100
Views
31
CrossRef citations to date
0
Altmetric
Review

Gastrointestinal pain in functional bowel disorders: sensory neurons as novel drug targets

Pages 107-123 | Published online: 02 Mar 2005

Bibliography

  • DROSSMAN DA, CORAZZIARI E, TALLEY NJ, THOMPSON WG, WHITEHEAD WE (Eds): Rome H. The Functional Gastrointestinal Disorders (2nd edi). Degnon Associates, McLean, USA (2000).
  • MAYER EA, COLLINS SM: Evolving pathophysiologic models of functional gastrointestinal disorders. Gastroenterology (2002) 122:2032-2048. •Expert review that conceptualises face, construct and predictive validity of animal models for FBDs.
  • DELVAUX M: Functional bowel disorders and irritable bowel syndrome in Europe. Aliment. Pharmacol Ther. (2003) 18\(Suppl. 3):75–79.
  • TALLEY NJ, DENNIS EH, SCHETTLER-DUNCAN VA, LACY BE, OLDEN KW, CROWELL MD: Overlapping upper and lower gastrointestinal symptoms in irritable bowel syndrome patients with constipation or diarrhea. Am.! Gastroenterol (2003) 98:2454–2459.
  • SANDLER RS, EVERHART JE, DONOWITZ M et al.: The burden of selected digestive diseases in the United States. Gastroenterology (2002) 122:1500–1511.
  • INADOMI JM, FENNERTY MB, BJORKMAN D: Systematic review: the economic impact of irritable bowel syndrome. Aliment. Pharmacol Ther: (2003) 18:671–682.
  • SCHWETZ I, BRADESI S, MAYER EA: Current insights into the pathophysiology of irritable bowel syndrome. Carr: Gastroenterol Rep. (2003) 5:331–336.
  • MAYER EA, GEBHART GF: Basic and clinical aspects of visceral hyperalgesia. Gastroenterology (1994) 107:271–293.
  • BUENO L, FIORAMONTI J, DELVAUX M, FREXINOS J: Mediators and pharmacology of visceral sensitivity: from basic to clinical investigations. Gastroenterology (1997) 112:1714–1743.
  • AZPIROZ F: Gastrointestinal perception: pathophysiological implications. Neurogastroenterol Mod]. (2002) 14:229–239.
  • BOUIN M, PLOURDE V, BOIVIN M et al.: Rectal distention testing in patients with irritable bowel syndrome: sensitivity, specificity, and predictive values of pain sensory thresholds. Gastroenterology (2002) 122:1771–1777.
  • ••Rectal hypersensitivity to distension is adistinct feature of IBS.
  • FURNESS JB, CLERC N: Responses of afferent neurons to the contents of the digestive tract, and their relation to endocrine and immune responses. Prog. Brain Res. (2000) 122:159–172.
  • HOLZER P: Gastrointestinal afferents as targets of novel drugs for the treatment of functional bowel disorders and visceral pain. Eur.J Pharmacol. (2001) 429:177–193.
  • •Expert review of drug targets on GI afferent neurons for the therapy of abdominal pain and FBDs.
  • HOLZER P: Sensory neurone responses to mucosal noxae in the upper gut: relevance to mucosal integrity and gastrointestinal pain. Neurogastroenterol Mod]. (2002) 14:459–475.
  • BERTHOUD HR, NEUHUBER WL: Functional and chemical anatomy of the afferent vagal system. Auton. Neurosci. (2000) 85:1–17.
  • ZAGON A: Does the vagus nerve mediate the sixth sense? Trends Neurosci. (2001) 24:671–673.
  • KERN MK, SHAKER R: Cerebral cortical registration of subliminal visceral stimulation. Gastroenterology (2002) 122:290–298.
  • MALAGELADA JR: The continuing dilemma of dyspepsia. Ailment. Pharmacol. Ther. (2001) 15\(Suppl. 1):6–9.
  • KELLOW JE, ECKERSLEY CM, JONES MP: Enhanced perception of physiological intestinal motility in the irritable bowel syndrome. Gastroenterology (1991) 101:1621–1627.
  • SIMREN M, ABRAHAMSSON H, BJORNSSON ES: An exaggerated sensory component of the gastrocolonic response in patients with irritable bowel syndrome. Gut (2001) 48:20–27.
  • FASS R, NALIBOFF B, HIGA L et al: Differential effect of long-term esophageal acid exposure on mechanosensitivity and chemosensitivity in humans. Gastroenterology (1998) 115:1363–1373.
  • TACK J, DEMEDTS I, DEHONDT G et al.: Clinical and pathophysiological characteristics of acute-onset functional dyspepsia. Gastroenterology (2002) 122:1738–1747.
  • SPILLER RC: Postinfectious irritable bowel syndrome. Gastroenterology (2003) 124:1662–1671.
  • CHADWICK VS, CHEN W, SHU D et al: Activation of the mucosal immune system in irritable bowel syndrome. Gastroenterology (2002) 122:1778–1783.
  • HALL W, BUCKLEY M, CROTTY P, O'MORAIN CA: Gastric mucosal mast cells are increased in Helicobacter pylori-negative functional dyspepsia. Gin. Gastmenterol. Hepatol (2003) 1:363–369.
  • BARBARA G, STANGHELLINI V, DE GIORGIO R et al.: Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome. Gastroenterology (2004) 126:693–702.
  • PLOURDE V, ST-PIERRE S, QUIRION R: Calcitonin gene-related peptide in viscerosensitive response to colorectal distension in rats. Ain. J. Physiol (1997) 273(1 Pt 1):G191–G196.
  • LAIRD JM, OLIVAR T, ROZA C, DE FELIPE C, HUNT SP, CERVERO F: Deficits in visceral pain and hyperalgesia of mice with a disruption of the tachylkinin NKI receptor gene. Neuroscience (2000) 98:345–352.
  • GSCHOSSMANN JM, COUTINHO SV, MILLER JC et al.: Involvement of spinal calcitonin gene-related peptide in the development of acute visceral hyperalgesia in the rat. Neurogastroenterol Mod] (2001) 13:229–236.
  • OZAKI N, BIELEFELDT K, SENGUPTA JN, GEBHART GF: Models of gastric hyperalgesia in the rat. Am. Physic] (2002) 283:G666–G676.
  • •Iodoacetarnide-induced gastritis and acetic acid-induced gastric ulceration cause hypersensitivity to gastric distension.
  • AL-CHAER ED, KAWASAKI M, PASRICHA PJ: A new model of chronic visceral hypersensitivity in adult rats induced by colon irritation during postnatal development. Gastroenterology (2000) 119:1276–1285.
  • COUTINHO SV, PLOTSKY PM, SABLAD M et al.: Neonatal maternal separation alters stress-induced responses to viscerosomatic nociceptive stimuli in rat. Am. Physic] (2002) 282:G307–G316.
  • LAMB K, KANG YM, GEBHART GE BIELEFELDT K: Gastric inflammation triggers hypersensitivity to acid in awake rats. Gastroenterology (2003) 125:1410–1418.
  • ••Exposure of the gastric mucosa toback-diffusing concentrations of hydrochloric acid elicits a visceromotor response indicative of pain, which is mediated by capsaicin-sensitive vagal afferents. Gastritis and gastric ulceration enhance the pain reaction to intragastric acid.
  • BERCIK P, DE GIORGIO R, BLENNERHASSETT P, VERDU EF, BARBARA G, COLLINS SM: Immune-mediated neural dysfunction in a murine model of chronic Helicobacter pylori infection. Gastroenterology (2002) 123:1205–1215.
  • MOAYYEDI P, DEEKS J, TALLEY NJ, DELANEY B, FORMAN D: An update of the Cochrane systematic review of Helicobacter pylori eradication therapy in nonulcer dyspepsia: resolving the discrepancy between systematic reviews. Am. Gastroenterol. (2003) 98:2621–2626.
  • VAIRA D, VAKIL N, RUGGE M et al.: Effect of Helicobacter pylori eradication on development of dyspeptic and reflux disease in healthy asymptomatic subjects. Gut (2003) 52:1543–1547.
  • COUTINHO SV, SU X, SENGUPTA JN, GEBHART GF: Role of sensitized pelvic nerve afferents from the inflamed rat colon in the maintenance of visceral hyperalgesia. Frog. Brain Res. (2000) 129:375–387.
  • KIRKUP AJ, BRUNSDEN AM, GRUNDY D: Receptors and transmission in the brain-gut axis: potential for novel therapies. I. Receptors on visceral afferents. Am. J. Physiol (2001) 280:G787-G794. •Expert review of drug targets on GI afferent neurons.
  • BIELEFELDT K, OZAKI N, GEBHART GF: Experimental ulcers alter voltage-sensitive sodium currents in rat gastric sensory neurons. Gastroenterology (2002) 122:394–405.
  • BIELEFELDT K, OZAKI N, GEBHART GF: Mild gastritis alters voltage-sensitive sodium currents in gastric sensory neurons in rats. Gastroenterology (2002) 122:752–661.
  • ••The hyperexcitability of DRG neuronsinnervating the inflamed stomach is related to an increase in tetrodotoxin-resistant Na* currents.
  • MOORE BA, STEWART TM, HILL C, VANNER SJ: TNBS ileitis evokes hyperexcitability and changes in ionic membrane properties of nociceptive DRG neurons. Am. I Physiol (2002) 282:G1045–G1051.
  • ••Experimental ileitis induced bytrinitrobenzene sulphonic acid causes hyperexcitability of DRG neurons innervating the inflamed ileum.
  • DANG K, BIELEFELDT K, GEBHART GF: Gastric ulcers reduce A-Type potassium currents in rat gastric sensory ganglion neurons. Am. Physiol (2004) 286:G573–G579.
  • WOOLF CJ, SALTER MW: Neuronal plasticity: increasing the gain in pain. Science (2000) 288:1765–1768.
  • BIELEFELDT K, OZAKI N, GEBHART GF: Role of nerve growth factor in modulation of gastric afferent neurons in the rat. Am. .1 Physiol (2003) 284:G499–G507.
  • LAMB K, KANG YM, GEBHART GE BIELEFELDT K: Nerve growth factor and gastric hyperalgesia in the rat. Neurogastroenterol Motil (2003) 15:355–361.
  • GONSALKORALE WM, PERREY C, PRAVICA V, WHORWELL PJ, HUTCHINSON IV: Interleuldn 10 genotypes in irritable bowel syndrome: evidence for an inflammatory component? Gut (2003) 52:91–93.
  • GWEE KA, COLLINS SM, READ NW et al: Increased rectal mucosal expression of interleukin 113 in recently acquired post-infectious irritable bowel syndrome. Gut (2003) 52:523–526.
  • WHITEHEAD WE, PALSSON 0, JONES KR: Systematic review of the comorbidity of irritable bowel syndrome with other disorders: what are the causes and implications? Gastroenterology (2002) 122:1140–1156.
  • HENNINGSEN P, ZIMMERMANN T, SATTEL H: Medically unexplained physical symptoms, anxiety, and depression: a meta-analytic review. Psychosom. Med. (2003) 65:528–533.
  • ANDREWS PL, SANGER GJ: Abdominal vagal afferent neurones: an important target for the treatment of gastrointestinal dysfunction. Carr. Opin. Pharmacol (2002) 2:650–656.
  • •Expert review of the pathophysiological roles of vagal afferent neurons in GI disease and of the pharmacological opportunities related to vagal afferents.
  • DONG X, HAN S, ZYLKA MJ, SIMON MI, ANDERSON DJ: A diverse family of GPCRs expressed in specific subsets of nociceptive sensory neurons. CO(2001) 106:619–632.
  • HAN SK, DONG X, HWANG JI, ZYLKA MJ, ANDERSON DJ, SIMON MI: Orphan G protein-coupled receptors MrgAl and MrgC11 are distinctively activated by RF-amide-related peptides through the Gaol pathway. Proc. Nati Acad. Sci. USA (2002) 99:14740–14745.
  • LEMBO PM, GRAZZINI E, GROBLEWSKI T et al.: Proenkephalin A gene products activate a new family of sensory neuron-specific GPCRs. Nat. Neurosci. (2002) 5:201–209.
  • PERRY MJ, LAWSON SN: Differences in expression of oligosaccharides, neuropeptides, carbonic anhydrase and neurofilament in rat primary afferent neurons retrogradely labelled via skin, muscle or visceral nerves. Neuroscience (1998) 85:293–310.
  • HORNBY PJ: Receptors and transmission in the brain-gut axis. II. Excitatory amino acid receptors in the brain-gut axis. Am. Physiol (2001) 280:G1055–G1060.
  • PARSONS CG: NMDA receptors as targets for drug action in neuropathic pain. Eur.j Pharmacol (2001) 429:71–78.
  • LECCI A, VALENTI C, MAGGI CA: Tachykinin receptor antagonists in irritable bowel syndrome. Curr: Opin. Investig. Drugs (2002) 3:589–601.
  • •Expert review of the possible implications of tachykinins in FBDs.
  • HOLZER P: Role of tachykinins in the gastrointestinal tract. In: Tachykinins. Handbook of Experimental Pharmacology (Vol. 164). Holzer P (Ed.), Springer, Berlin (2004). In Press.
  • •Expert review of the pathophysiological implications of tachykinins in the gut and of the emerging opportunities to target tachykinin receptors in the therapy of GI disease.
  • DE PONTI F, TONINI M: Irritable bowel syndrome: new agents targeting serotonin receptor subtypes. Drugs (2001) 61:317–332.
  • GERSHON MD: Serotonin and its implication for the management of irritable bowel syndrome. Rev Gastroenterol Disord. (2003) 3\(Suppl. 2):525–534. •Expert review of the role of 5-HT receptors in FBDs. Expert Opin. Ther. Targets (2004) 8(2)
  • MIWA J, ECHIZEN H, MATSUEDA K,UMEDA N: Patients with constipation-predominant irritable bowel syndrome (IBS) may have elevated serotonin concentrations in colonic mucosa as compared with diarrhea-predominant patients and subjects with normal bowel habits. Digestion (2001) 63:188–194.
  • CAMILLERI M, ATANASOVA E, CARLSON PJ et al.: Serotonin-transporter polymorphism pharmacogenetics in diarrhea-predominant irritable bowel syndrome. Gastroenterology (2002) 123:425–432.
  • KOZLOWSKI CM, GREEN A, GRUNDY D, BOISSONADE FM, BOUNTRA C: The 5-HT3 receptor antagonist alosetron inhibits the colorectal distention induced depressor response and spinal c-fos expression in the anaesthetised rat. Gut (2000) 46:474–480.
  • TALLEY NJ: Serotoninergic neuroenteric modulators. Lancet (2001) 358:2061–2068.
  • MOLLER-LISSNER SA, FUMAGALLI I,BARDHAN KD et al.: Tegaserod, a 5-HT4 receptor partial agonist, relieves symptoms in irritable bowel syndrome patients with abdominal pain, bloating and constipation. Aliment. Phannacol Ther. (2001) 15:1655–1666.
  • NOVICK J, MINER P, KRAUSE R et al: A randomized, double-blind, placebo-controlled trial of tegaserod in female patients suffering from irritable bowel syndrome with constipation. Aliment. Phannacol Ther. (2002) 16:1877–1888.
  • ••Tegaserod has a beneficial effect onabdominal pain in IBS.
  • COFFIN B, FARMACHIDI JP, ROEGG P, BASTIE A, BOUHASSIRA D: Tegaserod, a 5-HT4 receptor partial agonist, decreases sensitivity to rectal distension in healthy subjects. Aliment. Pharmacol Ther. (2003) 17:577–585.
  • YU S, LONG JM, MATHIS C, NASS PH, LACY BE, CROWELL MD: A 5-HT4 receptor partial agonist, tegaserod maleate, inhibits cortical and subcortical c-fos activation following noxious colorectal distension in the mouse. Neurogastroenterol Moth. (2001) 13:445.
  • SCHIKOWSKI A, THE WISSEN M, MATHIS C, ROSS HG, ENCK P: Serotonin Type-4 receptors modulate the sensitivity of intramural mechanoreceptive afferents of the cat rectum. Neurogastroenterol Motu. (2002) 14:221-227. Tegaserod reduces the sensitivity of rectal afferents to distension.
  • BLEY KR, HUNTER JC, EGLEN RM, SMITH JA: The role of IP prostanoid receptors in inflammatory pain. Trends Pharmacol Sci. (1998) 19:141–147.
  • SOUTHALL MD, VASKO MR: Prostaglandin receptor subtypes, EP3c and EP4, mediate the prostaglandin E2-induced eAMP production and sensitization of sensory neurons. J. Biol. Chem. (2001) 276:16083–16091.
  • HAUPT W, JIANG W, KREIS ME, GRUNDY D: Prostaglandin EP receptor subtypes have distinct effects on jejunal afferent sensitivity in the rat. Gastroenterology (2000) 119:1580–1589.
  • MAUBACH KA, GRUNDY D: The role of prostaglandins in the bradykinin-induced activation of serosal afferents of the rat jejunum M vitro. I Physiol (Lond) (1999) 515:277–285.
  • UENO A, MATSUMOTO H, NARABA H et al.: Major roles of prostanoid receptors IP and EP3 in endotwdn-induced enhancement of pain perception. Biochem. Pharmacol (2001) 62:157–160.
  • SARKAR S, HOBSON AR, HUGHES A et al.: The prostaglandin E2 receptor-1 (EP-1) mediates acid-induced visceral pain hypersensitivity in humans. Gastroenterology(2003) 124:18–25.
  • ••Acid-induced hypersensitivity of theoesophagus is attenuated by a PG EP' receptor antagonist.
  • STEINHOFF M, VERGNOLLE N, YOUNG SH et al.: Agonists of proteinase-activated receptor 2 induce inflammation by a neurogenic mechanism. Nat. Med. (2000) 6:151–158.
  • HOOGERWERF WA, ZOU L, SHENOY M et al: The proteinase-activated receptor 2 is involved in nociception. Neurosci. (2001) 21:9036–9042.
  • KIRKUP AJ, JIANG W, BUNNETT NW, GRUNDY D: Stimulation of proteinase-activated receptor 2 excites jejunal afferent nerves in anaesthetised rats. I. Physiol (Lond) (2003) 552:589–601.
  • ••A PAR-2 agonist stimulates spinal afferentsin the mesentery both by a direct and indirect mechanism.
  • COELHO AM, VERGNOLLE N, GUIARD B, FIORAMONTI J, BUENO L: Proteinases and proteinase-activated receptor 2: a possible role to promote visceral hyperalgesia in rats. Gastroenterology (2002) 122:1035–1047.
  • ••Intracolonic administration of subinflarnmatory doses of a PAR-2 agonist stimulates spinal afferents and induces prolonged rectal hyperalgesia, which involves activation of N.Ki receptors.
  • CENAC N, COELHO AM, NGUYEN C et al: Induction of intestinal inflammation in mouse by activation of proteinase-activated receptor-2. Am.! Pathol (2002) 161:1903–1915.
  • NGUYEN C, COELHO AM, GRADY E et al.: Colitis induced by proteinase-activated receptor-2 agonists is mediated by a neurogenic mechanism. Can. Physiol Pharmacol (2003) 81:920–927.
  • KIM JA, CHOI SC, YUN KJ et al.: Expression of protease-activated receptor 2 in ulcerative colitis. Inflamm. Bowe] Dis. (2003) 9:224–229.
  • GAO C, LIU S, HU HZ et al: Serine proteases excite myenteric neurons through protease-activated receptors in guinea pig small intestine. Gastroenterology (2002) 123:1554–1564.
  • KAWABATA A: Gastrointestinal functions of proteinase-activated receptors. Life Sci. (2003) 74:247–254.
  • •Expert review of the pathophysiological implications of PARs in the gut.
  • DUNN PM, ZHONG Y, BURNSTOCK G: P2X receptors in peripheral neurons. Frog. Neurobiol (2001) 65:107–134.
  • NORTH RA: Molecular physiology of P2X receptors. Physiol Rev (2002) 82:1013–1067.
  • ZHONG Y, DUNN PM, BARDINI M, FORD AP, COCKAYNE DA, BURNSTOCK G: Changes in P2X receptor responses of sensory neurons from P2X3-deficient mice. Eur.j NeuroscL (2001) 14:1784–1792.
  • BURNSTOCK G: Purine-mediated signalling in pain and visceral perception. Trends Pharmacol ScL (2001) 22:182–188.
  • VIRGINIO C, ROBERTSON G, SURPRENANT A, NORTH RA: Trinitrophenyl-substituted nucleotides are potent antagonists selective for P2X1, P2X3, and heteromeric P2X2/3 receptors. Pharmacol (1998) 53:969–973.
  • KIRKUP AJ, BOOTH CE, CHESSELL IP, HUMPHREY PP, GRUNDY D: Excitatory effect of P2X receptor activation on mesenteric afferent nerves in the anaesthetised rat. Physiol (Lond) (1999) 520:551–563.
  • BURGSTAHLER R, GRAFE P: Diadenosine pentaphosphate is more potent than ATP at P2X receptors in isolated rat vagus nerve. Neumreport (2001) 12:679–682.
  • VLASKOVSKA M, KASAKOV L, RONG W et al.: P2X3 knock-out mice reveal a major sensory role for urothelially released ATP J. Neurosci. (2001) 21:5670–5677.
  • WYNN G, RONG W, XIANG Z, BURNSTOCK G: Purinergic mechanisms contribute to mechanosensory transduction in the rat colorectum. Gastroenterology (2003) 125:1398–1409.
  • ••Distension of the colorecturn releasesadenosine triphosphate, which excites spinal afferent neurons via activation of ionotropic P2X ptifinoceptors.
  • COCKAYNE DA, HAMILTON SG, ZHU QM et al.: Urinary bladder hyporeflexia and reduced pain-related behaviour in P2X3-deficient mice. Nature (2000) 407:1011–1015.
  • PAGE AJ, O'DONNELL TA, BLACKSHAW LA: P2X purinoceptor-induced sensitization of ferret vagal mechanoreceptors in oesophageal inflammation. I Physiol. (Lond) (2000) 523:403–411.
  • HOLZER P: Acid-sensitive ion channels in gastrointestinal function.Curr. Opin. Phannacol (2003) 3:618–625.
  • •Expert review of the molecular pharmacology of acid-sensitive ion channels and their functional implications in the diseased gut.
  • XU GY, HUANG LY: Peripheral inflammation sensitizes P2X receptor-mediated responses in rat dorsal root ganglion neurons. Neurosci. (2002) 22:93–102.
  • YIANGOU Y, FACER P, BAECKER PA et al.: ATP-gated ion channel P2X3 is increased in human inflammatory bowel disease. Neurogastroenterol Moth. (2001) 13:365–369.
  • GIARONI C, KNIGHT GE, RUAN HZ et al.: P2 receptors in the murine gastrointestinal tract. Neuropharmacology (2002) 43:1313–1323.
  • JARVIS MF, BURGARD EC, MCGARAUGHTY S et al: A-317491, a novel potent and selective non-nucleotide antagonist of P2X3 and P2X213 receptors, reduces chronic inflammatory and neuropathic pain in the rat. Proc. Natl. Acad. Sci. USA (2002) 99:17179–17184.
  • ••Characterisation of the in vitro and in vivo pharmacology of A-317491 and its utility as an antihyperalgesic drug.
  • HONORE P, MIKUSA J, BIANCHI B et al: TNP-ATP, a potent P2X3 receptor antagonist, blocks acetic acid-induced abdominal constriction in mice: comparison with reference analgesics. Pain (2002) 96:99–105.
  • CLAPHAM DE: TRP channels as cellular sensors. Nature (2003) 426:517–524.
  • •Expert review of the role of transient receptor potential ion channels as sensory transducers with a broad modality spectrum.
  • CLAPHAM DE, MONTELL C, SCHULTZ G, JULIUS D; INTERNATIONAL UNION OF PHARMACOLOGY: International Union of Pharmacology. XLIII. Compendium of voltage-gated ion channels: transient receptor potential channels. Phannacol Rev (2003) 55:591–596.
  • CATERINA MJ, SCHUMACHER MA, TOMINAGA M, ROSEN TA, LEVINE JD, JULIUS D: The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature (1997) 389:816–824.
  • PATAPOUTIAN A, PEIER AM, STORY GM, VISWANATH V: ThermoTRP channels and beyond: mechanisms of temperature sensation. Nat. Rev. Neurosci. (2003) 4:529–539.
  • •Expert review of the role of transient receptor potential ion channels as transducers of cold, warmth and heat.
  • CATERINA MJ, JULIUS D: The vanilloid receptor: a molecular gateway to the pain pathway. Anna. Rev Neurosci. (2001) 24:487–517.
  • DI MARZO V, BLUMBERG PM, SZALLASI A: Endovanilloid signaling in pain. Curr. Opin. Neurobiol (2002) 12:372–379.
  • GUNTHORPE MJ, BENHAM CD, RANDALL A, DAVIS JB: The diversity in the vanilloid (TRPV) receptor family of ion channels. Trends Phannacol Sci. (2002) 23:183–191.
  • •Expert review of the role of TRPV transient receptor potential ion channels as broad spectrum nociceptors.
  • HWANG SW, OH U: Hot channels in airways: pharmacology of the vanilloid receptor. Carr: Opin. Phannacol (2002) 2:235–242.
  • •Expert review of intracellular signalling pathways, whereby the activity of the TRPV1 transient receptor potential ion channel is regulated.
  • TREVISANI M, SMART D, GUNTHORPE MJ et al: Ethanol elicits and potentiates nociceptor responses via the vanilloid receptor-1. Nat. Neurosci. (2002) 5:546–551.
  • PREMKUMAR LS, AHERN GP: Induction of vanilloid receptor channel activity by protein kinase C. Nature (2000) 408:985–990.
  • PRESCOTT ED, JULIUS D: A modular PIP2 binding site as a determinant of capsaicin receptor sensitivity. Science (2003) 300:1284–1288.
  • REEH PW, PETHO G: Nociceptor excitation by thermal sensitization - a hypothesis. Frog. Brain Res. (2000) 129:39–50.
  • CATERINA MJ, LEFFLER A, MALMBERG AB et al: Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science (2000) 288:306–313.
  • DAVIS JB, GRAY J, GUNTHORPE MJ et al.: Vanilloid receptor-1 is essential for inflammatory thermal hyperalgesia. Nature (2000) 405:183–187.
  • HOLZER P: Neural emergency system in the stomach. Gastroenterology(1998) 114:823–839.
  • PATTERSON LM, ZHENG H, WARD SM, BERTHOUD HR: Vanilloid receptor (VR1) expression in vagal afferent neurons innervating the gastrointestinal tract. Cell Tissue Res. (2003) 311:277–287.
  • ••Irnmunohistochemical analysis of theexpression of TRPV1 by vagal afferents innervating the rat stomach.
  • WARD SM, BAYGUINOV J, WON KJ, GRUNDY D, BERTHOUD HR: Distribution of the vanilloid receptor (VR1) in the gastrointestinal tract. Comp. Neurol (2003) 465:121–135.
  • ••Imrnunohistochemical analysis of the cellulardistribution of TRPV1 in the GI tract of the rat, guinea-pig and mouse and localisation of TRPV1 to spinal afferent nerve fibres.
  • POONYACHOTI S, KULKARNI-NARLA A, BROWN DR: Chemical coding of neurons expressing S-and lc-opioid receptor and Type I vanilloid receptor immunoreactivities in the porcine ileum. Cell Tissue Res. (2002) 307:23–33.
  • ANAVI-GOFFER S, COUTTS AA: Cellular distribution of vanilloid VR1 receptor immunoreactivity in the guinea-pig myenteric plexus. Eur.j Pharmacol. (2003) 458:61–71.
  • CHAN CL, FACER P, DAVIS JB et al: Sensory fibres expressing capsaicin receptor TRPV1 in patients with rectal hypersensitivity and faecal urgency. Lancet (2003) 361:385–391.
  • ••The expression of TRPV1 is enhanced in thecolon of patients with rectal hypersensitivity.
  • NOZAWA Y, NISHIHARA K, YAMAMOTO A, NAKANO M, AJIOKA H, MATSUURA N: Distribution and characterization of vanilloid receptors in the rat stomach. Neurosci. Lett. (2001) 309:33–36.
  • SU X, WACHTEL RE, GEBHART GF: Capsaicin sensitivity and voltage-gated sodium currents in colon sensory neurons from rat dorsal root ganglia. Am. J. Physiol. (1999) 277:G1180–G1188.
  • BLACKSHAW LA, PAGE AJ, PARTOSOEDARSO ER: Acute effects of capsaicin on gastrointestinal vagal afferents. Neuroscience (2000) 96:407–416.
  • HAMMER J, HAMMER HF, EHERERAJ, PETRITSCH W, HOLZER P, KREJS GJ: Intraluminal capsaicin does not affect fluid and electrolyte absorption in the human jejunum but does cause pain. Gut (1998) 43:252–255.
  • DREWES AM, SCHIPPER KP, DIMCEVSKI G et al.: Gut pain and hyperalgesia induced by capsaicin: a human experimental model. Pain (2003) 104:333–341.
  • ••Application of capsaicin to the human ileuminduces pain and mechanical hyperalgesia.
  • SCHMIDT B, HAMMER J, HOLZER P, HAMMER HF: Chemical nociception in the jejunum induced by capsaicin. Gut (2004). In Press.
  • ••Application of capsaicin to the humanjejunum induces pain, the abdominal localisation and perceptional quality of which are similar to distension-induced pain. Since it does not stimulate jejunal motility, capsaicin is thought to evoke pain by stimulation of jejunal chemoreceptors, presumably TRPV1.
  • LAIRD JM, MARTINEZ-CARO L, GARCIA-NICAS E, CERVERO F: A new model of visceral pain and referred hyperalgesia in the mouse. Pain (2001) 92:335–342.
  • HOLZER P: Capsaicin: cellular targets, mechanisms of action, and selectivity for thin sensory neurons. Pharmacol. Rev (1991) 43:143–201.
  • SZALLASI A: Vanilloid (capsaicin) receptors in health and disease. Am. j Clin. Pathol. (2002) 118:110–121.
  • LEMBECK F, SKOFITSCH G: Visceral pain reflex after pretreatment with capsaicin and morphine. Naunyn Schmiedebergs Arch. Pharmacol. (1982) 321:116–122.
  • DELAFOY L, RAYMOND F, DOHERTY AM, ESCHALIER A, DIOP L: Role of nerve growth factor in the trinitrobenzene sulfonic acid-induced colonic hypersensitivity. Pain (2003) 105:489–497.
  • LYSYJ, SISTIERY-ITTAH M, ISRAELIT Y et al.: Topical capsaicin - a novel and effective treatment for idiopathic intractable pruritus ani: a randomised, placebo controlled, crossover study. Gut (2003) 52:1323–1326.
  • BORTOLOTTI M, COCCIA G, GROSSI G, MIGLIOLI M: The treatment of functional dyspepsia with red pepper. Aliment. Pharmacol. Ther. (2002) 16:1075–1082.
  • ••Chronic administration of red peppercontaining capsaicin ameliorates the epigastric pain associated with functional dyspepsia.
  • SCHMULSON MJ, VALDOVINOS MA, MILKE P: Chili pepper and rectal hyperalgesia in irritable bowel syndrome. Am.j Gastroenterol. (2003) 98:1214–1215.
  • YIANGOU Y, FACER P, DYER NH et al: Vanilloid receptor 1 immunoreactivity in inflamed human bowel. Lancet (2001) 357:1338–1339.
  • JI RR, SAMAD TA, JIN SX, SCHMOLL R, WOOLF CJ: p38 MAPK activation by NGF in primary sensory neurons after inflammation increases TRPV1 levels and maintains heat hyperalgesia. Neuron (2002) 36:57–68.
  • MCVEY DC, VIGNA SR: The capsaicin VR1 receptor mediates substance P release in toxin A-induced enteritis in rats. Peptides (2001) 22:1439–1446.
  • KIHARA N, DE LA FUENTE SG, FUJINO K, TAKAHASHI T, PAPPAS TN, MANTYH CR: Val-dB:Ad receptor-1 containing primary sensory neurones mediate dextran sulphate sodium induced colitis in rats. Gut (2003) 52:713–719.
  • WALDMANN R, LAZDUNSKI M: H*-gated cation channels: neuronal acid sensors in the NaC/DEG family of ion channels. Curc Opin. Neurobiol. (1998) 8:418–424.
  • KELLENBERGER S, SCHILD L: Epithelial sodium channel/degenerin family of ion channels: a variety of functions for a shared structure. Physiol. Rev (2002) 82:735–767.
  • •Expert review of the molecular pharmacology of acid-sensing ion channels.
  • KRISHTAL 0: The ASICs: signaling molecules? Modulators? Trends Neurosci. (2003) 26:477-483.
  • •Expert review of the role of acid-sensing ion channels in sensory pathophysiology.
  • ALVAREZ DE LA ROSA D, ZHANG P, SHAO D, WHITE F, CANESSA CM: Functional implications of the localization and activity of acid-sensitive channels in rat peripheral nervous system. Proc. Natl. Acad. Sci. USA (2002) 99:2326–2331.
  • ••Localisation of the various types ofacid-sensing ion channels to different populations of DRG neurons.
  • BENSON CJ, XIE J, WEMMIE JA et al: Heteromultimers of DEG/ENaC subunits form H*-gated channels in mouse sensory neurons. Proc. Nati Acad. Sci. USA (2002) 99:2338–2343.
  • XIE J, PRICE MP, BERGER AL, WELSH MJ: DRASIC contributes to pH-gated currents in large dorsal root ganglion sensory neurons by forming heteromultimeric channels. Neurophysiol. (2002) 87:2835–2843.
  • WELSH MJ, PRICE MP, XIE J: Biochemical basis of touch perception: mechanosensory function of degenerin/epithelial Na' channels. J. Biol. Chem. (2002) 277:2369–2372.
  • PRICE MP, LEWIN GR, MCILWRATH SL et al.: The mammalian sodium channel BNC1 is required for normal touch sensation. Nature (2000) 407:1007–1011.
  • PRICE MP, MCILWRATH SL, XIE J et al: The DRASIC cation channel contributes to the detection of cutaneous touch and acid stimuli in mice. Neuron (2001) 32:1071–1083.
  • CHEN CC, ZIMMER A, SUN WH, HALL J, BROWNSTEIN MJ, ZIMMER A: A role for ASIC3 in the modulation of high-intensity pain stimuli. Proc. Natl. Acad. Sci. USA (2002) 99:8992–8997.
  • YIANGOU Y, FACER P, SMITH JA etal.: Increased acid-sensing ion channel ASIC-3 in inflamed human intestine. Ear. Castroenterol Hepatol (2001) 13:891–896.
  • MAMET J, BARON A, LAZDUNSKI M, VOILLEY N: Proinflammatory mediators, stimulators of sensory neuron excitability via the expression of acid-sensing ion channels. Neurosci. (2002) 22:10662–10670.
  • OZAKI N, GEBHART GF: Characterization of mechanosensitive splanchnic nerve afferent fibers innervating the rat stomach. Am. Physiol (2001) 281:G1449–G1459.
  • SU X, WACHTEL RE, GEBHART GF: Mechanosensitive potassium channels in rat colon sensory neurons. J. Neurophysiol (2000) 84:836–843.
  • RAYBOULD HE, GSCHOSSMAN JM, ENNES H, LEMBO T, MAYER EA: Involvement of stretch-sensitive calcium flux in mechanical transduction in visceral afferents. Anton. Nerv. Syst. (1999) 75:1–6.
  • SUZUKI M, MIZUNO A, KODAIRA K, IMAI M: Impaired pressure sensation in mice lacking TRPV4. Biol. Chem. (2003) 278:22664–22668.
  • ••The transient receptor potential ion channelTRPV4 senses both acidosis and pressure.
  • BANG H, KIM Y, KIM D: TREK-2, a new member of the mechanosensitive tandem-pore K.* channel family. j. Biol. Chem. (2000) 275:17412–17419.
  • BAKER MD, WOOD JN: Involvement of Na* channels in pain pathways. Bends Pharmacol Sci. (2001) 22:27–31.
  • DIB-HAJJ S, BLACK JA, CUMMINS TR, WAXMAN SG: NaN/Nav1.9: a sodium channel with unique properties. Trends Neurosci. (2002) 25:253–259.
  • •Expert review of the molecular pharmacology of the tetrodotoxin-resistant Na* channel, Na„1.9, and its functional implication in nociception.
  • FANG X, DJOUHRI L, BLACK JA, DIB-HAJJ SD, WAXMAN SG, LAWSON SN: The presence and role of the tetrodotoxin-resistant sodium channel Nav1.9 (NaN) in nociceptive primary afferent neurons. J. Neurosci. (2002) 22:7425–7433.
  • •Localisation of the tetrodotoxin-resistant Na* channel, Nay1.9, to different populations of DRG neurons.
  • DJOUHRI L, NEWTON R, LEVINSON SR, BERRY CM, CARRUTHERS B, LAWSON SN: Sensory and electrophysiological properties of guinea-pig sensory neurones expressing Na„ 1.7 (PN1) Na* channel a subunit protein. Physiol (Lend) (2003) 546:565–576.
  • DJOUHRI L, FANG X, OKUSE K, WOOD JN, BERRY CM, LAWSON SN: The TTX-resistant sodium channel Nav1.8 (SNS/PN3): expression and correlation with membrane properties in rat nociceptive primary afferent neurons. I Physiol (Lond) (2003) 550:739–752.
  • ••Localisation of the tetrodotoxin-resistantNa* channel, Nav1.8, to different populations of DRG neurons.
  • GOLD MS, ZHANG L, WRIGLEY DL, TRAUB RJ: Prostaglandin E2 modulates TTX-R 'Na in rat colonic sensory neurons. Neurophysiol (2002) 88:1512–1522.
  • ••The pro-inflammatory mediator PG E2enhances tetrodotoxin-resistant Na* currents in DRG neurons innervating the rat colon.
  • STEWART T, BEYAK MJ, VANNER S: Ileitis modulates potassium and sodium currents in guinea pig dorsal root ganglia sensory neurons. Physiol. (Lond) (2003) 552:797–807.
  • ••The hyperexcitability of DRG neuronsinnervating the inflamed ileum is related to an increase in tetrodotoxin-resistant Na* currents and a decrease in IQ- currents.
  • YOSHIMURA N, SEKI S, NOVAKOVIC SD et al.: The involvement of the tetrodotoxin-resistant sodium channel Nav1.8 (PN3/SNS) in a rat model of visceral pain. J. Neurosci. (2001) 21:8690–8696.
  • LAIRD JM, SOUSLOVA V, WOOD JN, CERVERO F: Deficits in visceral pain and referred hyperalgesia in Nav1.8 (SNS/PN3)-null mice. J. Neurosci. (2002) 22:8352–8356.
  • ••The tetrodotoxin-resistant Na* channel,Na1.8, mediates spontaneous activity in sensitised nociceptors innervating the mouse colon.
  • NESS TJ: Intravenous lidocaine inhibits visceral nociceptive reflexes and spinal neurons in the rat. Anesthesiology (2000) 92:1685–1691.
  • SU X, JOSHI SK, KARDOS S, GEBHART GF: Sodium channel blocking actions of the lc-opioid receptor agonist U50,488 contribute to its visceral antinociceptive effects. J. Neurophysiol (2002) 87:1271–1279.
  • •Non-selective inhibitors of voltage-gated Na* channels such as mexiletine and carbamazepine suppress the central signalling of colonic distension by spinal afferents.
  • BIELEFELDT K, OZAKI N, WHITEIS C, GEBHART GF: Amitriptyline inhibits voltage-sensitive sodium currents in rat gastric sensory neurons. DV. Dis. Sci. (2002) 47:959–966.
  • •The antidepressant drug amitryptiline is suggested to reduce pain by a use-dependent block of voltage-dependent Na* channels on sensory neurons.
  • CERVERO F, LAIRD JM: Role of ion channels in mechanisms controlling gastrointestinal pain pathways. Curl: Opin. Pharmacol (2003) 3:608–612.
  • •Expert review of the implications of ion channels in GI pain and hyperalgesia.
  • RASBAND MN, PARK EW, VANDERAH TW, LAI J, PORRECA F, TRIMMER JS: Distinct potassium channels on pain-sensing neurons. Proc. Natl. Acad. Sci. USA (2001) 98:13373–13378.
  • NEWTON RA, BINGHAM S, CASE PC, SANGER GJ, LAWSON SN: Dorsal root ganglion neurons show increased expression of the calcium channel a28-1 subunit following partial sciatic nerve injury. Brain Res. (2001) 95:1–8.
  • SUTTON KG, MARTIN DJ, PINNOCK RD, LEE K, SCOTT RH: Gabapentin inhibits high-threshold calcium channel currents in cultured rat dorsal root ganglion neurones. Br. Pharmacol (2002) 135:257–265.
  • EUTAMENE H, COELHO AM, THEODOROU V et al.: Antinociceptive effect of pregabalin in septic shock-induced rectal hypersensitivity in rats. Pharmacol Exp. The]: (2000) 295:162–167.
  • ••Pregabalin inhibits the colonic hyperalgesiaelicited by septic shock presumably via inhibition of voltage-dependent a28 Ca2' channel subunits in DRG neurons.
  • DIOP L, RAYMOND F, FARGEAU H, PETOUX F, CHOVET M, DOHERTY AM: Pregabalin (CI-1008) inhibits the trinitrobenzene sulfonic acid-induced chronic colonic allodynia in the rat. J. Pharmacol. Exp. Ther. (2002) 302:1013–1022.
  • ••Pregabalin counteracts the hyperalgesiaassociated with trinitrobenzene sulphonic acid-induced colitis, presumably via inhibition of voltage-dependent a28 Ca2' channel subunits in DRG neurons.
  • FENG Y, CUT M, WILLIS WD: Gabapentin markedly reduces acetic acid-induced visceral nociception. Anesthesiology (2003) 98:729–733.
  • JAIN KK: An evaluation of intrathecal ziconotide for the treatment of chronic pain. Expert Opin. Investig. Drugs (2000) 9:2403–2410.
  • HORVATH G, BRODACZ B, HOLZER-PETSCHE U: Role of calcium channels in the spinal transmission of nociceptive information from the mesentery. Pain (2001) 93:35–41.
  • GEBHART GF: Pathobiology of visceral pain: molecular mechanisms and therapeutic implications. IV. Visceral afferent contributions to the pathobiology of visceral pain. Am. Physiol (2000) 278:G834–G838.
  • SANGER GJ, HICKS GA: Drugs targeting functional bowel disorders: insights from animal studies. Carr: Opin. Pharmacol (2002) 2:678–683.
  • •Expert review of drug targets for FBDs.
  • MICHL T, JOCIC M, HEINEMANN A, SCHULIGOI R, HOLZER P: Vagal afferent signaling of a gastric mucosal acid insult to medullary, pontine, thalamic, hypothalamic and limbic, but not cortical, nuclei of the rat brain. Pain (2001) 92:19–27.
  • BLACKSHAW LA, GEBHART GF: The pharmacology of gastrointestinal nociceptive pathways. Carr: Opin. Pharmacol (2002) 2:642–649.
  • •Expert review of drug targets on GI afferent neurons with special emphasis on pain in FBDs.
  • CAMILLERI M: Drugs targeting functional bowel disorders: lessons from drug trials. Carr: Opin. Pharmacol (2002) 2:684–690.
  • •Expert review of clinical criteria and pitfalls in the development of novel drugs for FBDs.
  • SZALLASI A, BLUMBERG PM: Vanilloid (capsaicin) receptors and mechanisms. Pharmacol Rev (1999) 51:159–212.
  • WAHL P, FOGED C, TULLIN S, THOMSEN C: Iodo-resiniferatoxin, a new potent vanilloid receptor antagonist. Mol Pharmacol (2001) 59:9–15.
  • GARCIA-MARTINEZ C, HUMET M, PLANELLS-CASES R et al: Attenuation of thermal nociception and hyperalgesia by VR1 blockers. Proc. Natl. Acad. Sci. USA (2002) 99:2374–2379.
  • WANG Y, SZABO T, WELTER JD et al: High affinity antagonists of the vanilloid receptor. Mol Pharmacol (2002) 62:947–956.
  • LEE J, LEE J, KANG M et al: N-(3-acyloxy-2-benzylpropy1)-Ar- [4-(methylsulfonylamino)benzyl]thiourea analogues: novel potent and high affinity antagonists and partial antagonists of the vanilloid receptor.' Med. Chem. (2003) 46:3116–3126.
  • SUH YG, LEE YS, MIN KH et al.: Novel non-vanilloid VR1 antagonist of high analgesic effects and its structural requirement for VR1 antagonistic effects. Bioorg. Med. Chem. Lett. (2003) 13:4389-4393. Characterisation of the in vitro pharmacology of a non-vanilloid TRPV1 channel blocker.
  • SUN Q, TAFESSE L, ISLAM K et al: 4-(2-Pyridyl)piperazine-1-carboxamides: potent vanilloid receptor 1 antagonists. Bioorg. Med. Chem. Lett. (2003) 13:3611–3616.
  • ••Characterisation of the in vitropharmacology of a carboxarnide-type TRPV1 channel blocker with oral bioavailability in the rat.
  • GUNTHORPE MJ, RAMI HK, JERMAN JC et al: Identification and characterisation of SB-366791, a potent and selective vanilloid receptor (VR1/TRPV1) antagonist. Neuropharmacology (2004) 46:133–149.
  • ••Characterisation of the in vitropharmacology of a cinnarnide-type TRPV1 channel blocker.
  • MCDONNELL ME, ZHANG SP, NASSER N, DUBIN AE, DAX SL: 7-Hydroxynaphthalen 1 -yl-urea and -amide antagonists of human vanilloid receptor 1. Bioorg. Med. Chem. Lett. (2004) 14:531–534.
  • ••Characterisation of the in vitropharmacology of a series of 7-hydroxynaphthalenyl limas and amides as TRPV1 channel blockers.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.