NMDA receptor subunit expression and PAR2 receptor activation in colospinal afferent neurons (CANs) during inflammation induced visceral hypersensitivity
Tóm tắt
Visceral hypersensitivity is a clinical observation made when diagnosing patients with functional bowel disorders. The cause of visceral hypersensitivity is unknown but is thought to be attributed to inflammation. Previously we demonstrated that a unique set of enteric neurons, colospinal afferent neurons (CANs), co-localize with the NR1 and NR2D subunits of the NMDA receptor as well as with the PAR2 receptor. The aim of this study was to determine if NMDA and PAR2 receptors expressed on CANs contribute to visceral hypersensitivity following inflammation. Recently, work has suggested that dorsal root ganglion (DRG) neurons expressing the transient receptor potential vanilloid-1 (TRPV1) receptor mediate inflammation induced visceral hypersensitivity. Therefore, in order to study CAN involvement in visceral hypersensitivity, DRG neurons expressing the TRPV1 receptor were lesioned with resiniferatoxin (RTX) prior to inflammation and behavioural testing. CANs do not express the TRPV1 receptor; therefore, they survive following RTX injection. RTX treatment resulted in a significant decrease in TRPV1 expressing neurons in the colon and immunohistochemical analysis revealed no change in peptide or receptor expression in CANs following RTX lesioning as compared to control data. Behavioral studies determined that both inflamed non-RTX and RTX animals showed a decrease in balloon pressure threshold as compared to controls. Immunohistochemical analysis demonstrated that the NR1 cassettes, N1 and C1, of the NMDA receptor on CANs were up-regulated following inflammation. Furthermore, inflammation resulted in the activation of the PAR2 receptors expressed on CANs. Our data show that inflammation causes an up-regulation of the NMDA receptor and the activation of the PAR2 receptor expressed on CANs. These changes are associated with a decrease in balloon pressure in response to colorectal distension in non-RTX and RTX lesioned animals. Therefore, these data suggest that CANs contribute to visceral hypersensitivity during inflammation.
Tài liệu tham khảo
Mayer EA, Gebhart GF: Basic and clinical aspects of visceral hyperalgesia. Gastroenterology 1994, 107: 271–293.
Ritchie JA: The irritable colon syndrome--an unhappy coincidence? Tijdschr Gastroenterol 1973, 16: 243–253.
Lawson SN, Crepps BA, Perl ER: Relationship of substance P to afferent characteristics of dorsal root ganglion neurones in guinea-pig. J Physiol 1997,505(Pt 1):177–191. 10.1111/j.1469-7793.1997.00177.x
Miampamba M, Sharkey KA: Distribution of calcitonin gene-related peptide, somatostatin, substance P and vasoactive intestinal polypeptide in experimental colitis in rats. Neurogastroenterol Motil 1998, 10: 315–329. 10.1046/j.1365-2982.1998.00111.x
Traub RJ, Hutchcroft K, Gebhart GF: The peptide content of colonic afferents decreases following colonic inflammation. Peptides 1999, 20: 267–273. 10.1016/S0196-9781(98)00157-0
Honore P, Kamp EH, Rogers SD, Gebhart GF, Mantyh PW: Activation of lamina I spinal cord neurons that express the substance P receptor in visceral nociception and hyperalgesia. J Pain 2002, 3: 3–11.
Zhai QZ, Traub RJ: The NMDA receptor antagonist MK-801 attenuates c-Fos expression in the lumbosacral spinal cord following repetitive noxious and non-noxious colorectal distention. Pain 1999, 83: 321–329. 10.1016/S0304-3959(99)00116-5
Ji Y, Traub RJ: Spinal NMDA receptors contribute to neuronal processing of acute noxious and nonnoxious colorectal stimulation in the rat. J Neurophysiol 2001, 86: 1783–1791.
McRoberts JA, Coutinho SV, Marvizon JC, Grady EF, Tognetto M, Sengupta JN, et al.: Role of peripheral N-methyl-D-aspartate (NMDA) receptors in visceral nociception in rats. Gastroenterology 2001, 120: 1737–1748. 10.1053/gast.2001.24848
Traub RJ, Zhai Q, Ji Y, Kovalenko M: NMDA receptor antagonists attenuate noxious and nonnoxious colorectal distention-induced Fos expression in the spinal cord and the visceromotor reflex. Neuroscience 2002, 113: 205–211. 10.1016/S0306-4522(02)00170-7
Gaudreau GA, Plourde V: Involvement of N-methyl-d-aspartate (NMDA) receptors in a rat model of visceral hypersensitivity. Behav Brain Res 2004, 150: 185–189. 10.1016/j.bbr.2003.07.004
Zhou Q, Caudle RM, Price DD, Valle-Pinero AY, Verne GN: Selective up-regulation of NMDA-NR1 receptor expression in myenteric plexus after TNBS induced colitis in rats. Mol Pain 2006, 2: 3. 10.1186/1744-8069-2-3
Zhou Q, Price DD, Caudle RM, Verne GN: Visceral and somatic hypersensitivity in a subset of rats following TNBS-induced colitis. Pain 2007,134(1–2):9–15. 10.1016/j.pain.2007.03.029
Zhou Q, Price DD, Caudle RM, Verne GN: Spinal NMDA NR1 subunit expression following transient TNBS colitis. Brain Res 2009, 1279: 109–20. 10.1016/j.brainres.2009.04.038
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. 10.1053/gast.2002.32387
Cenac N, Andrews CN, Holzhausen M, Chapman K, Cottrell G, Andrade-Gordon P, et al.: Role for protease activity in visceral pain in irritable bowel syndrome. J Clin Invest 2007, 117: 636–647. 10.1172/JCI29255
Suckow SK, Caudle RM: Identification and immunohistochemical characterization of colospinal afferent neurons in the rat. Neuroscience 2008, 153: 803–813. 10.1016/j.neuroscience.2008.02.046
Jones RC III, Xu L, Gebhart GF: The mechanosensitivity of mouse colon afferent fibers and their sensitization by inflammatory mediators require transient receptor potential vanilloid 1 and acid-sensing ion channel 3. J Neurosci 2005, 25: 10981–10989. 10.1523/JNEUROSCI.0703-05.2005
Jones RC III, Otsuka E, Wagstrom E, Jensen CS, Price MP, Gebhart GF: Short-term sensitization of colon mechanoreceptors is associated with long-term hypersensitivity to colon distention in the mouse. Gastroenterology 2007, 133: 184–194. 10.1053/j.gastro.2007.04.042
Traub RJ, Herdegen T, Gebhart GF: Differential expression of c-fos and c-jun in two regions of the rat spinal cord following noxious colorectal distention. Neurosci Lett 1993, 160: 121–125. 10.1016/0304-3940(93)90394-Z
Traub RJ: Evidence for thoracolumbar spinal cord processing of inflammatory, but not acute colonic pain. Neuroreport 2000, 11: 2113–2116. 10.1097/00001756-200007140-00011
Traub RJ, Murphy A: Colonic inflammation induces fos expression in the thoracolumbar spinal cord increasing activity in the spinoparabrachial pathway. Pain 2002, 95: 93–102. 10.1016/S0304-3959(01)00381-5
Wang G, Tang B, Traub RJ: Differential processing of noxious colonic input by thoracolumbar and lumbosacral dorsal horn neurons in the rat. J Neurophysiol 2005, 94: 3788–3794. 10.1152/jn.00230.2005
Amadesi S, Nie J, Vergnolle N, Cottrell GS, Grady EF, Trevisani M, et al.: Protease-activated receptor 2 sensitizes the capsaicin receptor transient receptor potential vanilloid receptor 1 to induce hyperalgesia. J Neurosci 2004, 24: 4300–4312. 10.1523/JNEUROSCI.5679-03.2004
Fang X, Djouhri L, Black JA, Dib-Hajj SD, Waxman SG, Lawson SN: The presence and role of the tetrodotoxin-resistant sodium channel Na(v)1.9 (NaN) in nociceptive primary afferent neurons. J Neurosci 2002, 22: 7425–7433.
Rugiero F, Mistry M, Sage D, Black JA, Waxman SG, Crest M, et al.: Selective expression of a persistent tetrodotoxin-resistant Na+ current and NaV1.9 subunit in myenteric sensory neurons. J Neurosci 2003, 23: 2715–2725.
Vergnolle N: Protease-activated receptors and inflammatory hyperalgesia. Mem Inst Oswaldo Cruz 2005,100(Suppl 1):173–176.
Vergnolle N: Clinical relevance of proteinase activated receptors (pars) in the gut. Gut 2005, 54: 867–874. 10.1136/gut.2004.048876
Coutinho SV, Meller ST, Gebhart GF: Intracolonic zymosan produces visceral hyperalgesia in the rat that is mediated by spinal NMDA and non-NMDA receptors. Brain Res 1996, 736: 7–15. 10.1016/0006-8993(96)00661-0
Doyle CA, Hunt SP: Substance P receptor (neurokinin-1)-expressing neurons in lamina I of the spinal cord encode for the intensity of noxious stimulation: a c-Fos study in rat. Neuroscience 1999, 89: 17–28. 10.1016/S0306-4522(98)00276-0
Coutinho SV, Urban MO, Gebhart GF: The role of CNS NMDA receptors and nitric oxide in visceral hyperalgesia. Eur J Pharmacol 2001, 429: 319–325. 10.1016/S0014-2999(01)01331-0
Miranda A, Nordstrom E, Mannem A, Smith C, Banerjee B, Sengupta JN: The role of transient receptor potential vanilloid 1 in mechanical and chemical visceral hyperalgesia following experimental colitis. Neuroscience 2007, 148: 1021–1032. 10.1016/j.neuroscience.2007.05.034
De Schepper HU, De Man JG, Ruyssers NE, Deiteren A, Van Nassauw L, Timmermans JP, et al.: TRPV1 receptor signaling mediates afferent nerve sensitization during colitis-induced motility disorders in rats. Am J Physiol Gastrointest Liver Physiol 2008, 294: G245-G253. 10.1152/ajpgi.00351.2007
De Schepper HU, De Man JG, Van Nassauw L, Timmermans JP, Herman AG, Pelckmans PA, et al.: Acute distal colitis impairs gastric emptying in rats via an extrinsic neuronal reflex pathway involving the pelvic nerve. Gut 2007, 56: 195–202. 10.1136/gut.2006.104745
Burns GA, Stephens KE, Benson JA: Expression of mRNA for the N-methyl-D-aspartate (NMDAR1) receptor by the enteric neurons of the rat. Neurosci Lett 1994, 170: 87–90. 10.1016/0304-3940(94)90245-3
Giaroni C, Zanetti E, Chiaravalli AM, Albarello L, Dominioni L, Capella C, et al.: Evidence for a glutamatergic modulation of the cholinergic function in the human enteric nervous system via NMDA receptors. Eur J Pharmacol 2003, 476: 63–69. 10.1016/S0014-2999(03)02147-2
Valle-Pinero AY, Suckow SK, Zhou Q, Perez FM, Verne GN, Caudle RM: Expression of the N-methyl-d-aspartate receptor NR1 splice variants and NR2 subunit subtypes in the rat colon. Neuroscience 2007,147(1):164–73. 10.1016/j.neuroscience.2007.02.063
Hollmann M, Boulter J, Maron C, Beasley L, Sullivan J, Pecht G, et al.: Zinc potentiates agonist-induced currents at certain splice variants of the NMDA receptor. Neuron 1993, 10: 943–954. 10.1016/0896-6273(93)90209-A
Zheng X, Zhang L, Durand GM, Bennett MV, Zukin RS: Mutagenesis rescues spermine and Zn2+ potentiation of recombinant NMDA receptors. Neuron 1994, 12: 811–818. 10.1016/0896-6273(94)90334-4
Scott DB, Blanpied TA, Swanson GT, Zhang C, Ehlers MD: An NMDA receptor ER retention signal regulated by phosphorylation and alternative splicing. J Neurosci 2001, 21: 3063–3072.
Steinhoff M, Vergnolle N, Young SH, Tognetto M, Amadesi S, Ennes HS, et al.: Agonists of proteinase-activated receptor 2 induce inflammation by a neurogenic mechanism. Nat Med 2000, 6: 151–158. 10.1038/72247
Vergnolle N, Bunnett NW, Sharkey KA, Brussee V, Compton SJ, Grady EF, et al.: Proteinase-activated receptor-2 and hyperalgesia: A novel pain pathway. Nat Med 2001, 7: 821–826. 10.1038/89945
Hyun E, Andrade-Gordon P, Steinhoff M, Vergnolle N: Protease-activated receptor-2 activation: a major actor in intestinal inflammation. Gut 2008, 57: 1222–1229. 10.1136/gut.2008.150722
Nystedt S, Larsson AK, Aberg H, Sundelin J: The mouse proteinase-activated receptor-2 cDNA and gene. Molecular cloning and functional expression. J Biol Chem 1995, 270: 5950–5955. 10.1074/jbc.270.11.5950