Metabolite-Sensing Receptors: Emerging Targets for Modulating Chronic Pain Pathways

Current Issues in Molecular Biology, Год журнала: 2025, Номер 47(1), С. 63 - 63

Опубликована: Янв. 17, 2025

Chronic pain is a debilitating condition affecting millions worldwide, often resulting from complex interactions between the nervous and immune systems. Recent advances highlight critical role of metabolite-sensing G protein-coupled receptors (GPCRs) in various chronic types. These link metabolic changes with cellular responses, influencing inflammatory degenerative processes. Receptors such as free fatty acid receptor 1 (FFAR1/GPR40), 4 (FFAR4/GPR120), 2 (FFAR2/GPR43), Takeda 5 (TGR5/GPR131/GPBAR1) are key modulators nociceptive signaling. GPR40, activated by long-chain acids, exhibits strong anti-inflammatory effects reducing cytokine expression. Butyrate-activated GPR43 inhibits mediators like nitric oxide synthase-2 cyclooxygenase-2, mitigating inflammation. TGR5, bile regulates inflammation senescence through pathways NF-κB p38. promising therapeutic targets pain, addressing factors underlying sensitization tissue degeneration. This review explores molecular mechanisms their potential, challenges clinical application. By uncovering these mechanisms, could lead to safer, more effective management strategies.

Язык: Английский

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The gut microbiota promotes pain in fibromyalgia

Neuron, Год журнала: 2025, Номер unknown

Опубликована: Апрель 1, 2025

Fibromyalgia is a prevalent syndrome characterized by widespread pain in the absence of evident tissue injury or pathology, making it one most mysterious chronic conditions. The composition gut microbiota individuals with fibromyalgia differs from that healthy controls, but its functional role unknown. Here, we show fecal transplantation patients, not into germ-free mice induces and numerous molecular phenotypes parallel known changes including immune activation metabolomic profile alterations. Replacing substantially alleviated mice. An open-label trial women (Registry MOH_2021-11-04_010374) showed associated reduced improved quality life. We conclude altered has pain, highlighting as promising target for therapeutic interventions.

Язык: Английский

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Update on the development of TGR5 agonists for human diseases

European Journal of Medicinal Chemistry, Год журнала: 2024, Номер 271, С. 116462 - 116462

Опубликована: Апрель 28, 2024

Язык: Английский

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TGR5 Activation by Dietary Bioactives and Related Improvement in Mitochondrial Function for Alleviating Diabetes and Associated Complications

Journal of Agricultural and Food Chemistry, Год журнала: 2025, Номер unknown

Опубликована: Март 5, 2025

Takeda G protein-coupled receptor 5 (TGR5), also known as bile acid 1 (GPBAR1), is a cell surface involved in key physiological processes, including glucose homeostasis and energy metabolism. Recent research has focused on the role of TGR5 activation preventing or treating diabetes while highlighting its potential impact progression diabetic complications. Functional foods edible plants have emerged valuable sources natural compounds that can activate TGR5, offering therapeutic benefits for management. Despite growing interest, studies by dietary bioactive remain scattered. This Review aims to provide comprehensive analysis how bioactives act agents managing It explores mechanisms through both direct agonistic effects indirect pathways via modulation gut microbiota

Язык: Английский

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Activation of the bile acid receptors TGR5 and FXR in the spinal dorsal horn alleviates neuropathic pain

CNS Neuroscience & Therapeutics, Год журнала: 2023, Номер 29(7), С. 1981 - 1998

Опубликована: Март 7, 2023

Abstract Aims Beyond digestion, bile acids have been recognized as signaling molecules with broad paracrine and endocrine functions by activating plasma membrane receptor (Takeda G protein‐coupled 5, TGR5) the nuclear farnesoid X (FXR). The present study investigated role of in alleviating neuropathic pain TGR5 FXR. Method Neuropathic was induced spared nerve injury (SNI) sciatic nerve. or FXR agonist injected intrathecally. Pain hypersensitivity measured Von Frey test. amount detected using a acid assay kit. Western blotting immunohistochemistry were used to assess molecular changes. Results We found that downregulated, whereas expression cytochrome P450 cholesterol 7ahydroxylase (CYP7A1), rate‐limiting enzyme for synthesis, upregulated exclusively microglia spinal dorsal horn after SNI. Furthermore, receptors increased glial cells GABAergic neurons on day 7 Intrathecal injection either SNI alleviated established mechanical allodynia mice, effects blocked antagonist. Bile agonists inhibited activation ERK pathway horn. All above allodynia, cells, abolished intrathecal GABA A antagonist bicuculline. Conclusion These results suggest counteracts allodynia. effect mediated potentiating function receptors, which then neuronal sensitization

Язык: Английский

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Gut Microbiota Metabolite Messengers in Brain Function and Pathology at a View of Cell Type-Based Receptor and Enzyme Reaction

Biomolecules & Therapeutics, Год журнала: 2024, Номер 32(4), С. 403 - 423

Опубликована: Июнь 20, 2024

The human gastrointestinal (GI) tract houses a diverse microbial community, known as the gut microbiome comprising bacteria, viruses, fungi, and protozoa.The plays crucial role in maintaining body's equilibrium has recently been discovered to influence functioning of central nervous system (CNS).The communication between GI occurs through two-way network called gut-brain axis.The can modulate each other activated neuronal cells, immune system, metabolites produced by microbiome.Extensive research both preclinical clinical realms, highlighted complex relationship diseases associated with CNS, such Alzheimer's disease, Parkinson's amyotrophic lateral sclerosis.This review aims delineate receptor target enzymes linked microbiota explore their specific roles within brain, particularly impact on CNS-related diseases.

Язык: Английский

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Activation of TGR5 in the injured nerve site according to a prevention protocol mitigates partial sciatic nerve ligation–induced neuropathic pain by alleviating neuroinflammation

Pain, Год журнала: 2024, Номер unknown

Опубликована: Окт. 25, 2024

Abstract Neuropathic pain is a pervasive medical challenge currently lacking effective treatment options. Molecular changes at the site of peripheral nerve injury contribute to both and central sensitization, critical components neuropathic pain. This study explores role G-protein-coupled bile acid receptor (GPBAR1 or TGR5) in mechanisms underlying induced by partial sciatic ligation male mice. TGR5 was upregulated injured predominantly colocalized with macrophages. Perisciatic administration agonist, INT-777 according prevention protocol (50 μg/μL daily from postoperative day [POD] 0 POD6) provided sustained relief mechanical allodynia spontaneous pain, whereas antagonist, SBI-115 worsened Transcriptome sequencing linked activation reduced neuroinflammation, which further evidenced decrease myeloid cells pro-inflammatory mediators (eg, CCL3, CXCL9, interleukin [IL]-6, tumor necrosis factor [TNF] α) an increase CD86-CD206+ anti-inflammatory macrophages POD7. Besides, myeloid-cell-specific knockdown exacerbated substantiated bulk RNA-sequencing expression levels inflammatory (including CCL2, IL-6, TNF α, IL-1β) increased number monocytes/macrophages Furthermore, microglia spinal cord on POD7 POD14 altered when manipulated. Collectively, mitigates reducing while worsens enhancing neuroinflammation.

Язык: Английский

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Dietary Fatty Acid Composition Alters Gut Microbiome in Mice with Obesity-Induced Peripheral Neuropathy

Nutrients, Год журнала: 2025, Номер 17(4), С. 737 - 737

Опубликована: Фев. 19, 2025

Background: Peripheral neuropathy (PN), a complication of diabetes and obesity, progresses through complex pathophysiology. Lifestyle interventions to manage systemic metabolism are recommended prevent or slow PN, given the multifactorial risks obesity. A high-fat diet rich in saturated fatty acids (SFAs) induces which monounsaturated (MUFAs) rescues, independent weight loss, suggesting factors beyond impact nerve health. Interest has grown gut microbiome mechanisms is characterized by distinct microbiota signature that correlates with sciatic lipidome. Methods: Herein, we postulated SFA- versus MUFA-rich would composition correlate PN development. To assess causality, performed fecal transplantation (FMT) from donor mice fed lean recipient assessed metabolic phenotypes. Results: We found SFA-rich altered community structure, partially reversed. metrics correlated several microbial families, some containing genera feasible action for microbiome-mediated effects on PN. SFA MUFA FMT did not phenotypes although marginally induced motor Conclusions: The involvement diet-mediated changes gut–nerve axis may warrant further study.

Язык: Английский

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Spinal astrocytes involved in the pathogenesis and treatment of neuropathic pain

Frontiers in Cellular Neuroscience, Год журнала: 2025, Номер 19

Опубликована: Фев. 21, 2025

Neuropathic pain is a common and severe type of chronic pain, its pathogenesis has not been fully defined. Increasing evidence shows that spinal astrocytes play indispensable roles in the occurrence development neuropathic pain. Most studies have suggested activated can crosstalk with other glial cells neurons through morphological functional changes, exacerbating However, reactive dual role. As defense mechanism, increasing neuroprotection stimulating neurogenesis. Studies demonstrated potentially beneficial role for astrocyte activation In addition, therapeutic mechanisms multiple drugs neuromodulatory techniques are thought to be related astrocytes. This review highlights recent advances significance astrocytes, emphasizing need better understanding their treatment

Язык: Английский

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TRPC4 Mediates Trigeminal Neuropathic Pain via Ca²⁺‐ERK/P38‐ATF2 Pathway in the Trigeminal Ganglion of Mice

CNS Neuroscience & Therapeutics, Год журнала: 2025, Номер 31(4)

Опубликована: Апрель 1, 2025

ABSTRACT Background Trigeminal neuropathic pain (TNP) is a debilitating condition characterized by chronic facial pain, yet its underlying mechanisms remain incompletely understood. Transient Receptor Potential Canonical 4 (TRPC4) has been reported to promote the development of abnormal or hypersensitivity in pain. However, specific contribution TRPC4 TNP pathogenesis remains unclear. Aim This study aimed investigate role mouse model trigeminal induced constriction unilateral infraorbital nerve (CION). Methods Adult male/female mice were subjected either CION surgery sham surgery. Behavioral assays conducted assess pain‐like responses over 28‐day period. distribution ganglion (TG) was evaluated using Immunofluorescence. inhibitor ML204 and agonist Englerin A employed evaluate impact on behaviors. TRPC4‐overexpressing HEK293 cell via plasmid transfection. To function TRPC4, we cellular calcium imaging technology effects modulating analyzing dynamic changes intracellular ion concentrations primary neurons cells. Trpc4 shRNA used specifically knock down ganglion. Western blot analysis activation ERK, P38, ATF2 signaling pathways. Results Mice exhibited persistent behaviors significant increase expression TG neurons. pharmacological inhibition with attenuated CION‐induced behaviors, while naive mice. Calcium revealed that both overexpression elevated Ca² 2+ levels influx triggered ERK leading enhanced activation. Downregulation reduced ERK/P38 phosphorylation Conclusion provides first evidence plays critical promoting downstream transcription factor ‐ERK/P38 pathway.

Язык: Английский

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