Purinergic receptors: their role in nociception and primary afferent neurotransmission

doi:10.1016/S0959-4388(96)80060-2

Current Opinion in Neurobiology

Volume 6, Issue 4, August 1996, Pages 526-532

https://doi.org/10.1016/S0959-4388(96)80060-2 Get rights and content

Abstract

The recent discovery of a P2X purinoceptor (a ligand-gated ion channel triggered by ATP) that is selectively expressed by small-diameter sensory neurons has led to the exploration of the sources of ATP involved in the initiation of different types of nociception and pain, including sympathetic nerves, endothelial cells and tumour cells. In addition, the anti-nociceptive actions of adenosine via prejunctional P1 (A₁) purinoceptors in the spinal cord and the pain-enhancing actions of adenosine via P1(A₂) purinoceptors in the periphery have generated great interest in the development of P1 agonists and antagonists, as well as P2X antagonists as potential analgesic drugs.

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Cited by (315)

Overview for the study of P2 receptors: From P2 receptor history to neuropathic pain studies
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Since new roles of nucleotides as neurotransmitters were proposed by Geoffrey Burnstock, the roles of ATP and P2 receptors (P2Rs) have been extensively studied in pain signaling. This review primarily focuses on the history and roles of P2X2Rs and P2X2/3Rs in acute and chronic pain, and P2X4Rs in neuropathic pain after peripheral nerve injury (PNI). Spinal microglial activity mediated by P2X4Rs shows a very important contribution to evoking neuropathic pain, and P2X4Rs might be targets for the treatment of neuropathic pain. The advantage of P2X4Rs of microglia as therapeutic targets is that P2X4Rs are predominantly enhanced in activated microglia after PNI, and P2X4R blockers do not affect normal pain signaling. Currently, many excellent P2R-related drug candidates are being developed, and it seems that the day when we will use them in clinical practice is not too far away.
Pain, purines and Geoff
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The story of purinergic neurotransmission and regulation is intimately linked to studies of the somatosensory system. Burnstock's contributions to the discovery of ATP as a primary afferent neurotransmitter, as well as a signal of peripheral tissue damage that depolarised sensory neurons initiated a new period of pain research. The neuro-immune interactions that occur after tissue damage and are important for pain have now also been found to involve purinergic signalling, and adenosine has been demonstrated to have significant analgesic effects. In the pain field as in so many other areas of neuroscience and physiology, Burnstock's contributions have been critical to the expansion of our knowledge about the significance of purines. His mechanistic insights have profound significance for understanding the pain system and further underscore his stature as a pioneer and force for progress in biomedicine.
From astrocytes to satellite glial cells and back: A 25 year-long journey through the purinergic modulation of glial functions in pain and more
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Fundamental progresses have been made in pain research with a comprehensive understanding of the neuronal pathways which convey painful sensations from the periphery and viscera to the central nervous system and of the descending modulating pathways. Nevertheless, many patients still suffer from various painful conditions, which are often associated to other primary pathologies, and get no or poor relief from available painkillers. Thus, the interest of many researchers has concentrated on new and promising cellular targets and biochemical pathways. This is the case of glia cells, both in the peripheral and in the central nervous system, and of purinergic receptors. Starting from many intuitions and hypotheses raised by Prof. Geoffrey Burnstock, data have accumulated which clearly highlight the fundamental role exerted by several nucleotide and nucleoside receptors in the modulation of glial cell reaction to pain triggers and of their cross-talk with sensory neurons which significantly contributes to the transition from acute to chronic pain. The purinergic system has therefore become an appealing pharmacological target in pain research, also based on the quite unexpected discovery that purines are involved in ancient analgesic techniques such as acupuncture. A more in-depth understanding of the complex and intricated purine-orchestrated scenario in pain conditions will hopefully lead to the identification and clinical development of new and effective analgesics.
Nociceptive signaling mediated by P2X3, P2X4 and P2X7 receptors
2021, Biochemical Pharmacology
Chronic pain is a debilitating condition that often occurs following peripheral tissue inflammation and nerve injury. This pain, especially neuropathic pain, is a significant clinical problem because of the ineffectiveness of clinically available drugs. Since Burnstock proposed new roles of nucleotides as neurotransmitters, the roles of extracellular ATP and P2 receptors (P2Rs) in pain signaling have been extensively studied, and ATP-P2R signaling has subsequently received much attention as it can provide clues toward elucidating the mechanisms underlying chronic pain and serve as a potential therapeutic target. This review summarizes the literature regarding the role of ATP signaling via P2X3Rs (as well as P2X2/3Rs) in primary afferent neurons and via P2X4Rs and P2X7Rs in spinal cord microglia in chronic pain, and discusses their respective therapeutic potentials.
Health and ergogenic potential of oral adenosine-5′-triphosphate (ATP) supplementation
2021, Journal of Functional Foods
Adenosine triphosphate (ATP) is the primary compound that provides energy to drive many processes in living cells, including muscle contraction, neurotransmission, and cardiac function. Initial research used enteric-coated ATP that displayed no apparent efficacy. However, ATP disodium supplementation has demonstrated improved bioavailability and acute and chronic benefits to cardiovascular health, muscular performance, body composition, and recovery while attenuating muscle breakdown and fatigue. In this review, we provide a critical assessment of oral ATP’s bioavailability and its various health and ergogenic benefits.
Purinergic Mechanisms and Pain
2016, Advances in Pharmacology
There is a brief introductory summary of purinergic signaling involving ATP storage, release, and ectoenzymatic breakdown, and the current classification of receptor subtypes for purines and pyrimidines. The review then describes purinergic mechanosensory transduction involved in visceral, cutaneous, and musculoskeletal nociception and on the roles played by receptor subtypes in neuropathic and inflammatory pain. Multiple purinoceptor subtypes are involved in pain pathways both as an initiator and modulator. Activation of homomeric P2X3 receptors contributes to acute nociception and activation of heteromeric P2X2/3 receptors appears to modulate longer-lasting nociceptive sensitivity associated with nerve injury or chronic inflammation. In neuropathic pain activation of P2X4, P2X7, and P2Y₁₂ receptors on microglia may serve to maintain nociceptive sensitivity through complex neural–glial cell interactions and antagonists to these receptors reduce neuropathic pain. Potential therapeutic approaches involving purinergic mechanisms will be discussed.

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Purinergic receptors: their role in nociception and primary afferent neurotransmission

Abstract

Lancet

Pharmacol Ther

J Physiol (Lond)

Semin Neurosci

EMBO J

Pain

Circ Res

Cardiovasc Res

Neuroscience

Prog Neurobiol

Eur J Pharmacol

Neuroreport

Nature

Cancer Res

J Theor Biol

A P2X purinoceptor expressed by a subset of sensory neurons

Nature

Coexpression of P2X2 and P2X3 receptor subunits can account for ATP-gated currents in sensory neurons

Nature

P2 purinoceptors: historical perspective and classification

A basis for distinguishing two types of purinergic receptor

Nomenclature and classification of purinoceptors

Pharmacol Rev

Is there a basis for distinguishing two types of P2 purinoceptor?

Gen Pharmacol

Extracellular ATP: effects, sources and fate

Biochem J

Further subclassification of ATP receptors based on agonist studies

Trends Pharmacol Sci

Diadenosine polyphosphates (ApxA) as new neurotransmitters

Drug Dev Res

The numbering of cloned P2 purinoceptors

Drug Dev Res

Electrophysiological properties of P2X purinoceptors in rat superior cervical, nodose and guinea-pig coeliac neurones

J Physiol (Lond)

ATP receptor-mediated synaptic currents in the central nervous system

Nature

Distribution of [3H]α,β-methylene ATP binding sites in rat brain and spinal cord

Neuroreport

New insights on P2x purinoceptors

Naunyn Schmiedebergs Arch Pharmacol

A P2X purinoceptor cDNA conferring a novel pharmacological profile

FEBS Lett

On the innervation of trigeminal mesencephalic primary afferent neurons by adenosine deaminase-containing projections from the hypothalamus in the rat

Neuroscience

Coexpression of P2X₂ and P2X₃ receptor subunits can account for ATP-gated currents in sensory neurons

Is there a basis for distinguishing two types of P₂ purinoceptor?

Diadenosine polyphosphates (Ap_xA) as new neurotransmitters

Distribution of [³H]α,β-methylene ATP binding sites in rat brain and spinal cord

New insights on P_2x purinoceptors