Involvement of P2X7 receptors in chronic pain disorders

Purinergic Signalling https://doi.org/10.1007/s11302-021-09796-5 REVIEW ARTICLE Involvement of P2X7 receptors in chronic pain disorders Wen‑Jing Ren1 · Peter Illes1,2 Received: 26 April 2021 / Accepted: 11 May 2021 © The Author(s) 2021 Abstract 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 peripheral and central immune cells. Because of the involvement of P2X7Rs in immune functions and especially the initiation of macrophage/ microglial and astrocytic secretion of cytokines, chemokines, prostaglandins, proteases, reactive oxygen, and nitrogen species as well as the excitotoxic glutamate/ATP, this receptor type has a key role in chronic pain processes. Microglia are equipped with a battery of pattern recognition receptors that detect pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharide (LPS) from bacterial infections or danger associated molecular patterns (DAMPs) such as ATP. The co-stimulation of these receptors leads to the activation of the NLRP3 inflammasome and interleukin-1β (IL-1β) release. In the present review, we invite you to a journey through inflammatory and neuropathic pain, primary headache, and regulation of morphine analgesic tolerance, in the pathophysiology of which P2X7Rs are centrally involved. P2X7R bearing microglia and astrocyte-like cells playing eminent roles in chronic pain will be also discussed. Keywords Extracellular ATP · P2X7 receptor · Microglia · Astrocyte · Neuropathic pain · Inflammatory pain Wen‑Jing Ren has studied acupuncture and tuina at the Chengdu University of Traditional Chinese Medicine. She graduated from this University as a Master Student in 2020 and has without interruption continued her studies as a PhD Student. Besides taking part in the obligatory theoretical and practical courses she has worked experimentally on rats and mice to uncover the role of purinergic signaling in pain and major depression. She has published a couple of reviews and original papers in national and international journals. * Peter Illes 1 School of Acupuncture and Tuina, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China 2 Rudolf Boehm Institute for Pharmacology and Toxicology, University of Leipzig, 04109 Leipzig, Germany The P2X7 receptor The human (h) P2RX7 gene (R stands for receptor) is located on chromosome 12 and encodes 13 exons that translate into a 595 amino acid protein. A number of P2RX7 isoforms derived from alternative splicing were identified both in 13 Vol.:(0123456789) Purinergic Signalling humans and in rodents [1, 2]. Some variants are expressed and functional, for example, the human P2X7B receptor and the mouse and rat P2X7R variant k [3]. Several non-synonymous, intronic, or missense small nucleotide polymorphisms (SNPs) have been reported in the hP2RX7 gene, expressing both gain-of-function and loss-of-function receptors. Ionotropic P2X7 receptors are members of the P2X purinoceptor family [4, 5], which are located in the plasma membrane of various cell types and upon activation by high concentrations of ATP allow the inward flux of Na+/Ca2+ and the outward flux of K+, thereby inducing depolarization [6, 7]. P2XRs in general have a relatively simple structure consisting of assemblies of three identical linear protein subunits. These receptor subunits have N- and C-terminal intracellular tails, two transmembrane areas, and a large extracellular loop; the agonist-binding pouch of the receptor is located at the intersection of two neighboring subunits [8, 9]. The partial structure of the panda P2X7R [10] and later the full-length structure of the rat P2X7R [9] have been resolved, thereby identifying the kinetic changes occurring in the receptor structure after ATP-binding and the subsequent opening of the ion permeation pathway. The C-terminus of the receptor plays an important role in trafficking to the cell membrane; it also regulates receptor function (including signaling pathways), protein–protein interactions, and post-translational modifications [11–13]. Similar not only to P2X2 or P2X4Rs [14, 15] but also to transient receptor vanilloid channel 1 (TRPV1; [16, 17]) and acid-sensing ion channels (ASICs; [18, 19]), long-lasting occupation of the respective agonist-binding pouches was thought for a couple of years to result in a time-dependent dilation of the channels to constitute a pore through which molecules previously not passing the cell membrane barrier may diffuse into either direction. With respect to the above reported channel dilations, the interpretation of these early whole-cell recording patch-clamp data obtained by reversal potential measurements turned out to be misleading [20, 21]. Participation of associated channel-forming proteins has been implicated in diffusion of large cationic molecules through P2X7Rs (e.g., pannexin-1; [22]), but convincing evidence now supports the view that the P2X7R by itself is endowed with the ability to conduct large organic cations, although Fig. 1  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] 13 Purinergic Signalling at a slower pace than to conduct the smaller cations Na+, K+, and Ca2 [7, 23]. P2X7 receptors at immune cells ATP released from all types of damaged tissue via Panx-1 hemichannels or simply via the discontinuous cell membrane leads to stimulation of P2X7Rs and is associated with the activation of T-lymphocytes, and the differentiation of inflammatory T-helper lymphocytes (Th17) [12, 24, 25]. P2X7Rs also promote the chemotaxis of mye (...truncated)