Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Molecular Pain
Published in: Molecular Pain 1/2006

Open Access 01-12-2006 | Commentary

Nociceptors in cardiovascular functions: complex interplay as a result of cyclooxygenase inhibition

Authors: Louis S Premkumar, Manish Raisinghani

Published in: Molecular Pain | Issue 1/2006

Login to get access

Abstract

Prostaglandins (PGs) are requisite components of inflammatory pain as indicated by the efficacy of cyclooxygenase 1/2 (COX1/2) inhibitors. PGs do not activate nociceptive ion channels directly, but sensitize them by downstream mechanisms linked to G-protein coupled receptors. Antiinflammatory effects are purported to arise from inhibition of synthesis and/or release of proinflammatory agents. Release of these agents from peripheral and central terminals of sensory neurons modulates nociceptive input from the periphery and synaptic transmission at the first sensory synapse, respectively. Heart and blood vessels are densely innervated by sensory nerve endings that express chemo-, mechano-, and thermo-sensitive receptors. Activation of these receptors mediates synthesis and/or release of vasoactive agents by virtue of their Ca2+permeability. In this article, we discuss that inhibition of COX2 reduces PG synthesis and renders beneficial effects by preventing sensitization of nociceptors, but at the same time, it might contribute to deleterious cardiovascular effects by compromising the synthesis and/or release of vasoactive agents.
Appendix
Available only for authorised users
Literature
1.
Bogatcheva NV, Sergeeva MG, Dudek SM, Verin AD: Arachidonic acid cascade in endothelial pathobiology. Microvasc Res 2005, 69: 107–127. 10.1016/j.mvr.2005.01.007PubMedCrossRef
2.
Koistinaho J, Chan PH: Spreading depression-induced cyclooxygenase-2 expression in the cortex. Neurochem Res 2000, 25: 645–651. 10.1023/A:1007559003261PubMedCrossRef
3.
McQueen DS, Bond SM, Moores C, Chessell I, Humphrey PP, Dowd E: Activation of P2X receptors for adenosine triphosphate evokes cardiorespiratory reflexes in anaesthetized rats. J Physiol 1998, 507: 843–855. 10.1111/j.1469-7793.1998.843bs.xPubMedCentralPubMedCrossRef
4.
5.
Sutherland SP, Benson CJ, Adelman JP, McCleskey EW: Acid-sensing ion channel 3 matches the acid-gated current in cardiac ischemia-sensing neurons. Proc Natl Acad Sci USA 2001, 98: 711–716. 10.1073/pnas.011404498PubMedCentralPubMedCrossRef
6.
Snitsarev V, Whiteis CA, Abboud FM, Chapleau MW: Mechanosensory transduction of vagal and baroreceptor afferents revealed by study of isolated nodose neurons in culture. Auton Neurosci 2002, 98: 59–63. 10.1016/S1566-0702(02)00033-4PubMedCrossRef
7.
Ditting T, Linz P, Hilgers KF, Jung O, Geiger H, Veelken R: Putative role of epithelial sodium channels (ENaC) in the afferent limb of cardio renal reflexes in rats. Basic Res Cardiol 2003, 98: 388–400. 10.1007/s00395-003-0426-7PubMedCrossRef
8.
Maggi CA, Meli A: The sensory-efferent function of capsaicin-sensitive neurons. Gen Pharmacol 1988, 19: 1–43.PubMedCrossRef
9.
McDonald DM, Bowden JJ, Baluk P, Bunnett NW: Neurogenic inflammation. A model for studying efferent actions of sensory nerves. Adv Exp Med Biol 1996, 410: 453–462.PubMedCrossRef
10.
Seyedi N, Maruyama R, Levi R: Bradykinin activates a cross-signaling pathway between sensory and adrenergic nerve endings in the heart: a novel mechanism of ischemic norepinephrine release? J Pharmacol Exp Ther 1999, 290: 656–663.PubMed
11.
Moreau ME, Garbacki N, Molinaro G, Brown NJ, Marceau F, Adam A: The kallikrein-kinin system: current and future pharmacological targets. J Pharmacol Sci 2005, 99: 6–38. 10.1254/jphs.SRJ05001XPubMedCrossRef
12.
Narumiya S, FitzGerald GA: Genetic and pharmacological analysis of prostanoid receptor function. J Clin Invest 2001, 108: 25–30. 10.1172/JCI200113455PubMedCentralPubMedCrossRef
13.
Brain SD, Grant AD: Vascular actions of calcitonin gene-related peptide and adrenomedullin. Physiol Rev 2004, 84: 903–934. 10.1152/physrev.00037.2003PubMedCrossRef
14.
Wang DH: The vanilloid receptor and hypertension. Acta Pharmacol Sin 2005, 26: 286–294. 10.1111/j.1745-7254.2005.00057.xPubMedCrossRef
15.
Watson RE, Supowit SC, Zhao H, Katki KA, Dipette DJ: Role of sensory nervous system vasoactive peptides in hypertension. Braz J Med Biol Res 2002, 35: 1033–1045. 10.1590/S0100-879X2002000900004PubMedCrossRef
16.
Burnstock G: Vascular control by purines with emphasis on the coronary system. Eur Heart J 1989, 10: 15–21.PubMedCrossRef
17.
Holzer P, Maggi CA: Dissociation of dorsal root ganglion neurons into afferent and efferent-like neurons. Neuroscience 1998, 86: 389–398. 10.1016/S0306-4522(98)00047-5PubMedCrossRef
18.
Hua XY: Tachykinins and calcitonin gene-related peptide in relation to peripheral functions of capsaicin-sensitive sensory neurons. Acta Physiol Scand Suppl 1986, 551: 1–45.PubMed
19.
Julius D, Basbaum AI: Molecular mechanisms of nociception. Nature 2001, 413: 203–210. 10.1038/35093019PubMedCrossRef
20.
Caterina MJ, Julius D: The vanilloid receptor: a molecular gateway to the pain pathway. Annu Rev Neurosci 2001, 24: 487–517. 10.1146/annurev.neuro.24.1.487PubMedCrossRef
21.
Moriyama T, Higashi T, Togashi K, Iida T, Segi E, Sugimoto Y, Tominaga T, Narumiya S, Tominaga M: Sensitization of TRPV1 by EP1 and IP reveals peripheral nociceptive mechanism of prostaglandins. Mol Pain 2005, 1: 3. 10.1186/1744-8069-1-3PubMedCentralPubMedCrossRef
22.
Morenilla-Palao C, Planells-Cases R, Garcia-Sanz N, Ferrer-Montiel A: Regulated exocytosis contributes to protein kinase C potentiation of vanilloid receptor activity. J Biol Chem 2004, 279: 25665–25672. 10.1074/jbc.M311515200PubMedCrossRef
23.
Van Buren JJ, Bhat S, Rotello R, Pauza ME, Premkumar LS: Sensitization and translocation of TRPV1 by insulin and IGF-I. Mol Pain 2005, 1: 17. 10.1186/1744-8069-1-17PubMedCentralPubMedCrossRef
24.
Zygmunt PM, Petersson J, Andersson DA, Chuang H, Sorgard M, Di Marzo V, Julius D, Hogestatt ED: Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Nature 1999, 400: 452–457. 10.1038/22761PubMedCrossRef
25.
26.
Zahner MR, Li DP, Chen SR, Pan HL: Cardiac vanilloid receptor 1-expressing afferent nerves and their role in the cardiogenic sympathetic reflex in rats. J Physiol 2003, 551: 515–523. 10.1113/jphysiol.2003.048207PubMedCentralPubMedCrossRef
27.
Scotland RS, Chauhan S, Davis C, De Felipe C, Hunt S, Kabir J, Kotsonis P, Oh U, Ahluwalia A: Vanilloid receptor TRPV1, sensory C fibers, and vascular autoregulation: a novel mechanism involved in myogenic constriction. Circ Res 2004, 95: 1027–1034. 10.1161/01.RES.0000148633.93110.24PubMedCrossRef
28.
Wang L, Wang DH: TRPV1 gene knockout impairs postischemic recovery in isolated perfused heart in mice. Circulation 2005, 112: 3617–3623. 10.1161/CIRCULATIONAHA.105.556274PubMedCrossRef
29.
Pan HL, Chen SR: Sensing tissue ischemia: another new function for capsaicin receptors? Circulation 2004, 110: 1826–1831. 10.1161/01.CIR.0000142618.20278.7APubMedCrossRef
30.
Strecker T, Messlinger K, Weyand M, Reeh PW: Role of different proton-sensitive channels in releasing calcitonin gene-related peptide from isolated hearts of mutant mice. Cardiovasc Res 2005, 65: 405–410. 10.1016/j.cardiores.2004.10.013PubMedCrossRef
31.
Krause JE, Chenard BL, Cortright DN: Transient receptor potential ion channels as targets for the discovery of pain therapeutics. Curr Opin Investig Drugs 2005, 6: 48–57.PubMed
32.
Pedersen SF, Owsianik G, Nilius B: TRP channels: An overview. Cell Calcium 2005, 38: 233–252. 10.1016/j.ceca.2005.06.028PubMedCrossRef
33.
Alessandri-Haber N, Yeh JJ, Boyd AE, Parada CA, Chen X, Reichling DB, Levine JD: Hypotonicity induces TRPV4-mediated nociception in rat. Neuron 2003, 39: 497–511. 10.1016/S0896-6273(03)00462-8PubMedCrossRef
34.
Yang XR, Lin MJ, McIntosh LS, Sham JS: Functional Expression of Transient Receptor Potential Melastatin- and Vanilloid-Related Channels in Pulmonary Arterial and Aortic Smooth Muscle. Am J Physiol Lung Cell Mol Physiol 2006, 290: L1267-L1276. 10.1152/ajplung.00515.2005PubMedCrossRef
35.
Freichel M, Vennekens R, Olausson J, Stolz S, Philipp SE, Weissgerber P, Flockerzi V: Functional role of TRPC proteins in native systems: implications from knockout and knock-down studies. J Physiol 2005, 567: 59–66. 10.1113/jphysiol.2005.092999PubMedCentralPubMedCrossRef
36.
Premkumar LS, Raisinghani M, Pingle SC, Long C, Pimentel F: Downregulation of TRPM8 by Protein Kinase C-mediated dephosphorylation. J Neurosci 2005, 25: 11322–11329. 10.1523/JNEUROSCI.3006-05.2005PubMedCrossRef
37.
Waldmann R, Champigny G, Lingueglia E, De Weille JR, Heurteaux C, Lazdunski M: H(+)-gated cation channels. Ann N Y Acad Sci 1999, 30: 67–76. 10.1111/j.1749-6632.1999.tb11274.xCrossRef
38.
Baron A, Deval E, Salinas M, Lingueglia E, Voilley N, Lazdunski M: Protein kinase C stimulates the acid-sensing ion channel ASIC2a via the PDZ domain-containing protein PICK1. J Biol Chem 2002, 277: 50463–50468. 10.1074/jbc.M208848200PubMedCrossRef
39.
Berdiev BK, Xia J, Jovov B, Markert JM, Mapstone TB, Gillespie GY, Fuller CM, Bubien JK, Benos DJ: Protein kinase C isoform antagonism controls BNaC2 (ASIC1) function. J Biol Chem 2002, 277: 45734–45740. 10.1074/jbc.M208995200PubMedCrossRef
40.
Leonard AS, Yermolaieva O, Hruska-Hageman A, Askwith CC, Price MP, Wemmie JA, Welsh MJ: cAMP-dependent protein kinase phosphorylation of the acid-sensing ion channel-1 regulates its binding to the protein interacting with C-kinase-1. Proc Natl Acad Sci USA 2003, 100: 2029–2034. 10.1073/pnas.252782799PubMedCentralPubMedCrossRef
41.
Allen NJ, Attwell D: Modulation of ASIC channels in rat cerebellar Purkinje neurons by ischaemia-related signals. J Physiol 2002, 543: 521–529. 10.1113/jphysiol.2002.020297PubMedCentralPubMedCrossRef
42.
Drew LJ, Rohrer DK, Price MP, Blaver KE, Cockayne DA, Cesare P, Wood JN: Acid-sensing ion channels ASIC2 and ASIC3 do not contribute to mechanically activated currents in mammalian sensory neurons. J Physiol 2004, 556: 691–710. 10.1113/jphysiol.2003.058693PubMedCentralPubMedCrossRef
43.
Page AJ, Brierley SM, Martin CM, Martinez-Salgado C, Wemmie JA, Brennan TJ, Symonds E, Omari T, Lewin GR, Welsh MJ, Blackshaw LA: The ion channel ASIC1 contributes to visceral but not cutaneous mechanoreceptor function. Gastroenterology 2004, 127: 1739–1747. 10.1053/j.gastro.2004.08.061PubMedCrossRef
44.
45.
Mei Q, Liang BT: P2 purinergic receptor activation enhances cardiac contractility in isolated rat and mouse hearts. Am J Physiol Heart Circ Physiol 2001, 281: H334-H341.PubMed
46.
Lee YH, Lee SJ, Seo MH, Kim CJ, Sim SS: ATP-induced histamine release is in part related to phospholipase A2-mediated arachidonic acid metabolism in rat peritoneal mast cells. Arch Pharm Res 2001, 24: 552–556.PubMedCrossRef
47.
Boue-Grabot E, Archambault V, Seguela P: A protein kinase C site highly conserved in P2X subunits controls the desensitization kinetics of P2X(2) ATP-gated channels. J Biol Chem 2000, 275: 10190–10195. 10.1074/jbc.275.14.10190PubMedCrossRef
48.
Vial C, Tobin AB, Evans RJ: G-protein-coupled receptor regulation of P2X1 receptors does not involve direct channel phosphorylation. Biochem J 2004, 382: 101–110. 10.1042/BJ20031910PubMedCentralPubMedCrossRef
49.
Hung AC, Chu YJ, Lin YH, Weng JY, Chen HB, Au YC, Sun SH: Roles of protein kinase C in regulation of P2X(7) receptor-mediated calcium signalling of cultured type-2 astrocyte cell line, RBA-2. Cell Signal 2005, 17: 1384–1396. 10.1016/j.cellsig.2005.02.009PubMedCrossRef
50.
Vulchanova L, Arvidsson U, Riedl M, Wang J, Buell G, Surprenant A, North RA, Elde R: Differential distribution of two ATP-gated channels (P2X receptors) determined by immunocytochemistry. Proc Natl Acad Sci USA 1996, 93: 8063–8067. 10.1073/pnas.93.15.8063PubMedCentralPubMedCrossRef
51.
Lee Y, Rodriguez C, Dionne RA: The role of COX-2 in acute pain and the use of selective COX-2 inhibitors for acute pain relief. Curr Pharm Des 2005, 11: 1737–1755. 10.2174/1381612053764896PubMedCrossRef
52.
Tsujii M, Kawano S, DuBois RN: Cyclooxygenase-2 expression in human colon cancer cells increases metastatic potential. Proc Natl Acad Sci USA 1997, 94: 3336. 10.1073/pnas.94.7.3336PubMedCentralPubMedCrossRef
53.
Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davis B, Day R, Ferraz MB, Hawkey CJ, Hochberg MC, Kvien TK, Schnitzer TJ: Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med 2000, 343: 520–1528. 10.1056/NEJM200011233432103CrossRef
54.
Romano M, Claria J: Cyclooxygenase-2 and 5-lipoxygenase converging functions on cell proliferation and tumor angiogenesis: implications for cancer therapy. FASEB J 2003, 17: 1986–95. 10.1096/fj.03-0053revPubMedCrossRef
55.
Ross R: Atherosclerosis – an inflammatory disease. N Engl J Med 1999, 340: 115–126. 10.1056/NEJM199901143400207PubMedCrossRef
56.
Belton O, Byrne D, Kearney D, Leahy A, Fitzgerald DJ: Cyclooxygenase-1 and -2-dependent prostacyclin formation in patients with atherosclerosis. Circulation 2000, 102: 840–845.PubMedCrossRef
57.
Catella-Lawson F, McAdam B, Morrison BW, Kapoor S, Kujubu D, Antes L, Lasseter KC, Quan H, Gertz BJ, FitzGerald GA: Effects of specific inhibition of cyclooxygenase-2 on sodium balance, hemodynamics, and vasoactive eicosanoids. J Pharmacol Exp Ther 1999, 289: 735–741.PubMed
58.
Cheng Y, Austin SC, Rocca B, Koller BH, Coffman TM, Grosser T, Lawson JA, FitzGerald GA: Role of prostacyclin in the cardiovascular response to thromboxane A2. Science 2002, 296: 539–541. 10.1126/science.1068711PubMedCrossRef
59.
Couzin J: Drug safety. FDA panel urges caution on many anti-inflammatory drugs. Science 2005, 307: 1183–1185. 10.1126/science.307.5713.1183aPubMedCrossRef
60.
Lenzer J: FDA advisers warn: COX 2 inhibitors increase risk of heart attack and stroke. Br Med J 2005, 330: 440. 10.1136/bmj.330.7489.440CrossRef
61.
Lloyd-Jones DM, Wang TJ, Leip EP, Larson MG, Levy D, Vasan RS, D'Agostino RB, Massaro JM, Beiser A, Wolf PA, Benjamin EJ: Lifetime risk for development of atrial fibrillation: the Framingham Heart Study. Circulation 2004, 110: 1042–1046. 10.1161/01.CIR.0000140263.20897.42PubMedCrossRef
Metadata
Title
Nociceptors in cardiovascular functions: complex interplay as a result of cyclooxygenase inhibition
Authors
Louis S Premkumar
Manish Raisinghani
Publication date
01-12-2006
Publisher
BioMed Central
Published in
Molecular Pain / Issue 1/2006
Electronic ISSN: 1744-8069
DOI
https://doi.org/10.1186/1744-8069-2-26

Other articles of this Issue 1/2006

Molecular Pain 1/2006 Go to the issue

Research

Depression of presynaptic excitation by the activation of vanilloid receptor 1 in the rat spinal dorsal horn revealed by optical imaging

Research

Genetic polymorphisms in monoamine neurotransmitter systems show only weak association with acute post-surgical pain in humans

Research

Ionic basis of a mechanotransduction current in adult rat dorsal root ganglion neurons

Research

Moderate hypoxia influences excitability and blocks dendrotoxin sensitive K+ currents in rat primary sensory neurones

Research

Sodium channel expression in the ventral posterolateral nucleus of the thalamus after peripheral nerve injury

Methodology

Intrathecal long-term gene expression by self-complementary adeno-associated virus type 1 suitable for chronic pain studies in rats