P2X3 and P2X2/3 Receptors Play a Crucial Role in Articular Hyperalgesia Development Through Inflammatory Mechanisms in the Knee Joint Experimental Synovitis

Teixeira, Juliana Maia; Bobinski, Franciane; Parada, Carlos Amílcar; Sluka, Kathleen A.; Tambeli, Cláudia Herrera

doi:10.1007/s12035-016-0146-2

Cited by 40 publications

(26 citation statements)

References 82 publications

(84 reference statements)

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“…This is also observed in humans where intracutaneous injections of ATP elicited discharge of afferent neurons innervating the peroneal nerve (Hilliges et al, ). P2X3 has very limited expression, predominantly located on afferent neurons, including those innervating the skin, viscera, and knee joint (Bradbury et al, ; Teixeira, Bobinski, Parada, Sluka, & Tambeli, ). Inhibition of P2X3‐dependent action potential of afferent neurons innervating peripheral tissue and nerves is therefore the likely mechanism mediating the in vivo effects of MK‐7264 in pain models.…”

Section: Discussionmentioning

confidence: 99%

Action of MK‐7264 (gefapixant) at human P2X3 and P2X2/3 receptors and in vivo efficacy in models of sensitisation

Richards

Gever

Ford

et al. 2019

British J Pharmacology

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Background and Purpose The P2X3 receptor is an ATP‐gated ion channel expressed by sensory afferent neurons and is used as a target to treat chronic sensitisation conditions. The first‐in‐class, selective P2X3 and P2X2/3 receptor antagonist, the diaminopyrimidine MK‐7264 (gefapixant), has progressed to Phase III trials for refractory or unexplained chronic cough. We used patch clamp to elucidate the pharmacology and kinetics of MK‐7264 and rat models of hypersensitivity and hyperalgesia to test its efficacy on these conditions. Experimental Approach Whole‐cell patch clamp of 1321N1 cells expressing human P2X3 and P2X2/3 receptors was used to determine mode of MK‐7264 action, potency, and kinetics. The analgesic efficacy was assessed using paw withdrawal threshold and limb weight distribution in rat models of inflammatory, osteoarthritic, and neuropathic sensitisation. Key Results MK‐7264 is a reversible allosteric antagonist at human P2X3 and P2X2/3 receptors. Experiments with the slowly desensitising P2X2/3 heteromer revealed concentration‐ and state‐dependency to wash‐on, with faster rates and greater inhibition when applied before agonist compared to during agonist application. The wash‐on rate (τ value) for MK‐7264 at maximal concentrations was much lower when applied before compared to during agonist application. In vivo, MK‐7264 displayed efficacy comparable to naproxen in inflammatory and osteoarthritic sensitisation models and gabapentin in neuropathic sensitisation models, increasing paw withdrawal threshold and decreasing weight‐bearing discomfort. Conclusions and Implications MK‐7264 is a reversible and selective P2X3 and P2X2/3 antagonist, exerting allosteric antagonism via preferential activity at closed channels. Its efficacy in rat models supports its clinical investigation for chronic sensitisation conditions.

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Section: Discussionmentioning

confidence: 99%

Action of MK‐7264 (gefapixant) at human P2X3 and P2X2/3 receptors and in vivo efficacy in models of sensitisation

Richards

Gever

Ford

et al. 2019

British J Pharmacology

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“…Furthermore, a recent study shows the activation of pyroptosis in OA fibroblast‐like synoviocytes by ATP together with TLR‐4 ligands . Finally, ATP increases pain sensitivity (hyperalgesia) via binding to the purinergic P2X3 and P2X2/3 receptors .…”

Section: Alarmins In Osteoarthritismentioning

confidence: 98%

Inflammation in osteoarthritis: is it time to dampen the alarm(in) in this debilitating disease?

Bosch

2018

Clinical and Experimental Immunology

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Summary Osteoarthritis (OA) is the most common joint disease that strongly reduces the quality of life in patients; However, no disease‐modifying therapy is available. For a long time, OA was considered a non‐inflammatory disease that was the result of ‘wear‐and‐tear’ and abnormal mechanics, and therefore many considered the term ‘osteoarthritis’ a misnomer. However, during the last decades the notion arose that inflammation is not only present in the majority of OA patients but, rather, actively involved in the progression of the disease. Influx of immune cells is observed in the synovium and a plethora of inflammatory mediators is present in tissues and fluids from OA patients. These mediators cause the production of degrading enzymes that break down the cartilage matrix, which is the main hallmark of OA. Alarmins, which belong to the group of danger signals, have been implicated in many inflammatory diseases. They are among the first factors to be released upon cell stress due to, for example, infection, damage and inflammation. They attract and activate cells of the immune system and therefore lie at the base of the inflammatory reaction. In this narrative review, an overview of the history of OA, the evolving concept of inflammation as important factor in the OA pathogenesis, and particularly the central role that alarmins play in the initiation and maintenance of the low‐grade inflammatory response in OA, is provided. Moreover, the targeting of alarmins as a promising approach to dampen the inflammation in OA is highlighted.

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“…ATP levels in knee synovial fluid of patients with OA are related to pain intensity ( Kumahashi et al, 2011 ). P2X3 and P2X2/3R play an important role in the development of articular hyperalgesia of arthritic joints ( Teixeira et al, 2016 ). In the long-term complications following total hip arthroplasty, different polymorphic variants of the P2X7R are associated with high or reduced periprosthetic osteolysis ( Mrazek et al, 2010 ).…”

Section: Musculoskeletal Diseasesmentioning

confidence: 99%

Purinergic Signalling: Therapeutic Developments

2017

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Purinergic signalling, i.e., the role of nucleotides as extracellular signalling molecules, was proposed in 1972. However, this concept was not well accepted until the early 1990’s when receptor subtypes for purines and pyrimidines were cloned and characterised, which includes four subtypes of the P1 (adenosine) receptor, seven subtypes of P2X ion channel receptors and 8 subtypes of the P2Y G protein-coupled receptor. Early studies were largely concerned with the physiology, pharmacology and biochemistry of purinergic signalling. More recently, the focus has been on the pathophysiology and therapeutic potential. There was early recognition of the use of P1 receptor agonists for the treatment of supraventricular tachycardia and A2A receptor antagonists are promising for the treatment of Parkinson’s disease. Clopidogrel, a P2Y12 antagonist, is widely used for the treatment of thrombosis and stroke, blocking P2Y12 receptor-mediated platelet aggregation. Diquafosol, a long acting P2Y2 receptor agonist, is being used for the treatment of dry eye. P2X3 receptor antagonists have been developed that are orally bioavailable and stable in vivo and are currently in clinical trials for the treatment of chronic cough, bladder incontinence, visceral pain and hypertension. Antagonists to P2X7 receptors are being investigated for the treatment of inflammatory disorders, including neurodegenerative diseases. Other investigations are in progress for the use of purinergic agents for the treatment of osteoporosis, myocardial infarction, irritable bowel syndrome, epilepsy, atherosclerosis, depression, autism, diabetes, and cancer.

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P2X3 and P2X2/3 Receptors Play a Crucial Role in Articular Hyperalgesia Development Through Inflammatory Mechanisms in the Knee Joint Experimental Synovitis

Cited by 40 publications

References 82 publications

Action of MK‐7264 (gefapixant) at human P2X3 and P2X2/3 receptors and in vivo efficacy in models of sensitisation

Action of MK‐7264 (gefapixant) at human P2X3 and P2X2/3 receptors and in vivo efficacy in models of sensitisation

Inflammation in osteoarthritis: is it time to dampen the alarm(in) in this debilitating disease?

Purinergic Signalling: Therapeutic Developments

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