The therapeutic promise of ATP antagonism at P2X3 receptors in respiratory and urological disorders

被引:74
作者
Ford, Anthony P. [1 ]
Undem, Bradley J. [2 ]
机构
[1] Afferent Pharmaceut Inc, San Mateo, CA 94401 USA
[2] Johns Hopkins Univ, Sch Med, Baltimore, MD USA
关键词
P2X3; AF-219; visceral disorders; afferent sensitization; airways hyperreactivity; cough; urinary symptoms; IN-VITRO; URINARY-BLADDER; C-FIBERS; ADENOSINE 5'-TRIPHOSPHATE; MOLECULAR-MECHANISMS; INDUCED ENHANCEMENT; NERVE PREPARATION; AFFERENT NEURONS; MAJOR CLASSES; NEURAL CREST;
D O I
10.3389/fncel.2013.00267
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
A sensory role for ATP was proposed long before general acceptance of its extracellular role. ATP activates and sensitizes signal transmission at multiple sites along the sensory axis, across multiple synapses. P2X and P2Y receptors mediate ATP modulation of sensory pathways and participate in dysregulation, where ATP action directly on primary afferent neurons (PANs), linking receptive field to CNS, has received much attention. Many PANs, especially C-fibers, are activated by ATP, via P2X3-containing trimers. P2X3 knock-out mice and knock-down in rats led to reduced nocifensive activity and visceral reflexes, suggesting that antagonism may offer benefit in sensory disorders. Recently, drug-like P2X3 antagonists, active in a many inflammatory and visceral pain models, have emerged. Significantly, these compounds have no overt CNS action and are inactive versus acute nociception. Selectively targeting ATP sensitization of PANs may lead to therapies that block inappropriate chronic signals at their source, decreasing drivers of peripheral and central wind-up, yet leaving defensive nociceptive and brain functions unperturbed. This article reviews this evidence, focusing on how ATP sensitization of PANs in visceral hollow organs primes them to chronic discomfort, irritation and pain (symptoms) as well as exacerbated autonomic reflexes (signs), and how the use of isolated organ-nerve preparations has revealed this mechanism. Urinary and airways systems share many features: dependence on continuous afferent traffic to brainstem centers to coordinate efferent autonomic outflow; loss of descending inhibitory influence in functional and sensory disorders; dependence on ATP in mediating sensory responses to diverse mechanical and chemical stimuli; a mechanistically overlapping array of existing medicines for pathological conditions. These similarities may also play out in terms of future treatment of signs and symptoms, in the potential for benefit of P2X3 antagonists.
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页数:10
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共 77 条
[1]  
Abdulqawi R., 2013, P EUR RESP SOC ANN C
[2]   Cellular and Molecular Mechanisms of Pain [J].
Basbaum, Allan I. ;
Bautista, Diana M. ;
Scherrer, Gregory ;
Julius, David .
CELL, 2009, 139 (02) :267-284
[3]   Effects of aerosolized adenosine 5′-triphosphate vs adenosine 5′-monophosphate on dyspnea and airway caliber in healthy nonsmokers and patients with asthma [J].
Basoglu, OK ;
Pelleg, A ;
Essilfie-Quaye, S ;
Brindicci, C ;
Barnes, PJ ;
Kharitonov, SA .
CHEST, 2005, 128 (04) :1905-1909
[4]   Intravenous ATP infusions can be safely administered in the home setting: a study in pre-terminal cancer patients [J].
Beijer, Sandra ;
Gielisse, Eric A. R. ;
Hupperets, Pierre S. ;
van den Borne, Ben E. E. M. ;
van den Beuken-van Everdingen, Marieke ;
Nijziel, Marten R. ;
van Henten, Arjen M. J. ;
Dagnelie, Pieter C. .
INVESTIGATIONAL NEW DRUGS, 2007, 25 (06) :571-579
[5]   Acute nociception mediated by hindpaw P2X receptor activation in the rat [J].
BlandWard, PA ;
Humphrey, PPA .
BRITISH JOURNAL OF PHARMACOLOGY, 1997, 122 (02) :365-371
[6]   IDENTIFICATION OF ALGOGENIC SUBSTANCES IN HUMAN ERYTHROCYTES [J].
BLEEHEN, T ;
HOBBIGER, F ;
KEELE, CA .
JOURNAL OF PHYSIOLOGY-LONDON, 1976, 262 (01) :131-149
[7]   OBSERVATIONS ON ALGOGENIC ACTIONS OF ADENOSINE COMPOUNDS ON HUMAN BLISTER BASE PREPARATION [J].
BLEEHEN, T ;
KEELE, CA .
PAIN, 1977, 3 (04) :367-377
[8]   The discovery and development of analgesics: new mechanisms, new modalities [J].
Burgess, Gillian ;
Williams, Dic .
JOURNAL OF CLINICAL INVESTIGATION, 2010, 120 (11) :3753-3759
[9]   Discovery of purinergic signalling, the initial resistance and current explosion of interest [J].
Burnstock, G. .
BRITISH JOURNAL OF PHARMACOLOGY, 2012, 167 (02) :238-255
[10]  
Burnstock G., 2013, EXP PHYSIOL, DOI [10.1113/expphysiol.2013.071951, DOI 10.1113/EXPPHYSI0L.2013.071951.[]