Abstract
Endothelin-1 (ET-1) acts on endothelial cells to enhance mechanical stimulation–induced
release of adenosine triphosphate (ATP), which in turn can act on sensory neurons
innervating blood vessels to contribute to vascular pain, a phenomenon we have referred
to as stimulus-dependent hyperalgesia (SDH). In the present study, we evaluated the
role of the major classes of ATP release mechanisms to SDH: vesicular exocytosis,
plasma membrane–associated ATP synthase, ATP-binding cassette transporters, and ion
channels. Inhibitors of vesicular exocytosis (ie, monensin, brefeldin A, and bafilomycin),
plasma membrane–associated ATPase (ie, oligomycin and pigment epithelium–derived factor
peptide 34-mer), and connexin ion channels (carbenoxolone and flufenamic acid) but
not ATP-binding cassette transporter (ie, dipyridamole, nicardipine, or CFTRinh-172) attenuated SDH. This study reports a role of ATP in SDH and suggests novel targets
for the treatment of vascular pain syndromes.
Perspective
ET-1 acts on endothelial cells to produce mechanical stimulation–induced hyperalgesia.
Inhibitors of 3 different ATP release mechanisms attenuated this SDH. This study provides
support for a role of ATP in SDH and suggests novel targets for the treatment of vascular
pain syndromes.
Key words
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to The Journal of PainAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Imaging exocytosis of ATP-containing vesicles with TIRF microscopy in lung epithelial A549 cells.Purinergic Signal. 2012; 8: 59-70
- Multiple receptors involved in peripheral alpha 2, mu, and A1 antinociception, tolerance, and withdrawal.J Neurosci. 1997; 17: 735-744
- Role of protein kinase A in the maintenance of inflammatory pain.J Neurosci. 1999; 19: 2181-2186
- Evidence that release of adenosine triphosphate from endothelial cells during increased shear stress is vesicular.J Cardiovasc Pharmacol. 2001; 38: 900-908
- Release of vasoactive substances from endothelial cells by shear stress and purinergic mechanosensory transduction.J Anat. 1999; 194: 335-342
- Purinergic regulation of vascular tone and remodelling.Auton Autacoid Pharmacol. 2009; 29: 63-72
- Schwann cells: Activated peripheral glia and their role in neuropathic pain.Brain Behav Immun. 2007; 21: 522-527
- Ecto-F1Fo ATP synthase/F1 ATPase: Metabolic and immunological functions.Curr Opin Lipidol. 2006; 17: 279-284
- A P2X purinoceptor expressed by a subset of sensory neurons.Nature. 1995; 377: 428-431
- Cell surface F1Fo ATP synthase: A new paradigm?.Ann Med. 2006; 38: 429-438
- Influence of the endothelium on contractile effects of 5-hydroxytryptamine and selective 5-HT agonists in canine basilar artery.Br J Pharmacol. 1989; 96: 170-178
- Conduction slowing by the gap junctional uncoupler carbenoxolone.Cardiovasc Res. 2003; 60: 288-297
- Inhibition of tumor cell surface ATP synthesis by pigment epithelium-derived factor: Implications for antitumor activity.Int J Oncol. 2012; 41: 219-227
- Mechanisms mediating vibration-induced chronic musculoskeletal pain analyzed in the rat.J Pain. 2010; 11: 369-377
- ATP release from vascular endothelia occurs across Cx43 hemichannels and is attenuated during hypoxia.PLoS One. 2008; 3: e2801
- Thrombin-induced ATP release from human umbilical vein endothelial cells.Am J Physiol Cell Physiol. 2012; 302: C915-C923
- ATP release through connexin hemichannels in corneal endothelial cells.Invest Ophthalmol Vis Sci. 2005; 46: 1208-1218
- Increased capsaicin receptor TRPV1 in skin nerve fibres and related vanilloid receptors TRPV3 and TRPV4 in keratinocytes in human breast pain.BMC Womens Health. 2005; 5: 2
- Glial cells and chronic pain.Neuroscientist. 2010; 16: 519-531
- Imaging and characterization of stretch-induced ATP release from alveolar A549 cells.J Physiol. 2013; 591: 1195-1215
- Pain and immunity.Joint Bone Spine. 2012; 79: 228-236
- Fenamates: A novel class of reversible gap junction blockers.J Pharmacol Exp Ther. 2001; 298: 1033-1041
- Feasibility study of B16 melanoma therapy using oxidized ATP to target purinergic receptor P2X7.Eur J Pharmacol. 2012; 695: 20-26
- Volume-regulated anion channels serve as an auto/paracrine nucleotide release pathway in aortic endothelial cells.J Gen Physiol. 2002; 119: 511-520
- Maxi-anion channel and pannexin 1 hemichannel constitute separate pathways for swelling-induced ATP release in murine L929 fibrosarcoma cells.Am J Physiol Cell Physiol. 2012; 303: C924-C935
- Structural changes and recovery of function after arterial injury.Arterioscler Thromb. 1992; 12: 307-317
- Kruger L. Light A.R. Translational Pain Research: From Mouse to Man, p. Chapter 2. CRC Press, Boca Raton, FL2010
- Inhibition of P-glycoprotein and multidrug resistance-associated proteins modulates the intracellular concentration of lopinavir in cultured CD4 T cells and primary human lymphocytes.J Antimicrob Chemother. 2007; 60: 987-993
- Vascular endothelial cells mediate mechanical stimulation-induced enhancement of endothelin hyperalgesia via activation of P2X2/3 receptors on nociceptors.J Neurosci. 2013; 33: 2849-2859
- Mechanical stimulation enhances endothelin-1 hyperalgesia.Neuroscience. 2011; 178: 189-195
- Role of endothelial cells in antihyperalgesia induced by a triptan and beta-blocker.Neuroscience. 2012; 232: 83-89
- Sexual dimorphism in endothelin-1 induced mechanical hyperalgesia in the rat.Exp Neurol. 2012; 233: 505-512
- Shared mechanisms for opioid tolerance and a transition to chronic pain.J Neurosci. 2010; 30: 4660-4666
- CFTR mediates noradrenaline-induced ATP efflux from DRG neurons.Mol Pain. 2011; 7: 72
- Cystic fibrosis transmembrane regulator inhibitors CFTR(inh)-172 and GlyH-101 target mitochondrial functions, independently of chloride channel inhibition.J Pharmacol Exp Ther. 2010; 333: 60-69
- Vagotomy-induced enhancement of mechanical hyperalgesia in the rat is sympathoadrenal-mediated.J Neurosci. 1998; 18: 3043-3309
- Endothelin-B receptor activation triggers an endogenous analgesic cascade at sites of peripheral injury.Nat Med. 2003; 9: 1055-1061
- Brefeldin A: Insights into the control of membrane traffic and organelle structure.J Cell Biol. 1992; 116: 1071-1080
- ATP is released from guinea pig ureter epithelium on distension.Am J Physiol Renal Physiol. 2002; 282: F281-F288
- Hypergravity induces ATP release and actin reorganization via tyrosine phosphorylation and RhoA activation in bovine endothelial cells.Pflugers Arch. 2009; 457: 711-719
- Mechanisms of ATP release and signalling in the blood vessel wall.Cardiovasc Res. 2012; 95: 269-280
- Altered ATP release and metabolism in dorsal root ganglia of neuropathic rats.Mol Pain. 2008; 4: 66
- Endothelial cells cultured from human umbilical vein release ATP, substance P and acetylcholine in response to increased flow.Proc Biol Sci. 1990; 241: 245-248
- Vascular endothelial growth factor (VEGF) in the pathogenesis of diabetic nephropathy of type 1 diabetes mellitus.Curr Drug Targets. 2011; 12: 107-114
- Presence or absence of TrkA protein distinguishes subsets of small sensory neurons with unique cytochemical characteristics and dorsal horn projections.J Comp Neurol. 1995; 361: 404-416
Nicholls DG, Ferguson S: Bioenergetics, 4th ed. London, Academic Press, p 434, 2013
- Pigment epithelium-derived factor binds to cell-surface F(1)-ATP synthase.FEBS J. 2010; 277: 2192-2205
- ATP release and Ca2+ signalling by human bronchial epithelial cells following Alternaria aeroallergen exposure.J Physiol. 2013; 591: 4595-4609
- The major role of peripheral release of histamine and 5-hydroxytryptamine in formalin-induced nociception.Neuroscience. 2001; 102: 937-944
- ATP-binding cassette transporters at the blood-brain barrier in ischaemic stroke.Curr Pharm Des. 2011; 17: 2787-2792
- Endothelial cell biology: Role in the inflammatory response.Adv Clin Chem. 2010; 52: 109-130
- Quantitative structure–activity relationship analysis and molecular dynamics simulation to functionally validate nonsynonymous polymorphisms of human ABC transporter ABCB1 (P-glycoprotein/MDR1).Biochemistry. 2007; 46: 7678-7693
- Vincristine-induced neuropathy. A clinical study of fifty leukemic patients.Neurology. 1969; 19: 367-374
- The influence of circulatory and gut luminal challenges on bidirectional intestinal barrier permeability in rats.Scand J Gastroenterol. 1997; 32: 995-1004
- High glucose and free fatty acids induce beta cell apoptosis via autocrine effects of ADP acting on the P2Y(13) receptor.Purinergic Signal. 2013; 9: 67-79
- The endothelium: Influencing vascular smooth muscle in many ways.Can J Physiol Pharmacol. 2012; 90: 713-738
- Involvement of the cystic fibrosis transmembrane conductance regulator in the acidosis-induced efflux of ATP from rat skeletal muscle.J Physiol. 2010; 588: 4563-4578
- cAMP/protein kinase A activates cystic fibrosis transmembrane conductance regulator for ATP release from rat skeletal muscle during low pH or contractions.PLoS One. 2012; 7: e50157
- Volume-regulated chloride channels associated with the human multidrug-resistance P-glycoprotein.Nature. 1992; 355: 830-833
- Dipyridamole enhances digoxin bioavailability via P-glycoprotein inhibition.Clin Pharmacol Ther. 2003; 73: 51-60
- ATP and purinergic receptor-dependent membrane traffic in bladder umbrella cells.J Clin Invest. 2005; 115: 2412-2422
- Cholesterol loading increases the translocation of ATP synthase beta chain into membrane caveolae in vascular endothelial cells.Biochim Biophys Acta. 2006; 1761: 1182-1190
- PI3K, Rho, and ROCK play a key role in hypoxia-induced ATP release and ATP-stimulated angiogenic responses in pulmonary artery vasa vasorum endothelial cells.Am J Physiol Lung Cell Mol Physiol. 2009; 297: L954-L964
- Disposition of naringenin via glucuronidation pathway is affected by compensating efflux transporters of hydrophilic glucuronides.Mol Pharm. 2009; 6: 1703-1715
- Visualization of flow-induced ATP release and triggering of Ca2+ waves at caveolae in vascular endothelial cells.J Cell Sci. 2011; 124: 3477-3483
- Involvement of cell surface ATP synthase in flow-induced ATP release by vascular endothelial cells.Am J Physiol Heart Circ Physiol. 2007; 293: H1646-H1653
- BCRP transports dipyridamole and is inhibited by calcium channel blockers.Pharm Res. 2005; 22: 2023-2034
Article info
Publication history
Published online: May 01, 2014
Accepted:
April 8,
2014
Received in revised form:
March 25,
2014
Received:
February 11,
2014
Footnotes
Supported by National Institutes of Health grant AR063312.
The authors report no conflicts of interest.
Identification
Copyright
© 2014 American Pain Society. Published by Elsevier Inc. All rights reserved.
