiple factors such as subcellular receptor distribution, influence of local circuitry and sex. Repeated opioid use causes tolerance to their pain-relieving effects but can exacerbate some undesirable effects limiting their clinical utility. A detailed understanding of the physiological adaptations that contribute to the development of tolerance is critical to develop mitigation strategies. This study found that within medial thalamic projection neurons, chronic morphine treatment induced adaptations that were not ubiquitous. Instead, prior morphine exposure increased morphine effects at thalamic terminals in the dorsomedial striatum only in male mice, but decreased morphine effects at medial thalamic cell bodies in both sexes. In mice lacking phosphorylation sites on MOR, chronic morphine treatment decreased, rather than increased, morphine effects at thalamic terminals in the dorsomedial striatum, implicating receptor phosphorylation in driving adaptations observed in wild-type mice.

2023 Nov 21 - Proc Natl Acad Sci U S A
Editor's Pick

A peptidomimetic modulator of the Ca2.2 N-type calcium channel for chronic pain.

Authors: Gomez K, Santiago U, Nelson TS, Allen HN, Calderon-Rivera A, Hestehave S, Rodríguez Palma EJ, Zhou Y, Duran P, Loya-Lopez S, Zhu E, Kumar U, Shields R, Koseli E, McKiver B, Giuvelis D, Zuo W, Inyang KE, Dorame A, Chefdeville A, Ran D, Perez-Miller S, Lu Y, Liu X, Handoko , Arora PS, Patek M, Moutal A, Khanna M, Hu H, Laumet G, King T, Wang J, Damaj MI, Korczeniewska OA, Camacho CJ, Khanna R
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Transmembrane Ca2.2 (N-type) voltage-gated calcium channels are genetically and pharmacologically validated, clinically relevant pain targets. Clinical block of Ca2.2 (e.g., with Prialt/Ziconotide) or indirect modulation [e.g., with gabapentinoids such as Gabapentin (GBP)] mitigates chronic pain but is encumbered by side effects and abuse liability. The cytosolic auxiliary subunit collapsin response mediator protein 2 (CRMP2) targets Ca2.2 to the sensory neuron membrane and regulates their function via an intrinsically disordered motif. A CRMP2-derived peptide (CBD3) uncouples the Ca2.2-CRMP2 interaction to inhibit calcium influx, transmitter release, and pain. We developed and applied a molecular dynamics approach to identify the dipeptide in CBD3 as the anchoring Ca2.2 motif and designed pharmacophore models to screen 27 million compounds on the open-access server ZincPharmer. Of 200 curated hits, 77 compounds were assessed using depolarization-evoked calcium influx in rat dorsal root ganglion neurons. Nine small molecules were tested electrophysiologically, while one (CBD3063) was also evaluated biochemically and behaviorally. CBD3063 uncoupled Ca2.2 from CRMP2, reduced membrane Ca2.2 expression and Ca currents, decreased neurotransmission, reduced fiber photometry-based calcium responses in response to mechanical stimulation, and reversed neuropathic and inflammatory pain across sexes in two different species without changes in sensory, sedative, depressive, and cognitive behaviors. CBD3063 is a selective, first-in-class, CRMP2-based peptidomimetic small molecule, which allosterically regulates Ca2.2 to achieve analgesia and pain relief without negative side effect profiles. In summary, CBD3063 could potentially be a more effective alternative to GBP for pain relief.