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![Schematic diagram of the first- and second-order pain neurons. The peripheral and central terminals of a dorsal root ganglion (DRG) neuron as well as its cell body contain P2X3 and P2Y1Rs. ATP released by various pathways from peripheral tissues or visceral organs may stimulate pain-inducing P2X3Rs and analgesia-inducing P2Y1Rs. Glutamate and ATP are sensory neurotransmitters in the synapse formed by the central axon terminals of DRG neurons and the spinothalamic neuron conducting the ascending information to the thalamus. Neuronal P2X3Rs in the dorsal root spinal horn increase the release of neurotransmitter glutamate. Satellite glial cells of the DRG and astrocytes of the dorsal root of the spinal cord possess P2X7Rs, which may release upon activation by ATP interleukin-1β (IL-1β) and the gliotransmitters glutamate/ATP. Microglial cells in the spinal cord dorsal horn are endowed with P2X4Rs, whose activation leads to the secretion of brain derived neurotrophic factor (BDNF) involved in the generation of allodynia and hyperalgesia being the main hallmarks of neuropathic pain. R, receptor; Glu, glutamate. Note that P2X2Rs were omitted from the cell body of the spinothalamic neuron. Reproduced with permission from [84]](publication/356409511/figure/fig1/AS:11431281118913564@1675913636917/Schematic-diagram-of-the-first-and-second-order-pain-neurons-The-peripheral-and-central.png)
Schematic diagram of the first- and second-order pain neurons. The peripheral and central terminals of a dorsal root ganglion (DRG) neuron as well as its cell body contain P2X3 and P2Y1Rs. ATP released by various pathways from peripheral tissues or visceral organs may stimulate pain-inducing P2X3Rs and analgesia-inducing P2Y1Rs. Glutamate and ATP are sensory neurotransmitters in the synapse formed by the central axon terminals of DRG neurons and the spinothalamic neuron conducting the ascending information to the thalamus. Neuronal P2X3Rs in the dorsal root spinal horn increase the release of neurotransmitter glutamate. Satellite glial cells of the DRG and astrocytes of the dorsal root of the spinal cord possess P2X7Rs, which may release upon activation by ATP interleukin-1β (IL-1β) and the gliotransmitters glutamate/ATP. Microglial cells in the spinal cord dorsal horn are endowed with P2X4Rs, whose activation leads to the secretion of brain derived neurotrophic factor (BDNF) involved in the generation of allodynia and hyperalgesia being the main hallmarks of neuropathic pain. R, receptor; Glu, glutamate. Note that P2X2Rs were omitted from the cell body of the spinothalamic neuron. Reproduced with permission from [84]
Source publication
Chronic pain is caused by cellular damage with an obligatory inflammatory component. In response to noxious stimuli, high levels of ATP leave according to their concentration gradient, the intracellular space through discontinuities generated in the plasma membrane or diffusion through pannexin-1 hemichannels, and activate P2X7Rs localized at perip...
Citations
... Macrophage and Schwann cell P2X4R also promote cytokine and brain-derived neurotrophic factor release implicated in injured nerve regeneration and remyelination [26,33]. P2X7 receptors, primarily found on immune cells and microglia [34,35], are upregulated [34,36,37] and have a significant role in chronic inflammatory and neuropathic pain [34,35,37]. Notably, tolerance to morphine generated through repetitive dosing is accompanied by an upregulation of P2X7R [34,35] such that P2X7R inhibition reestablishes morphine analgesia [35]. ...
... Macrophage and Schwann cell P2X4R also promote cytokine and brain-derived neurotrophic factor release implicated in injured nerve regeneration and remyelination [26,33]. P2X7 receptors, primarily found on immune cells and microglia [34,35], are upregulated [34,36,37] and have a significant role in chronic inflammatory and neuropathic pain [34,35,37]. Notably, tolerance to morphine generated through repetitive dosing is accompanied by an upregulation of P2X7R [34,35] such that P2X7R inhibition reestablishes morphine analgesia [35]. ...
... P2X7 receptors, primarily found on immune cells and microglia [34,35], are upregulated [34,36,37] and have a significant role in chronic inflammatory and neuropathic pain [34,35,37]. Notably, tolerance to morphine generated through repetitive dosing is accompanied by an upregulation of P2X7R [34,35] such that P2X7R inhibition reestablishes morphine analgesia [35]. Similar to P2X4R, Schwann cell P2X7R promotes axon regrowth and myelination [35]. ...
The information provided from the papers reviewed here about the role of epigenetics in chronic craniofacial neuropathic pain is critically important because epigenetic dysregulation during the development and maintenance of chronic neuropathic pain is not yet well characterized, particularly for craniofacial pain. We have noted that gene expression changes reported vary depending on the nerve injury model and the reported sample collection time point. At a truly chronic timepoint of 10 weeks in our model of chronic neuropathic pain, functional groupings of genes examined include those potentially contributing to anti-inflammation, nerve repair/regeneration, and nociception. Genes altered after treatment with the epigenetic modulator LMK235 are discussed. All of these differentials are key in working toward the development of diagnosis-targeted therapeutics and likely for the timing of when the treatment is provided. The emphasis on the relevance of time post-injury is reiterated here.
... We also found that the activation of the NLRP3 inflammatory pathway by P2 × 7R may be intrinsic to the development of NP, and the results suggest that the inflammatory overreaction activated downstream of P2 × 7R is the direct cause of NP, with the NLRP3 signaling pathway being the main contributor. The involvement of P2 × 7R in the headache process has already been reported, as P2 × 7R is involved in the migraine process by activating NLRP3 and thus releasing IL-1β during migraine development [51]. Additional articles have also demonstrated that P2 × 7R/NLRP3 is a key factor NP + rTMS-stimulation + oe-NC + Control group. ...
This study investigates the effectiveness of repetitive transcranial magnetic stimulation (rTMS) as a nonpharmacological approach to treating neuropathic pain (NP), a major challenge in clinical research. Conducted on male Sprague-Dawley rats with NP induced through chronic constriction injury of the sciatic nerve, the research assessed pain behaviors and the impact of rTMS on molecular interactions within the amygdala. Through a comprehensive analysis involving Mechanical Withdrawal Threshold (MWT), Thermal Withdrawal Latency (TWL), RNA transcriptome sequencing, RT-qPCR, Western blotting, immunofluorescence staining, and Co-Immunoprecipitation (Co-IP), the study focused on the expression and interaction of integrin αvβ3 and its receptor P2X7R. Findings reveal that rTMS significantly influences the expression of integrin αvβ3 in NP models, suggesting an inhibition of the NP-associated NLRP3 inflammatory pathway through the disruption of integrin αvβ3-P2X7R interactions. These outcomes highlight the potential of rTMS in alleviating NP by targeting molecular interactions within the amygdala, offering a promising therapeutic avenue for managing NP.
... Multiple factors contribute to the development of pain, and it is widely acknowledged that inflammatory cytokines play a crucial role in this process. The role of adenosine triphosphate (ATP) and P 2 X 7 purine receptors in the release of inflammatory cytokines during pain has been consistently demonstrated by numerous studies [1]. In response to damage of the plasma membrane of surrounding cells or the entry of an infectious pathogen, high concentrations of ATP enter the extracellular space through breaks in the cell membrane or by diffusion through pannexin-1 hemichannels. ...
... In this regard, the P 2 X 7 R is participated in many pathological conditions associated with chronic inflammation and tissue degradation, such as arthritis, Crohn's disease, asthma and many others [25]. A large number of studies prove that P 2 X 7 R is closely related to neuronal excitation, neurosensitization, neuroinflammation, pain transmission and chronic pain [1]. ...
Aim: The ability of synthetic 1,4-naphthoquinones (1,4-NQs) to prevent adenosine triphosphate (ATP)-induced and purinergic P2X7 receptor (P2X7R) mediated inflammation in macrophage and neurodegeneration of neuronal cells in vitro was previously established. The aim of the present study was to investigate analgesic-like and anti-inflammatory activity of 1,4-NQs thioglucoside derivatives, compounds U-286 and U-548, in in vivo experiments. Methods: Spectrofluorimetry approach and YO-PRO-1 fluorescent dye uptake determination were applied to study the effect of 1,4-NQs upon ATP-induced P2X7R mediated macropore formation in mouse neuroblastoma Neuro-2a cells and macrophages RAW 264.7 cells. An acetic acid-induced writhing test, hot plate test, and carrageenan-induced paw edema test were used as an in vivo mouse models to study the ability of 1,4-NQs to inhibit pain and inflammation. In the in vivo experiments, compounds were administered to mice intraperitoneally at dosages of 0.1 mg/kg, 1.0 mg/kg and 10.0 mg/kg. A group of animals that received injections of sterile water was used as a control. Each dosage group and the control group consisted of 6 mice. Results: In the present work the analgesic-like and anti-inflammatory activity of 1,4-NQs, U-286 and U-548, was demonstrated. Compound U-548 showed a significant inhibitory effect in antinociceptive tests reducing the number of mouse writhings and eliminating the latent time of mouse hind paw licking, correspondingly. Selected compounds were able to almost completely reduce the size of carrageenan-induced paw edema 24 h after injection and had a potent anti-inflammatory activity. Observed effects were accompanied with aptitude of studied 1,4-NQs to inhibit the formation of purinergic P2X7R macropore associated with inflammation and nociceptive pain. Conclusions: The results obtained allow to consider compounds U-286 and U-548 and as a pharmacological basis for the development of new analgesic-like and anti-inflammatory drugs.
... P2X7R plays a significant role in immune functions, particularly in triggering the release of cytokines and chemokines by microglial cells and astrocytes. As a result, these receptors have a crucial function in chronic pain mechanisms [77]. Research shows that the development of morphine analgesic tolerance is partly mediated by activating P2X7R in the ventrolateral midbrain periaqueductal gray matter [78]. ...
We aimed to explore the impact of the cerebellum on the decline in spatial working memory following morphine dependence and withdrawal. Two groups of male Wistar rats received intraperitoneal injections of either saline (1 ml/kg) or morphine (10 mg/kg) twice daily for 10 days, serving as the control and dependent groups. Additionally, a withdrawal group underwent a 30-day withdrawal period after the dependence phase. Spatial working memory was assessed using a Y maze test. ELISA and western blot were used to assess protein levels in the cerebellum. On day 1, morphine impaired spatial working memory, deteriorated further after 10 days of morphine use, and nearly returned to its initial level following a 30-day withdrawal period. On day 10, significant increases in TNF-α, IL-1β, and CXCL12 and a notable decrease in IL-10 levels were detected in the morphine-dependent group, which did not completely restore in the withdrawal group. The protein levels of CXCR4, TLR4, P2X7R, and NF-κB sharply increased in the morphine-dependent group. However, these levels almost returned to normal after withdrawal. In the morphine-dependent group, BDNF decreased, while TrkB and CREB1 increased noticeably. Nevertheless, after withdrawal, TrkB and CREB1 but not BDNF levels returned to normal. In the morphine-dependent group, both CACNA1 and KCNMA1 decreased significantly and after withdrawal, only KCNMA1 showed partial restoration, while CACNA1 did not. It can be concluded that inflammation/NF-κB and BDNF/TrkB/CREB pathways play key roles in neural adaptation within the cerebellum, contributing to the decline in spatial working memory after both morphine dependence and withdrawal.
... An alternative Ca 2+ signaling pathway might involve Ca 2+ influx across the plasma membrane via ion channels such as P2X receptors. Among the known P2X receptor isoforms, P2X7 mediates LPS-induced inflammation [54]. On the other hand, interleukin 1 beta upregulates P2X7 expression in human astrocytes [55]. ...
Satellite glial cells (SGCs), a major type of glial cell in the autonomic ganglia, closely envelop the cell body and even the synaptic regions of a single neuron with a very narrow gap. This structurally unique organization suggests that autonomic neurons and SGCs may communicate reciprocally. Glial Ca²⁺ signaling is critical for controlling neural activity. Here, for the first time we identified the machinery of store-operated Ca²⁺ entry (SOCE) which is critical for cellular Ca²⁺ homeostasis in rat sympathetic ganglia under normal and pathological states. Quantitative real-time PCR and immunostaining analyses showed that Orai1 and stromal interaction molecules 1 (STIM1) proteins are the primary components of SOCE machinery in the sympathetic ganglia. When the internal Ca²⁺ stores were depleted in the absence of extracellular Ca²⁺, the number of plasmalemmal Orai1 puncta was increased in neurons and SGCs, suggesting activation of the Ca²⁺ entry channels. Intracellular Ca²⁺ imaging revealed that SOCE was present in SGCs and neurons; however, the magnitude of SOCE was much larger in the SGCs than in the neurons. The SOCE was significantly suppressed by GSK7975A, a selective Orai1 blocker, and Pyr6, a SOCE blocker. Lipopolysaccharide (LPS) upregulated the glial fibrillary acidic protein and Toll-like receptor 4 in the sympathetic ganglia. Importantly, LPS attenuated SOCE via downregulating Orai1 and STIM1 expression. In conclusion, sympathetic SGCs functionally express the SOCE machinery, which is indispensable for intracellular Ca²⁺ signaling. The SOCE is highly susceptible to inflammation, which may affect sympathetic neuronal activity and thereby autonomic output.
... Along with P2X7R, other P2X receptors may be involved with chronic pain and sleep disorders (Bernier et al., 2018;Ren and Illes, 2022). P2X4R on the dorsal root ganglion and spinal cord are stimulated by chronic nerve injury and inflammation, rather than by acute pain signals (Aby et al., 2018). ...
... Acute pain has a high diagnostic value for tissue damage and facilitates healing by prompting protective responses like immobilization. 76 However, when pain transitions to a chronic state, its diagnostic value diminishes, evolving into an independent condition that significantly impacts patient lives. Due to the diversity of functions and mechanisms of microglial P2X7R, as well as its active response in inflammation, P2X7R becomes a major focus of the pain field. ...
Background
Pain is a rapid response mechanism that compels organisms to retreat from the harmful stimuli and triggers a repair response. Nonetheless, when pain persists for extended periods, it can lead to adverse changes into in the individual’s brain, negatively impacting their emotional state and overall quality of life. Microglia, the resident immune cells in the central nervous system (CNS), play a pivotal role in regulating a variety of pain‐related disorders. Specifically, recent studies have shed light on the central role that microglial purinergic ligand‐gated ion channel 7 receptor (P2X7R) plays in regulating pain. In this respect, the P2X7R on microglial membranes represents a potential therapeutic target.
Aims
To expound on the intricate link between microglial P2X7R and pain, offering insights into potential avenues for future research.
Methods
We reviewed 140 literature and summarized the important role of microglial P2X7R in regulating pain, including the structure and function of P2X7R, the relationship between P2X7R and microglial polarization, P2X7R‐related signaling pathways, and the effects of P2X7R antagonists on pain regulation.
Results
P2X7R activation is related to M1 polarization of microglia, while suppressing P2X7R can transfer microglia from M1 into M2 phenotype. And targeting the P2X7R‐mediated signaling pathways helps to explore new therapy for pain alleviation. P2X7R antagonists also hold potential for translational and clinical applications in pain management.
Conclusions
Microglial P2X7R holds promise as a potential novel pharmacological target for clinical treatments due to its distinctive structure, function, and the development of antagonists.
... Furthermore, sustained stimulation triggers a transition to a nonselective pore that is permeable to aqueous solutes with molecular masses <900 Da [7], which is still poorly understood. P2X7R is expressed in dendritic cells, macrophages, lymphocytes, microglia, as well as in the spinal cord, brain, uterus, skeletal muscle, prostate, stomach, colon, lung, placenta, and other tissues [8]. P2X7R exhibits cation-selective channel behavior in response to brief stimulation and is permeable to Na + , K + , and Ca 2+ ions [9]. ...
P2X7 receptor (P2X7R) has a key role in different pathological conditions, importantly overexpressed and activated in cancers. We explored the structure activity relationship (SAR) of three novel pyrazines, quinoline-carboxamide and oxadiazole series. Their selective inhibitory potency in Ca2+ mobilization assay using h-P2X7R-MCF-7 cells improved with phenyl ring substitutions (-OCF3, -CF3, and -CH3) in carboxamide and oxadiazole derivatives, respectively. However, highly electronegative fluoro, chloro, and iodo substitutions enhanced affinity. 1e, 2f, 2e, 1d, 2 g and 3e were most potent and selective toward h-P2X7R (IC50 values 0.457, 0.566, 0.624, 0.682, 0.813 and 0.890 µM, respectively) and were inactive at h-P2X4R, h-P2X2R, r-P2Y6R, h-P2Y2R, t-P2Y1R expressed in MCF-7 and 1321N1 astrocytoma cells. Cell viability (MTT assay at 100 µM, cell line) for 3e was 62% (HEK-293T), 70% (1321N1 astrocytoma) and 85% (MCF-7). >75% cell viability was noted for 2 g and >80% for 2e and 1d in all non-transfected cell lines. Anti-proliferative effects, compared to control (Bz-ATP), of selective antagonists (10 µM) were 3e (11%) 1d, (19%) 1e, (70%, P = 0.005) and 2f, (24%), indicating involvement of P2X7R. Apoptotic cell death by flow cytometry showed 1e to be most promising, with 35% cell death (PI positive cells), followed by 2e (25%), 2f (20%), and 1d (19%), compared to control. Fluorescence microscopic analysis of apoptotic changes in P2X7R-transfected cell lines was established. 1e and 2f at 1X and 2X IC50 increased cellular shrinkage, nuclear condensation and PI/DAPI fluorescence. In-silico antagonist modeling predicted ligand receptor interactions, and all compounds obeyed Lipinski rules. These results suggest that pyrazine, quinoline-carboxamide and oxadiazole derivatives could be moderately potent P2X7R antagonists for in vivo studies and anti-cancer drug development.
... Consequently, P2X7 is involved in several physiological and pathological processes, including inflammation, immune responses, cell proliferation and programmed cell death, such as apoptosis and pyroptosis. In the nervous system, for example, P2X7 has been shown to play a crucial role in various neuropathological conditions, including neurodegeneration, chronic pain and brain injury [10]. The accumulation of eATP at inflammatory sites triggers a range of pathophysiological ...
Macropore formation and current facilitation are intriguing phenomena associated with ATP-gated P2X7 receptors (P2X7). Macropores are large pores formed in the cell membrane that allow the passage of large molecules. The precise mechanisms underlying macropore formation remain poorly understood, but recent evidence suggests two alternative pathways: a direct entry through the P2X7 pore itself, and an indirect pathway triggered by P2X7 activation involving additional proteins, such as TMEM16F channel/scramblase. On the other hand, current facilitation refers to the progressive increase in current amplitude and activation kinetics observed with prolonged or repetitive exposure to ATP. Various mechanisms, including the activation of chloride channels and intrinsic properties of P2X7, have been proposed to explain this phenomenon. In this comprehensive review, we present an in-depth overview of P2X7 current facilitation and macropore formation, highlighting new findings and proposing mechanistic models that may offer fresh insights into these untangled processes.
... Of the P2X receptor members, the P2X7 receptor (P2X7) has been the most widely studied, which is largely due to its presence in leukocytes and lymphoid organs as well as its various roles in inflammation and immunity and related disorders including infectious diseases [3]. Various physiological and pathophysiological roles of P2X7 have also been found in many organs and tissues including those of the bone [4], cardiovascular system [5,6], eye [7], exocrine system [8], gastrointestinal tract [9], kidney [10], liver [11], lung [12], nervous system [13,14], skeletal muscle [15] and skin [16], and it has further been involved in cancer [17,18], pain [19] hematopoiesis [20], and metabolism [21]. This broad range of roles reflects the wide cellular and tissue distribution of P2X7, which might partly reflect its dominant presence in leukocytes compared to other cell types [22], while its presence in neurons remains debated [23,24]. ...
The P2X7 receptor is a trimeric ligand-gated cation channel activated by extracellular adenosine 5′-triphosphate. The study of animals has greatly advanced the investigation of P2X7 and helped to establish the numerous physiological and pathophysiological roles of this receptor in human health and disease. Following a short overview of the P2X7 distribution, roles and functional properties, this article discusses how animal models have contributed to the generation of P2X7-specific antibodies and nanobodies (including biologics), recombinant receptors and radioligands to study P2X7 as well as to the pharmacokinetic testing of P2X7 antagonists. This article then outlines how mouse and rat models have been used to study P2X7. These sections include discussions on preclinical disease models, polymorphic P2X7 variants, P2X7 knockout mice (including bone marrow chimeras and conditional knockouts), P2X7 reporter mice, humanized P2X7 mice and P2X7 knockout rats. Finally, this article reviews the limited number of studies involving guinea pigs, rabbits, monkeys (rhesus macaques), dogs, cats, zebrafish, and other fish species (seabream, ayu sweetfish, rainbow trout and Japanese flounder) to study P2X7.
