Abstract
CB1 and TRPV1 receptors modulate enteric neurotransmission and colonic inflammation. This study investigates early electrophysiological changes in distal colon of wild-type and receptor deficient mice after an inflammatory insult set by dinitrobenzene sulfonic acid (DNBS). Colitis was induced by DNBS in CB1−/− mice, TRPV1−/− mice, and their respective wild-type littermates. Electrophysiological properties consisting of membrane potentials and electrically induced inhibitory junction potentials (IJP) of circular smooth muscle cells were evaluated at different time points. Additionally a histological colitis severity score was evaluated in CB1+/+ and CB1−/− mice 24 h after DNBS. Inflammation caused spontaneous atropine insensitive rhythmic action potentials in CB1−/− and TRPV1−/− mice but not in wild-type animals. This indicates that membrane stability is disturbed, which in turn indicates a lack of protective mechanisms. Focal electrical neuronal stimulation of the myenteric plexus induced IJP in the smooth muscle cells. Twenty-four hours after initiation of inflammation, the duration of the IJP is prolonged in all animals, indicating disturbances within neuromuscular interaction. In CB1−/− mice, it is interesting that the duration of IJP was significantly extended, as compared to CB1+/+ mice pointing toward missing protective mechanisms in the CB1−/− mice. Inflammatory insults in the mouse colon induce reproducible changes in the electrophysiological properties and such changes correlate with duration of colitis. In mutants, these electrophysiological changes display different patterns, suggesting the lack of protective properties for neuromuscular interactions and membrane stability.
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Reddy SN, Bazzocchi G, Chan S, Akashi K, Villanueva-Meyer J, Yanni G, Mena I, Snape WJJ (1991) Colonic motility and transit in health and ulcerative colitis. Gastroenterology 101:1289–1297
Annese V, Bassotti G, Napolitano G, Usai P, Andriulli A, Vantrappen G (1997) Gastrointestinal motility disorders in patients with inactive Crohn's disease. Scand J Gastroenterol 32:1107–1117
Bossone C, Hosseini JM, Pineiro-Carrero V, Shea-Donohue D (2001) Alterations in spontaneous contractions in vitro after repeated inflammation of rat distal colon. Am J Physiol Gastrointest Liver Physiol 280:G949–G957
Koch TR, Carney JA, Go VL, Szurszewski JH (1988) Spontaneous contractions and some electrophysiologic properties of circular muscle from normal sigmoid colon and ulcerative colitis. Gastroenterology 95:77–84
Moreels TG, De Man JG, Dick JM, Nieuwendijk RJ, De Winter BY, Lefebvre RA, Herman AG, Pelckmans PA (2001) Effect of TNBS-induced morphological changes on pharmacological contractility of the rat ileum. Eur J Pharmacol 423:211–222
Moreels TG, Nieuwendijk RJ, De Man JG, De Winter BY, Herman AG, Van Marck EA, Pelckmans PA (2004) Concurrent infection with Schistosoma mansoni attenuates inflammation induced changes in colonic morphology, cytokine levels, and smooth muscle contractility of trinitrobenzene sulphonic acid induced colitis in rats. Gut 53:99–107
Weisbrodt NW, Lai M, Bowers RL, Harari Y, Castro GA (1994) Structural and molecular changes in intestinal smooth muscle induced by Trichinella spiralis infection. Am J Physiol 266:G856–G862
Massa F, Marsicano G, Hermann H, Cannich A, Monory K, Cravatt BF, Ferri GL, Sibaev A, Storr M, Lutz B (2004) The endogenous cannabinoid system protects against colonic inflammation. J Clin Invest 113(7):1202–1209
Massa F, Sibaev A, Marsicano G, Blaudzun H, Storr M, Lutz B (2005) Vanilloid receptor (TRPV-1) deficient mice show increased susceptibility to dinitrobenzene sulfonic acid-induced colitis. J Mol Med 1–5 (E pub)
Milton NG (2002) Anandamide and noladin ether prevent neurotoxicity of the human amyloid-beta peptide. Neurosci Lett 332:127–130
Marsicano G, Wotjak CT, Azad SC, Bisogno T, Rammes G, Cascio MG, Hermann H, Tang J, Hofmann C, Zieglgänsberger W, Di Marzo V, Lutz B (2001) The endogenous cannabinoid system controls extinction of aversive memories. Nature 418:530–534
Caterina MJ, Leffler A, Malmberg AB, Martin WJ, Trafton J, Petersen-Zeitz KR, Koltzenburg M, Basbaum AI, Julius D (2000) Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science 288(5464):306–313
Sibaev A, Franck H, Vanderwinden JM, Allescher HD, Storr M (2003) Structural differences in the enteric neural network in murine colon: impact on electrophysiology. Am J Physiol Gastrointest Liver Physiol 285(6):G1325–G1334
Siegmund B, Lehr HA, Fantuzzi G, Dinarello CA (2001) IL-1 beta-converting enzyme (caspase-1) in intestinal inflammation. Proc Natl Acad Sci USA 98:13249–13254
Wirtz S, Finotto S, Kanzler S, Lohse AW, Blessing M, Lehr HA, Galle PR, Neurath MF (1999) Cutting edge: chronic intestinal inflammation in STAT-4 transgenic mice: characterization of disease and adoptive transfer by TNF- plus IFN-gamma-producing CD4+ T cells that respond to bacterial antigens. J Immunol 162(4):1884–1888
Hosseini JM, Goldhill JM, Bossone C, Pineiro-Carrero V, Shea-Donohue D (1999) Progressive alterations in circular smooth muscle contractility in TNBS-induced colitis in rats. Neurogastroenterol Motil 11:347–356
Myers BS, Dempsey DT, Yasar S, Martin JS, Parkman HP, Ryan JP (1997) Acute experimental distal colitis alters colonic transit in rats. J Surg Res 69:107–112
De Man JG, Moreels TG, De Winter BY, Bogers JJ, Van Marck EA, Herman AG, Pelckmans PA (2001) Disturbance of the prejunctional modulation of cholinergic neurotransmission during chronic granulomatous inflammation of the mouse ileum. Br J Pharmacol 133:695–707
Der T, Bercik P, Donelly G, Jackson T, Berezin I, Collins SM, Huizinga JD (2000) Interstitial cells of cajal and inflammation-induced motor dysfunction in the mouse small intestine. Gastroenterology 119:1590–1599
Aube AC, Cherbut C, Barbier M, Xing JH, Roze C, Galmiche JP (1999) Altered myoelectrical activity in noninflamed ileum of rats with colitis induced by trinitrobenzene sulphonic acid. Neurogastroenterol Motil 11:55–62
Ward SM, Dalziel HH, Thornbury KD, Westfall DP, Sanders KM (1992) Nonadrenergic, noncholinergic inhibition and rebound excitation in canine colon depend on nitric oxide. Am J Physiol 262:G237–G243
Khaspekov LG, Brenz Verca MS, Frumkina LE, Hermann H, Marsicano G, Lutz B (2004) Involvement of brain-derived neurotrophic factor in cannabinoid receptor-dependent protection against excitotoxicity. Eur J Neurosci 17:1691–1698
Jackson SJ, Baker D, Cuzner SL, Diemel LT (2004) Cannabinoid-mediated neuroprotection following interferon-gamma treatment in a three-dimensional mouse brain aggregate cell culture. Eur J Neurosci 20:2267–2275
Marsicano G, Goodenough S, Monory K, Hermann H, Eder M, Cannich A, Azad SC, Cascio MG, Gutierez SO, van der Stelt M, Lopez-Rodriguez ML, Casanova E, Schutz G, Zieglgansberger W, Di Marzo V, Behl C, Lutz B (2003) CB1 cannabinoid receptors and on-demand defense against excitotoxicity. Science 302:84–88
Cho SH, Park HJ, Chung JP, Lee YH, Ji SW, No TW, Lee SI (2004) Altered colonic transit in TNBS-induced experimental colitis in guinea pig and distribution of nitric oxide synthase in the colonic wall. Korean J Gastroenterol 44:308–313
Izzo AA, Mascolo N, Borrelli F, Capasso F (1998) Excitatory transmission to the circular muscle of the guinea-pig ileum: evidence for the involvement of cannabinoid CB1 receptors. Br J Pharmacol 124:1363–1368
Pertwee RG, Fernando SR, Nash JE, Coutts AA (1996) Further evidence for the presence of cannabinoid CB1 receptors in guinea-pig small intestine. Br J Pharmacol 118:2199–2205
Croci T, Manara L, Aureggi G, Guagnini F, Rinaldi-Carmona M, Maffrand JP, Le Fur G, Mukenge S, Ferla G (1998) In vitro functional evidence of neuronal CB1 receptors in human ileum. Br J Pharmacol 125:1393–1395
Storr M, Gaffal E, Saur D, Schusdziarra V, Allescher HD (2002) Influence of cannabinoids on neurotransmission in rat gastric fundus. Can J Physiol Pharmacol 80:67–76
Storr M, Sibaev A, Marsicano G, Lutz B, Schusdziarra V, Timmermans JP, Allescher HD (2004) Cannabinoid receptor type 1 modulates excitatory and inhibitory neurotransmission in mouse colon. Am J Physiol Gastrointest Liver Physiol 286(1):G110–G117
Izzo AA, Mascolo N, Capasso F (2001) The gastrointestinal pharmacology of cannabinoids. Curr Opin Pharmacol 1:597–603
Izzo AA, Pinto L, Borrelli F, Capasso R, Mascolo N, Capasso F (2000) Central and peripheral cannabinoid modulation of gastrointestinal transit in physiological states or during the diarrhoea induced by croton oil. Br J Pharmacol 129:1627–1632
Acknowledgements
We thank B. Cravatt for discussions and suggestions and B. Wölfel for her excellent technical assistance, mouse breeding, and genotyping. This work was supported by grants from the Deutsche Forschungsgemeinschaft (STO 645/2-1), the FÖFOLE-program of the University of Munich (MS-357), and by a scholarship from the Hertie-Foundation (to B.Lutz).
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Sibaev, A., Massa, F., Yüce, B. et al. CB1 and TRPV1 receptors mediate protective effects on colonic electrophysiological properties in mice. J Mol Med 84, 513–520 (2006). https://doi.org/10.1007/s00109-006-0040-x
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DOI: https://doi.org/10.1007/s00109-006-0040-x