Papers of the Week

Helicobacter pylori (H. pylori) manipulates the host immune system to establish a persistent colonization, posing a serious threat to human health, but the mechanisms remain poorly understood. Here we integrate single-cell RNA sequencing and TCR profiling for analyzing 187,192 cells from 11 H. pylori-negative and 12 H. pylori-positive individuals to describe the human gastric ecosystem reprogrammed by H. pylori infection, as manifested by impaired antigen presentation and phagocytosis function. We further delineate a monocyte-to-C1QC macrophage differentiation trajectory driven by H. pylori infection, while T cell responses exhibit broad functional impairment and hyporesponsiveness with restricted clonal expansion capacity. We also identify an HLA-DRs- and CTLA4-expressing T cell population residing in H. pylori-inhabited stomach that potentially contribute to immune evasion. Together, our findings provide single-cell resolution information into the immunosuppressive microenvironment shaped by H. pylori infection, offering critical insights for developing novel therapeutic approaches to eliminate this globally prevalent pathogen.

Pain sensation often involves mechanical modalities. Mechanically activated (MA) ion channels on sensory neurons underly responsiveness to mechanical stimuli. MA current properties have mainly been derived from rodent sensory neurons. This study aimed to address gaps in knowledge regarding MA current properties in trigeminal (TG) neurons of a higher order species, common marmoset non-human primates (NHP). MA currents triggered by a piezo-actuator were recorded in patch clamp configuration . MA responses were associated with action potential (AP) properties, such as width, dV/dt on the falling phase, and presence/absence of AP firing in NHP TG neurons. According to responsiveness to mechanical stimuli and AP properties, marmoset TG neurons were clustered into 4 S-type and 5 M-type groups. S-type TG neurons had broader AP with two dV/dt peaks on the AP falling phase. Only one S-type group of NHP TG neurons produced small MA currents. M-type TG neurons had narrow AP without two dV/dt peaks on the AP falling phase. M-type NHP TG neurons, except one group, showed MA currents. We additionally used immunohistochemistry to confirm presence of known sensory neuronal types such as un-myelinated peptidergic CGRP/trpV1, un-myelinated non-peptidergic MrgprD and CGRP/trpV1, and myelinated peptidergic CGRP/trpV1 and non-peptidergic CGRP and PV NHP TG neurons. Overall, marmoset TG neurons and associated MA currents have many similarities compared to reported data from mouse sensory neurons. However, there are notable differences such as lower percentage of small NHP TG neurons responding to mechanical stimuli, and absence fast inactivating MA currents. Understanding the mechanical responses in trigeminal (TG) neurons is pivotal for elucidating the mechanisms of somatosensation and gaining insights into the cellular basis of acute and chronic pain in head and neck area. Mechanically activated (MA) currents have mainly been characterized in rodent sensory neurons. However, extrapolating these findings to humans may have significant implications. Thus, identifying specific properties of MA currents from non-human primates (NHPs) is of fundamental importance, underscoring the relevance of this study. MA currents triggered by a piezo-actuator were studied in NHP TG neurons using patch-clamp electrophysiology. Based on electrical properties of neurons, 9 distinct types of NHP TG neurons were identified. Overall, NHP TG neurons have many similarities with reported properties of mouse dorsal root ganglion (DRG) and TG neurons. However, there are notable differences such as a low percentage of neurons responding to mechanical stimuli among the smaller TG neurons and an absence of fast inactivating MA currents.

The purpose of this review is to provide an update on the clinical course and management of migraine in women.

Somatosensory neurons encode detailed information about touch and temperature and are the peripheral drivers of pain. Here by combining functional imaging with multiplexed in situ hybridization, we determined how heat and mechanical stimuli are encoded across neuronal classes and how inflammation transforms this representation to induce heat hypersensitivity, mechanical allodynia and continuing pain. Our data revealed that trigeminal neurons innervating the cheek exhibited complete segregation of responses to gentle touch and heat. By contrast, heat and noxious mechanical stimuli broadly activated nociceptor classes, including cell types proposed to trigger select percepts and behaviours. Injection of the inflammatory mediator prostaglandin E2 caused long-lasting activity and thermal sensitization in select classes of nociceptors, providing a cellular basis for continuing inflammatory pain and heat hypersensitivity. We showed that the capsaicin receptor TRPV1 (ref. ) has a central role in heat sensitization but not in spontaneous nociceptor activity. Unexpectedly, the responses to mechanical stimuli were minimally affected by inflammation, suggesting that tactile allodynia results from the continuing firing of nociceptors coincident with touch. Indeed, we have demonstrated that nociceptor activity is both necessary and sufficient for inflammatory tactile allodynia. Together, these findings refine models of sensory coding and discrimination at the cellular and molecular levels, demonstrate that touch and temperature are broadly but differentially encoded across transcriptomically distinct populations of sensory cells and provide insight into how cellular-level responses are reshaped by inflammation to trigger diverse aspects of pain.

The mu-opioid receptor (MOR), a member of the G-protein-coupled receptor superfamily, is pivotal in pain modulation and analgesia. Biased agonism at MOR offers a promising avenue for developing safer opioid therapeutics by selectively engaging specific signaling pathways. This study presents a comprehensive analysis of biased agonists using a newly curated database, BiasMOR, comprising 166 unique molecules with annotated activity data for GTPγS, cAMP, and β-arrestin assays. Advanced structure-activity relationship (SAR) analyses, including network similarity graphs, maximum common substructures, and activity cliff identification, reveal critical molecular features underlying bias signaling. Modelability assessments indicate high suitability for predictive modeling, with RMODI indices exceeding 0.96 and SARI indices highlighting moderately continuous SAR landscapes for cAMP and β-arrestin assays. Interaction patterns for biased agonists are discussed, including key residues such as D, Y, and Y. Comparative studies of enantiomer-specific interactions further underscore the role of ligand-induced conformational states in modulating signaling pathways. This work underscores the potential of combining computational and experimental approaches to advance the understanding of MOR-biased signaling, paving the way for safer opioid therapies. The database provided here will serve as a starting point for designing biased mu opioid receptor ligands and will be updated as new data become available. Increasing the repertoire of biased ligands and analyzing molecules collectively, as the database described here, contributes to pinpointing structural features responsible for biased agonism that can be associated with biological effects still under debate.

Complex Regional Pain Syndrome (CRPS) presents significant diagnostic challenges due to its diverse clinical presentation. This study aims to describe the diagnostic trajectory of patients labeled with CRPS, focusing on referral patterns, application of the Budapest criteria, and accuracy of CRPS diagnosis.

Chronic pain affects millions globally, yet no universally effective treatment exists. The primary motor cortex (M1) has been a key target for chronic pain therapies, with electrical stimulation of the M1 (eMCS) showing promise. However, the mechanisms underlying M1-mediated analgesic effects are not fully understood. We investigated the role of the primary somatosensory cortex (S1) in M1-mediated analgesia using a neuropathic pain mouse model. In this model, neuropathic pain is associated with increased spontaneous activity of layer V pyramidal neurons (LV-PNs) in the S1, partly attributed to the reduced activity of somatostatin-expressing inhibitory neurons (SST INs), which normally suppress LV-PNs. While manipulation of either LV-PNs or SST INs has been shown to alleviate pain, the role of S1 in M1-mediated analgesia has not been identified. Using multichannel silicon probes, we applied eMCS to neuropathic mice and observed significant analgesia. Histological analyses revealed that eMCS activated SST INs and suppressed hyperactivity of LV-PNs in the S1, suggesting that eMCS suppresses pain by modulating S1 neuronal circuits, alongside other pain-related regions. Notably, eMCS induced long-lasting analgesia, persisting for at least two days post-stimulation. These findings implicate S1 as a critical mediator of eMCS-induced analgesia and suggest eMCS as a potential durable therapeutic strategy for chronic pain. Chronic pain is a devastating disorder that affects over 25% of the global population. The lack of universally and entirely effective treatments, combined with severe social and economic burdens posed by the side effects of current analgesics, underscores the need to explore multifaceted approaches. In this study, we applied a silicon probe to target layer 5 of the M1 region of mice and delivered electrical stimulation to a chronic constriction injury mouse model. Our findings demonstrated that eMCS induced analgesic effects on mechanical stimuli, with the effect notably persisting for at least two days after the cessation of eMCS. As a potential mechanism, we identified SST+ neuronal activation in S1, along with other previously known brain regions influenced by eMCS.

The neural mechanisms underlying sex-specific pain, in which males and females exhibit distinct responses to pain, remain poorly understood. Here we show that in a mouse model of male-specific pain hypersensitivity response to pain conditioning environments (contextual pain hypersensitivity model), elevated free-testosterone leads to hyperactivity of glutamatergic neurons in the medial preoptic area (Glu) through activation of androgen receptor signaling, which in turn induces contextual pain hypersensitivity in male mice. Although not observed in naïve female mice, this pain phenotype could be induced in females via chronic administration of testosterone propionate. In addition, Glu neurons send excitatory inputs to GABAergic neurons in the ventrolateral periaqueductal gray (GABA) that are required for contextual pain hypersensitivity. Our study thus demonstrates that testosterone/androgen receptor signaling enhances Glu→ GABA pathway activity, which drives a male-specific contextual pain hypersensitivity, providing insight into the basis of sexually dimorphic pain response.

Sensory-motor integration is crucial in the processing of chronic pain. The primary motor cortex (M1) is emerging as a promising target for chronic pain treatment. However, it remains elusive how nociceptive sensory inputs influence M1 activity and how rectifying M1 defects, in turn, regulates pain processing at cellular and network levels. We show that injury/inflammation leads to hypoactivity of M1 pyramidal neurons by excitation-inhibition imbalance between the primary somatosensory cortex (S1) and the M1. The impaired M1 output further weakens inputs to excitatory parvalbumin neurons of the lateral hypothalamus (LH) and impairs the descending inhibitory system, hence exacerbating spinal nociceptive sensitivity. When rectifying M1 defects with repetitive transcranial magnetic stimulation (rTMS), the imbalance of the S1-M1 microcircuitry can be effectively reversed, which aids in restoring the ability of the M1 to trigger the descending inhibitory system, thereby alleviating nociceptive hypersensitivity. Thus, a sensory-motor-sensory loop is identified for pain-related interactions between the sensory and motor systems and can be potentially exploited for treating chronic pain.