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Papers Of The Week
2024 Oct 01 - Nat Immunol
Editor's Pick

MrgprA3 neurons drive cutaneous immunity against helminths through selective control of myeloid-derived IL-33.

Authors: Inclan-Rico JM, Napuri CM, Lin C, Hung LY, Ferguson AA, Liu X, Wu Q, Pastore CF, Stephenson A, Femoe UM, Musaigwa F, Rossi HL, Freedman BD, Reed DR, Macháček T, Horák P, Abdus-Saboor I, Luo W, Herbert DR
Read Abstract
Skin uses interdependent cellular networks for barrier integrity and host immunity, but most underlying mechanisms remain obscure. Herein, we demonstrate that the human parasitic helminth Schistosoma mansoni inhibited pruritus evoked by itch-sensing afferents bearing the Mas-related G-protein-coupled receptor A3 (MrgprA3) in mice. MrgprA3 neurons controlled interleukin (IL)-17 γδ T cell expansion, epidermal hyperplasia and host resistance against S. mansoni through shaping cytokine expression in cutaneous antigen-presenting cells. MrgprA3 neuron activation downregulated IL-33 but induced IL-1β and tumor necrosis factor in macrophages and type 2 conventional dendritic cells partially through the neuropeptide calcitonin gene-related peptide. Macrophages exposed to MrgprA3-derived secretions or bearing cell-intrinsic IL-33 deletion showed increased chromatin accessibility at multiple inflammatory cytokine loci, promoting IL-17/IL-23-dependent changes to the epidermis and anti-helminth resistance. This study reveals a previously unrecognized intercellular communication mechanism wherein itch-inducing MrgprA3 neurons initiate host immunity against skin-invasive parasites by directing cytokine expression patterns in myeloid antigen-presenting cell subsets.

2024 Oct 04 - Nat Commun
Editor's Pick

The single-cell transcriptomic atlas iPain identifies senescence of nociceptors as a therapeutical target for chronic pain treatment.

Authors: Techameena P, Feng X, Zhang K, Hadjab S
Read Abstract

Chronic pain remains a significant medical challenge with complex underlying mechanisms, and an urgent need for new treatments. Our research built and utilized the iPain single-cell atlas to study chronic pain progression in dorsal root and trigeminal ganglia. We discovered that senescence of a small subset of pain-sensing neurons may be a driver of chronic pain. This mechanism was observed in animal models after nerve injury and in human patients diagnosed with chronic pain or diabetic painful neuropathy. Notably, treatment with senolytics, drugs that remove senescent cells, reversed pain symptoms in mice post-injury. These findings highlight the role of cellular senescence in chronic pain development, demonstrate the therapeutic potential of senolytic treatments, and underscore the value of the iPain atlas for future pain research.


2024 Sep 28 - Brain Behav Immun
Editor's Pick

Upregulation of delta opioid receptor by meningeal interleukin-10 prevents relapsing pain.

Authors: Inyang KE, Sim J, Clark KB, Geron M, Monahan K, Evans C, O'Connell P, Laumet S, Peng B, Ma J, Heijnen CJ, Dantzer R, Scherrer G, Kavelaars A, Bernard M, Aldhamen YA, Folger JK, Bavencoffe A, Laumet G
Read Abstract

Chronic pain often includes periods of transient amelioration and even remission that alternate with severe relapsing pain. While most research on chronic pain has focused on pain development and maintenance, there is a critical unmet need to better understand the mechanisms that underlie pain remission and relapse. We found that interleukin (IL)-10, a pain resolving cytokine, is produced by resident macrophages in the spinal meninges during remission from pain and signaled to IL-10 receptor-expressing sensory neurons. Using unbiased RNA-sequencing, we identified that IL-10 upregulated expression and antinociceptive activity of δ-opioid receptor (δOR) in the dorsal root ganglion. Genetic or pharmacological inhibition of either IL-10 signaling or δOR triggered relapsing pain. Overall, our findings, from electrophysiology, genetic manipulation, flow cytometry, pharmacology, and behavioral approaches, indicate that remission of pain is not simply a return to the naïve state. Instead, remission is an adapted homeostatic state associated with lasting pain vulnerability resulting from persisting neuroimmune interactions within the nociceptive system. Broadly, this sheds light on the elusive mechanisms underlying recurrence a common aspect across various chronic pain conditions.


2024 Sep 28 - Brain Behav Immun
Editor's Pick

Inflammatory pain resolution by mouse serum-derived small extracellular vesicles.

Authors: Lin Z, Luo X, Wickman JR, Reddy D, DaCunza JT, Pande R, Tian Y, Kasimoglu EE, Triana V, Lee J, Furdui CM, Pink D, Sacan A, Ajit SK
Read Abstract

Current treatments for chronic pain have limited efficacy and significant side effects, warranting research on alternative strategies for pain management. One approach involves using small extracellular vesicles (sEVs), or exosomes, to transport beneficial biomolecular cargo to aid pain resolution. Exosomes are 30-150 nm sEVs that can be beneficial or harmful depending on their source and cargo composition. We report a comprehensive multi-modal analysis of different aspects of sEV characterization, miRNAs, and protein markers across sEV sources. To investigate the short and long-term effects of mouse serum-derived sEVs in pain modulation, sEVs from naïve control or spared nerve injury (SNI) model male donor mice were injected intrathecally into naïve male recipient mice. These sEVs transiently increased basal mechanical thresholds, an effect mediated by opioid signaling as this outcome was blocked by naltrexone. Mass Spectrometry of sEVs detected endogenous opioid peptide leu-enkephalin. sEVs from naïve female mice have higher levels of leu-enkephalin compared to male and showed stronger effects in male recipients. In investigating the long-term effect of sEVs, we observed that a single prophylactic intrathecal injection of sEVs two weeks prior to induction of the pain model in recipient mice accelerated recovery from inflammatory pain after complete Freund’s adjuvant (CFA) injection. Our exploratory studies examining immune cell populations in spinal cord and dorsal root ganglion using ChipCytometry suggested alterations in immune cell populations 14 days post-CFA. Flow cytometry confirmed increases in CD206 macrophages in the spinal cord in sEV-treated mice. Collectively, these studies demonstrate multiple mechanisms by which sEVs can attenuate pain.


2024 Sep 27 - Sci Adv
Editor's Pick

A neural circuit for alcohol withdrawal-induced hyperalgesia in a nondependent state.

Authors: Yang XL, Gao W, Dong WY, Zheng C, Wang S, Wei HR, Luo Y, Zhang Z, Chen Y, Jin Y
Read Abstract

Alcohol use disorder is highly prevalent worldwide, with characteristically severe pain sensitivity during withdrawal. Here, we established a mouse model of hyperalgesia during ethanol withdrawal (EW) before addiction to investigate the window for onset and underlying mechanisms. Viral tracing with in vivo microendoscopic and two-photon calcium imaging identified a circuit pathway from dorsal hippocampal CA1 glutamatergic neurons (dCA1) to anterior cingulate cortex glutamatergic neurons (ACC) activated in EW mice with hyperalgesia. Chemogenetic inhibition of this pathway can alleviate hyperalgesia in EW mice, whereas artificial activation recapitulates EW-induced hyperalgesia in naïve mice. These findings demonstrate that the dCA1 → ACC neuronal pathway participates in driving EW-induced hyperalgesia before ethanol dependence in mice.


2024 Sep 24 - Pain
Editor's Pick

Dual Kv7.2/3-TRPV1 modulators inhibit nociceptor hyperexcitability and alleviate pain without target-related side effects.

Authors: Raveh A, Pen Y, Silberman A, Peretz A, Attali B, Maile L, Davidson S, Brown AD, Kennedy JD, Belinson H
Read Abstract

Persistent or chronic pain is the primary reason people seek medical care, yet current therapies are either limited in efficacy or cause intolerable side effects. Diverse mechanisms contribute to the basic phenomena of nociceptor hyperexcitability that initiates and maintains pain. Two prominent players in the modulation of nociceptor hyperexcitability are the transient receptor potential vanilloid type 1 (TRPV1) ligand-gated ion channel and the voltage-gated potassium channel, Kv7.2/3, that reciprocally regulate neuronal excitability. Across many drug development programs targeting either TRPV1 or Kv7.2/3, significant evidence has been accumulated to support these as highly relevant targets; however, side effects that are poorly separated from efficacy have limited the successful clinical translation of numerous Kv7.2/3 and TRPV1 drug development programs. We report here the pharmacological profile of 3 structurally related small molecule analogues that demonstrate a novel mechanism of action (MOA) of dual modulation of Kv7.2/3 and TRPV1. Specifically, these compounds simultaneously activate Kv7.2/3 and enable unexpected specific and potent inhibition of TRPV1. This in vitro potency translated to significant analgesia in vivo in several animal models of acute and chronic pain. Importantly, this specific MOA is not associated with any previously described Kv7.2/3 or TRPV1 class-specific side effects. We suggest that the therapeutic potential of this MOA is derived from the selective and specific targeting of a subpopulation of nociceptors found in rodents and humans. This efficacy and safety profile supports the advancement of dual TRPV1-Kv7.2/3 modulating compounds into preclinical and clinical development for the treatment of chronic pain.


2024 Sep 27 - Sci Adv
Editor's Pick

Kappa opioids inhibit spinal output neurons to suppress itch.

Authors: Sheahan TD, Warwick CA, Cui AY, Baranger DAA, Perry VJ, Smith KM, Manalo AP, Nguyen EK, Koerber HR, Ross SE
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Itch is a protective sensation that drives scratching. Although specific cell types have been proposed to underlie itch, the neural basis for itch remains unclear. Here, we used two-photon Ca imaging of the dorsal horn to visualize neuronal populations that are activated by itch-inducing agents. We identify a convergent population of spinal interneurons recruited by diverse itch-causing stimuli that represents a subset of neurons that express the gastrin-releasing peptide receptor (GRPR). Moreover, we find that itch is conveyed to the brain via GRPR-expressing spinal output neurons that target the lateral parabrachial nuclei. We then show that the kappa opioid receptor agonist nalfurafine relieves itch by selectively inhibiting GRPR spinoparabrachial neurons. These experiments provide a population-level view of the spinal neurons that respond to pruritic stimuli, pinpoint the output neurons that convey itch to the brain, and identify the cellular target of kappa opioid receptor agonists for the inhibition of itch.


2024 Sep 25 - Sci Transl Med
Editor's Pick

B cells drive neuropathic pain-related behaviors in mice through IgG-Fc gamma receptor signaling.

Authors: Lacagnina MJ, Willcox KF, Boukelmoune N, Bavencoffe A, Sankaranarayanan I, Barratt DT, Zuberi YA, Dayani D, Chavez MV, Lu JT, Farinotti AB, Shiers S, Barry AM, Mwirigi JM, Tavares-Ferreira D, Funk GA, Cervantes AM, Svensson CI, Walters ET, Hutchinson MR, Heijnen CJ, Price TJ, Fiore NT, Grace PM
Read Abstract

Neuroimmune interactions are essential for the development of neuropathic pain, yet the contributions of distinct immune cell populations have not been fully unraveled. Here, we demonstrate the critical role of B cells in promoting mechanical hypersensitivity (allodynia) after peripheral nerve injury in male and female mice. Depletion of B cells with a single injection of anti-CD20 monoclonal antibody at the time of injury prevented the development of allodynia. B cell-deficient (muMT) mice were similarly spared from allodynia. Nerve injury was associated with increased immunoglobulin G (IgG) accumulation in ipsilateral lumbar dorsal root ganglia (DRGs) and dorsal spinal cords. IgG was colocalized with sensory neurons and macrophages in DRGs and microglia in spinal cords. IgG also accumulated in DRG samples from human donors with chronic pain, colocalizing with a marker for macrophages and satellite glia. RNA sequencing revealed a B cell population in naive mouse and human DRGs. A B cell transcriptional signature was enriched in DRGs from human donors with neuropathic pain. Passive transfer of IgG from injured mice induced allodynia in injured muMT recipient mice. The pronociceptive effects of IgG are likely mediated through immune complexes interacting with Fc gamma receptors (FcγRs) expressed by sensory neurons, microglia, and macrophages, given that both mechanical allodynia and hyperexcitability of dissociated DRG neurons were abolished in nerve-injured FcγR-deficient mice. Consistently, the pronociceptive effects of IgG passive transfer were lost in FcγR-deficient mice. These data reveal that a B cell-IgG-FcγR axis is required for the development of neuropathic pain in mice.


2024 Sep 17 - JCI Insight
Editor's Pick

Peripherally restricted PICK1 inhibitor mPD5 ameliorates pain behaviors in murine inflammatory and neuropathic pain models.

Authors: Jensen KL, Christensen NR, Goddard CM, Jager SE, Noes-Holt G, Kanneworff IB, Jakobsen A, Jiménez-Fernández L, Peck EG, Sivertsen L, Comaposada-Baro R, Houser GA, Mayer FP, Diaz-delCastillo M, Topp ML, Hopkins C, Thomsen CD, Ibrahim Soltan AB, Tidenmand FG, Arleth L, Heegaard AM, Sørensen AT, Madsen KL
Read Abstract

Chronic pain is a complex, debilitating, and escalating health problem worldwide, impacting one in five adults. Current treatment is compromised by dose-limiting side effects including high abuse liability, loss of ability to function socially and professionally, fatigue, drowsiness, and apathy. PICK1 has emerged as a promising target for the treatment of chronic pain conditions. Here, we developed and characterized a cell-permeable fatty acid conjugated bivalent peptide inhibitor of PICK1 and assessed its effects on acute and chronic pain. The myristoylated myr-NPEG4-(HWLKV)2 (mPD5), self-assembled into core-shell micelles that provided favourable pharmacodynamic properties and relieved evoked mechanical and thermal hypersensitivity, as well as ongoing hypersensitivity, and anxio-depressive symptoms in mouse models of neuropathic and inflammatory pain following subcutaneous administration. No overt side effects were associated with mPD5 administration, and it had no effect on acute nociception. Finally, neuropathic pain was relieved far into the chronic phase (18 weeks post SNI surgery) and while the effect of a single injection ceased after a few hours, repeated administration provided pain relief lasting up to 20 hours after the last injection.


2024 Sep 17 - Adv Sci (Weinh)
Editor's Pick

Establishment of a Magnetically Controlled Scalable Nerve Injury Model.

Authors: Yang T, Liu X, Cao R, Zhou X, Li W, Wu W, Yu W, Zhang X, Guo Z, Cui S
Read Abstract

Animal models of peripheral nerve injury (PNI) serve as the fundamental basis for the investigations of nerve injury, regeneration, and neuropathic pain. The injury properties of such models, including the intensity and duration, significantly influence the subsequent pathological changes, pain development, and therapeutic efficacy. However, precise control over the intensity and duration of nerve injury remains challenging within existing animal models, thereby impeding accurate and comparative assessments of relevant cases. Here, a new model that provides quantitative and off-body controllable injury properties via a magnetically controlled clamp, is presented. The clamp can be implanted onto the rat sciatic nerve and exert varying degrees of compression under the control of an external magnetic field. It is demonstrated that this model can accurately simulate various degrees of pathology of human patients by adjusting the magnetic control and reveal specific pathological changes resulting from intensity heterogeneity that are challenging to detect previously. The controllability and quantifiability of this model may significantly reduce the uncertainty of central response and inter-experimenter variability, facilitating precise investigations into nerve injury, regeneration, and pain mechanisms.

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