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Purinergic P2 Receptors As Targets for Novel Analgesics

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Purinergic P2 Receptors As Targets for Novel Analgesics Pharmacology & Therapeutics 110 (2006) 433 – 454 www.elsevier.com/locate/pharmthera Purinergic P2 receptors as targets for novel analgesics Geoffrey Burnstock * Autonomic Neuroscience Centre, Royal Free and University College Medical School, Rowland Hill Street, London NW3 2PF, UK Abstract Following hints in the early literature about adenosine 5V-triphosphate (ATP) injections producing pain, an ion-channel nucleotide receptor was cloned in 1995, P2X3 subtype, which was shown to be localized predominantly on small nociceptive sensory nerves. Since then, there has been an increasing number of papers exploring the role of P2X3 homomultimer and P2X2/3 heteromultimer receptors on sensory nerves in a wide range of organs, including skin, tongue, tooth pulp, intestine, bladder, and ureter that mediate the initiation of pain. Purinergic mechanosensory transduction has been proposed for visceral pain, where ATP released from epithelial cells lining the bladder, ureter, and intestine during distension acts on P2X3 and P2X2/3, and possibly P2Y, receptors on subepithelial sensory nerve fibers to send messages to the pain centers in the brain as well as initiating local reflexes. P1, P2X, and P2Y receptors also appear to be involved in nociceptive neural pathways in the spinal cord. P2X4 receptors on spinal microglia have been implicated in allodynia. The involvement of purinergic signaling in long-term neuropathic pain and inflammation as well as acute pain is discussed as well as the development of P2 receptor antagonists as novel analgesics. D 2005 Elsevier Inc. All rights reserved. Keywords: Purinergic; P2X receptor; P2Y receptor; Analgesic; ATP; Signaling Abbreviations: a,h-meATP, a,h-methylene ATP; ABC, ATP binding cassette; ATP, adenosine 5V-triphosphate; BzATP, 3V-O-(4-benzoyl)benzoyl ATP; CFA, complete Freund’s adjuvant; CGRP, calcitonin gene-related peptide; CNS, central nervous system; DHEA, dehydroepiandrosterone; DRG, dorsal root ganglia; GABA, g-amino butyric acid; GDNF, glial cell line-derived neurotrophic factor; HSPs, heat shock proteins; IBS, irritable bowel syndrome; IB4, isolectin B4; IL, interleukin; IGLEs, intraganglionic laminar nerve endings; mRNA, messenger ribonucleic acid; NA, noradrenaline; NEBs, neuroepithelial bodies; NG, nodose ganglia; NMDA, N-methyl-d- aspartate; NO, nitric oxide; NTS, nucleus tractus solitarius; PAF, platelet-activating factor; pERK, phosphorylated extracellular signal-regulated protein kinase; PKC, protein kinase C; PPADS, pyridoxal-5V-phosphate-6-azophenyl-2V,4V disulphonic acid; RVM, rostral ventromedial medulla; TG, trigeminal ganglia; TMP, tetramethylpyrazine; TNP-ATP, trinitrophenol-ATP; TRPV, transient receptor potential vanilloid channels; UTP, uridine 5V-triphosphate; VR1, vanilloid receptor type 1. Contents 1. Introduction ............................................... 434 2. Purinergic signaling: physiological reflexes and nociception . .................... 434 2.1. Purinergic receptors expressed by sensory neurons . .................... 434 2.1.1. P2X receptors...................................... 434 2.1.2. P2Y receptors...................................... 435 2.1.3. Interactions between P2 and vanilloid receptors .................... 437 2.2. Evidence for purinergic mechanosensory transduction in different organs ........... 438 2.2.1. Urinary bladder ..................................... 438 2.2.2. Ureter .......................................... 438 2.2.3. Gut ........................................... 438 2.2.4. Lung .......................................... 439 2.2.5. Carotid body ...................................... 439 2.2.6. Tooth pulp ....................................... 439 2.2.7. Special senses organs.................................. 439 2.2.8. Skin, muscle, and joints ................................ 440 2.3. Sources of ATP involved in mechanosensory transduction ................... 440 * Tel.: +44 207 830 2948; fax: +44 207 830 2949. E-mail address: [email protected]. 0163-7258/$ - see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.pharmthera.2005.08.013 434 G. Burnstock / Pharmacology & Therapeutics 110 (2006) 433–454 3. Neuropathic, inflammatory, and cancer pain............................... 441 3.1. Peripheral purinergic mechanisms ................................ 441 3.1.1. Sensory ganglia ..................................... 441 3.1.2. Urinary bladder ..................................... 442 3.1.3. Gut ........................................... 442 3.1.4. Lung........................................... 443 3.1.5. Joints .......................................... 443 3.2. Central purinergic mechanisms .................................. 443 3.2.1. Spinal cord ....................................... 443 3.2.2. Brain .......................................... 443 3.2.3. Microglia and glial–neuron interactions......................... 444 3.3. Cancer pain............................................ 446 4. Purinergic therapeutic developments for the treatment of pain . ................... 446 5. Conclusions ............................................... 447 Acknowledgments .............................................. 447 References .................................................. 447 1. Introduction ureter, bladder, and gut, where ATP released from epithelial cells during distension, acted on P2X3 homomultimeric and There were early hints that adenosine 5V-triphosphate (ATP) P2X2/3 heteromultimeric receptors on subepithelial sensory might be involved in pain including the demonstration of pain nerves initiating impulses in sensory pathways to pain centers produced by injection of ATP into human skin blisters (Keele in the central nervous system (CNS) (Burnstock, 1999)(Fig. & Armastrong, 1964; Collier et al., 1966; Bleehen & Keele, 2A). Subsequent studies of bladder (Cockayne et al., 2000; 1977), ATP involvement in migraine (Burnstock, 1981), and Vlaskovska et al., 2001; Rong et al., 2002), ureter (Knight et ATP participation in pain pathways in the spinal cord (Jahr & al., 2002; Rong & Burnstock, 2004), and gut (Wynn et al., Jessell, 1983; Fyffe & Perl, 1984; Salter & Henry, 1985). A 2003, 2004) have produced evidence in support of this significant advance was made when the P2X3 ionotropic ion hypothesis (see also Burnstock, 2001a). channel purinergic receptor was cloned in 1995 and shown to The aim of the present article is to review the large number be localized predominantly on small nociceptive sensory of papers that have appeared since 2001 to elaborate on this neurons in dorsal root ganglia (DRG) (Chen et al., 1995, theme and to explore the purinergic drugs under development Lewis et al., 1995). Later, Burnstock (1996) put forward a for the treatment of pain. unifying purinergic hypothesis for the initiation of pain, suggesting that ATP released as a cotransmitter with noradren- 2. Purinergic signaling: physiological reflexes and nociception aline (NA) and neuropeptide Y from sympathetic nerve terminal varicosities might be involved in sympathetic pain 2.1. Purinergic receptors expressed by sensory neurons (causalgia and reflex sympathetic dystrophy); that ATP released from vascular endothelial cells of microvessels during 2.1.1. P2X receptors reactive hyperemia is associated with pain in migraine, angina, A comprehensive review of P2X receptor expression and and ischemia; and that ATP released from tumor cells function in sensory neurons in DRG, nodose (NG), trigeminal (containing high levels) damaged during abrasive activity (TG), and petrosal ganglia was presented in 2001 (Dunn et al., reaches P2X3 receptors on nociceptive sensory nerves. This 2001). All P2X subtypes, except P2X7, are found in sensory hasbeenfollowedbyanincreasingnumberofpapers neurones, although the P2X3 receptor has the highest level of expanding on this concept. Immunohistochemical studies expression [both in terms of messenger ribonucleic acid showed that the nociceptive fibers expressing P2X3 receptors (mRNA) and protein]. P2X2/3 heteromultimers are particularly arose largely from the population of small neurons that labeled prominent in the nodose ganglion. P2X3 and P2X2/3 receptors with the lectin isolectin B4 (IB4)(Vulchanova et al., 1996; are expressed on isolectin B4 (IB4) binding subpopulations of Bradbury et al., 1998). The central projections of these small nociceptive neurons. Species differences are recognized. neurons were shown to be in inner lamina II of the dorsal There have been a remarkably large number of studies of P2X horn and peripheral projections demonstrated to skin, tooth receptor-mediated signaling in sensory ganglia since this pulp, tongue, and subepithelial regions of visceral organs. A review and some of these are discussed below. schematic illustrating the initiation of nociception on primary The decreased sensitivity to noxious stimuli, associated with afferent fibers in the periphery and purinergic relay pathways the loss of IB4-binding neurons expressing P2X3 receptors, in the spinal cord was presented by Burnstock and Wood indicates that these sensory neurons are essential for the (1996) (Fig. 1). signaling of acute pain (Vulchanova et al., 2001). The loss of A hypothesis was proposed that purinergic mechanosensory IB4 binding neurons also led to compensatory changes relating transduction occurred in visceral tubes and sacs, including to recovery of sensitivity to acute pain. G. Burnstock / Pharmacology & Therapeutics 110 (2006) 433–454 435 terminals. Oxytocin also inhibits ATP-activated currents
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