The Experts below are selected from a list of 1050 Experts worldwide ranked by ideXlab platform
Nicolas Cenac - One of the best experts on this subject based on the ideXlab platform.
-
targeting fatty acid amide hydrolase and transient receptor Potential vanilloid 1 simultaneously to modulate colonic motility and visceral sensation in the mouse a pharmacological intervention with n arachidonoyl serotonin aa 5 ht
Neurogastroenterology and Motility, 2017Co-Authors: Mohammad Bashashati, Jakub Fichna, Fabiana Piscitelli, Raffaele Capasso, Angelo A Izzo, A Sibaev, J P Timmermans, Nicolas CenacAbstract:BackgroundEndocannabinoid anandamide (AEA) inhibits intestinal motility and visceral pain, but it may also be proalgesic through transient receptor Potential vanilloid-1 (TRPV1). AEA is degraded by fatty acid amide hydrolase (FAAH). This study explored whether dual inhibition of FAAH and TRPV1 reduces diarrhea and abdominal pain. MethodsImmunostaining was performed on myenteric plexus of the mouse colon. The effects of the dual FAAH/TRPV1 inhibitor AA-5-HT on electrically induced contractility, Excitatory Junction Potential (EJP) and fast (f) and slow (s) inhibitory Junction Potentials (IJP) in the mouse colon, colonic propulsion and visceromotor response (VMR) to rectal distension were studied. The colonic levels of endocannabinoids and fatty acid amides were measured. Key ResultsCB1-positive neurons exhibited TRPV1;only some TRPV1 positive neurons did not express CB1. CB1 and FAAH did not colocalize. AA-5-HT (100nM-10M) decreased colonic contractility by similar to 60%;this effect was abolished by TRPV1 antagonist 5-IRTX, but not by CB1 antagonist, SR141716. AA-5-HT (1M-10M) inhibited EJP by similar to 30% and IJPs by similar to 50%. The effects of AA-5-HT on Junction Potentials were reversed by SR141716 and 5`-IRTX. AA-5-HT (20mg/kg;i.p.) inhibited colonic propulsion by similar to 30%;SR141716 but not 5`-IRTX reversed this effect. AA-5-HT decreased VMR by similar to 50%-60%;these effects were not blocked by SR141716 or 5`-IRTX. AA-5-HT increased AEA in the colon. Conclusions and InferencesThe effects of AA-5-HT on visceral sensation and colonic motility are differentially mediated by CB1, TRPV1 and non-CB1/TRPV1 mechanisms, possibly reflecting the distinct neuromodulatory roles of endocannabinoid and endovanilloid FAAH substrates in the mouse intestine.
-
Regulation of the Enteric Neuromotor and Sensory Functions in the Mouse With N-Arachidonoyl-Serotonin (AA-5-HT), a Dual Fatty Acid Amide Hydrolase (FAAH) Inhibitor and TRPV1 Antagonist
'Elsevier BV', 2016Co-Authors: Mohammad Bashashati, Jakub Fichna, Fabiana Piscitelli, Raffaele Capasso, Angelo A Izzo, A Sibaev, J P Timmermans, Nicolas Cenac, Nathalie Vergnolle, Vincenzo Di MarzoAbstract:Background: Endocannabinoid N-arachidonoylethanolamine (AEA, anandamide) is a double- edged sword: it inhibits intestinal motility and visceral pain through its neuroinhibitory effects, but may also have proalgesic or proinflammatory effects by activating transient receptor Potential vanilloid-1 (TRPV1). AEA levels may be increased by inhibition of fatty acid amide hydrolase (FAAH). We hypothesize that N-arachidonoyl-serotonin (AA-5-HT), as a dual FAAH inhibitor and TRPV1 antagonist, enhances the beneficial effects of AEA by: (1) increasing its endogenous levels and (2) blocking TRPV1. Dual FAAH and TRPV1 blockade may be a Potential treatment for GI hypermotility and visceral hyperalgesia. Methods: Male CD1 mice were used in this study. Whole-mount preparations of the colonic myenteric plexus were immunostained for cannabinoid-1 (CB1) receptor, TRPV1 and FAAH. The effects of AA-5-HT on the following parameters were studied: (1) colonic contractility induced by electrical field stimulation (EFS; 4 Hz); in vitro, (2) Excitatory Junction Potential (EJP) and fast (f) and slow (s) inhibitory Junction Potential (IJP); in vitro, (3) colonic expulsion of a bead; in vivo, (4) visceral hyperalgesia to distensive stimuli and visceromotor response (VMR) induced by intra-colonic administration of the protease-activated receptor-2 activating peptide SLIGRL (20μg/mouse); in vivo and (5) colonic levels of AEA, 2-AG, palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), measured by mass spectrometry. Results: CB1-immunoreactive enteric neurons exhibited TRPV1 immunoreactivity. Only some TRPV1-positive neurons also expressed CB1 receptors, which were not co-localized with FAAH. AA-5-HT (100nM- 10μM) decreased EFS induced colonic longitudinal muscle contractility by ~60% at the highest concentration. These effects were abolished by the TRPV1 antagonist, 5` -IRTX (75nM), but not by the CB1 antagonist, SR141716 (100nM). Electrical stimulation of the enteric neurons induced EJP followed by fIJP and sIJP. AA-5-HT inhibited EJP at 1μM by ~30% and fIJP and sIJP at 10μM by ~50%. Both SR141716 (1μM) and 5` - IRTX (1μM) reversed the effects of AA-5-HT on the Junction Potentials. AA-5-HT (20mg/ kg i.p.) inhibited colonic propulsion by ~30 %. This effect was blocked by SR141716 (1mg/ kg), but not by 5` -IRTX (0.75mg/kg). AA-5-HT (20mg/kg) decreased VMR by ~50-60% at distention levels of 30-60mmHg. This effect was not sensitive to SR141716 or5` -IRTX. AA- 5-HT (20mg/kg) significantly increased colonic AEA, but not 2-AG, PEA or OEA levels. Conclusion: Dual inhibition of FAAH and TRPV1 channels has neuromodulatory effects in the mouse intestine. The effects of AA-5-HT on visceral sensation and intestinal motility parameters are differentially mediated by CB1, TRPV1 and non-CB1/TRPV1-mediated mechanisms
Carlo Alberto Maggi - One of the best experts on this subject based on the ideXlab platform.
-
antimuscarinic calcium channel blocker and tachykinin nk2 receptor antagonist actions of otilonium bromide in the circular muscle of guinea pig colon
Naunyn-schmiedebergs Archives of Pharmacology, 1999Co-Authors: Paolo Santicioli, Vladimir P Zagorodnyuk, Anna Rita Renzetti, Carlo Alberto MaggiAbstract:We have analyzed, by the sucrose gap method, the action of otilonium bromide, a quaternary ammonium derivative in use for the symptomatic therapy of irritable bowel syndrome, on the electrical and mechanical responses initiated by different stimuli in the circular muscle of the guinea-pig proximal colon. Otilonium bromide produced a concentration-dependent inhibition of membrane depolarization (IC50 4.1 µM), action Potentials (APs) and contraction (IC50 3.7 µM) produced by the muscarinic receptor agonist, methacholine. It also produced a concentration-dependent inhibition of APs and accompanying contraction (IC50 31 µM) produced by KCl (30 mM), and had a biphasic effect on the cholinergic Excitatory Junction Potential (e.j.p.) produced by single pulse electrical field stimulation: at low concentrations (0.1–0.3 µM) otilonium bromide enhanced the e.j.p. and, at higher concentrations (IC50 22 µM and 16 µM toward depolarization and contraction), produced a concentration-dependent inhibition. Otilonium bromide eliminated the APs superimposed on the depolarization induced by the tachykinin NK1 receptor agonist, [Sar9]substance P-sulphone and suppressed the corresponding contraction (IC50 43 µM) but had little effect on the sustained membrane depolarization induced by this agonist. On the other hand, otilonium bromide produced a similar inhibitory effect on both membrane depolarization and contraction (IC50 38 µM and 45 µM, respectively) induced by the tachykinin NK2 receptor agonist [βAla8]neurokinin A (4–10). When tested in the presence of nifedipine (1 µM), otilonium bromide had no effect on the membrane depolarization induced by [Sar9]substance P-sulphone but inhibited in a concentration-dependent manner the depolarization induced by [βAla8]neurokinin A (4–10) (IC50 41 µM). In contrast, the blocker of receptor-operated cation channels, SKF 96365, inhibited with similar potency the depolarization induced by both [Sar9]substance P-sulphone and [βAla8]neurokinin A (4–10) (IC50 60 µM and 54 µM, respectively). In radioligand binding experiments otilonium bromide produced a concentration-dependent inhibition of the binding of both an agonist ([125I]neurokinin A, K i 7.2 µM) and an antagonist ([3H]SR 48968, K i 2.2 µM) to membranes of Chinese hamster ovary cells transfected with the human tachykinin NK2 receptor. In conclusion, the present findings demonstrate that, in the µM range of concentrations, otilonium bromide acts as a muscarinic and tachykinin NK2 receptor antagonist and as a calcium channel blocker. The latter property is likely to account for its ability to suppress contraction initiated by the tachykinin NK1 receptor agonist. Therefore multiple mechanisms of action account for the ability of otilonium bromide to reduce stimulated motility of intestinal smooth muscle.
-
tachykinin nk1 and nk2 receptors mediate non adrenergic non cholinergic Excitatory neuromuscular transmission in the guinea pig stomach
Neuroscience, 1997Co-Authors: Vladimir P Zagorodnyuk, Carlo Alberto MaggiAbstract:Abstract By using selective tachykinin NK 1 and NK 2 receptor antagonists and agonists, we studied the Excitatory non-adrenergic non-cholinergic transmission to the circular muscle of the corpus of guinea-pig stomach by the sucrose-gap method. After elimination of inhibitory Junction Potentials by apamin (0.1 μM), l -nitroarginine (30 μM) and tetraethylammonium (10 mM), electrical field stimulation (10 Hz) in the presence of atropine (1 μM) and nifedipine (1 μM) evoked a pure Excitatory Junction Potential and contraction. The selective tachykinin NK 2 receptor antagonist, MEN 11420, concentration-dependently inhibited the non-adrenergic non-cholinergic Excitatory Junction Potential (EC 50 =0.09 μM) and contraction (EC 50 =0.04 μM) evoked by electrical field stimulation. On the other hand, the selective NK 1 receptor antagonist GR 82334 (3 μM) only slightly (by about 30%) inhibited the Excitatory Junction Potential while leaving the contraction unaffected. The combined administration of GR 82334 (1 μM) and MEN 11420 (0.3 μM) produced an additive inhibition of the Excitatory Junction Potential, significantly larger than that produced by each antagonist alone. In the presence of both GR 82334 (1 μM) and MEN 11420 (0.3 μM), the P 2 purinoreceptor antagonist pyridoxalphosphate-6-azophenyl-2′,4′-disulphonic acid (30 μM) remarkably inhibited the fast component of the Excitatory Junction Potential. In the presence of atropine (1 μM), indomethacin (3 μM) and guanethidine (3 μM) either the selective NK 2 receptor agonist, [ β Ala 8 ]neurokinin A (4–10) (0.01 μM), or the selective NK 1 receptor agonist, [Sar 9 ]substance P sulfone (0.3 μM), produced tetrodotoxin-(1 μM) and nifedipine-(1 μM) resistant depolarization and contraction. The [Sar 9 ]substance P sulfone (0.3 μM)-induced contraction, but not that induced by [ β Ala 8 ]neurokinin A (4–10) (0.01 μM), was potentiated by apamin (0.1 μM) plus l -nitroarginine (30 μM). In the presence of atropine (1 μM), indomethacin (3 μM), guanethidine (3 μM), apamin (0.1 μM) and l -nitroarginine (30 μM), the selective tachykinin NK 2 and NK 1 receptor agonists, [ β Ala 8 ]neurokinin A (4–10) and [Sar 9 ]substance P sulfone, both produced a concentration-dependent depolarization and contraction of the circular muscle. MEN 11420 inhibited the responses to [ β Ala 8 ]neurokinin A (4–10) without affecting the responses to [Sar 9 ]substance P sulfone, while GR 82334 inhibited the responses to [Sar 9 ]substance P sulfone but not that to [ β Ala 8 ]neurokinin A (4–10). These data provide evidence that tachykinin NK 2 receptors predominantly mediate the non-adrenergic non-cholinergic Excitatory transmission to the circular muscle of the corpus of guinea-pig stomach. In addition, after blocking the non-adrenergic non-cholinergic inhibitory Junction Potential by apamin, l -nitroarginine and tetraethylammonium, the fast component of the non-adrenergic non-cholinergic Excitatory Junction Potential could be mediated by adenosine triphosphate.
-
tachykinin nk1 and nk2 receptors mediate non adrenergic noncholinergic Excitatory neuromuscular transmission in the human ileum
Neuropeptides, 1997Co-Authors: Vladimir P Zagorodnyuk, P Santicioli, Damiano Turini, Carlo Alberto MaggiAbstract:Abstract Tachykinin NK 1 and NK 2 receptor selective antagonists and agonists were used to study Excitatory nonadrenergic non-cholinergic (NANC) transmission in circular muscle strips from human ileum by the sucrose-gap method. In the presence of atropine (1 μM), guanethidine (3 μM), indomethacin (3 μM), apamin (0.1 μM) and N ω -nitro-L-arginine (L-NOARG, 30 μM), electrical field simulation (EFS) produced a NANC inhibitory Junction Potential (i.j.p.) followed by NANC Excitatory Junction Potential (e.j.p.) with superimposed action Potentials and contraction of the circular muscle of human ileum. The selective tachykinin NK 1 receptor antagonist, GR 82334 (0.1–3 μM) produced a concentration-dependent inhibition of the EFS-evoked NANC e.j.p. (IC 50 = 0.21 μM) and contraction (IC 50 = 0.21 μM). The selective tachykinin NK 2 receptor antagonist, MEN 10627 (0.01–1 μM), likewise produced a concentration-dependent inhibition of the EFS-evoked NANC e.j.p. (IC 50 = 0.07 μM) and contraction (IC 50 = 0.03 μM). Either antagonist was more effective in inhibiting the mechanical than the electrical response to EFS. Neither GR 82334 nor MEN 10627 had any effect on the apamin- and L-NOARG-resistant NANC i.j.p. Activation of the NK 1 or NK 2 receptors by the selective receptor agonists, [Sar 9 ]substance P (SP) sulfone and [βAla 8 ]neurokinin A (NKA) (4–10), respectively (0.3 μM for 20 s each), produced depolarization with superimposed action Potentials and contractions. GR 82334 selectively inhibited the responses to [Sar 9 ]]SP sulfone, without affecting the responses to [βAla 8 ]NKA (4–10). MEN 10627 inhibited the responses to [βAla 8 ]NKA (4–10), without affecting the responses to [Sar 9 ]SP sulfone. We conclude that both tachykinin NK 1 and NK 2 receptors co-operate in producing NANC excitation and contraction of the circular muscle in human ileum.
-
the possible role of atp and pacap as mediators of apamin sensitive nanc inhibitory Junction Potentials in circular muscle of guinea pig colon
British Journal of Pharmacology, 1996Co-Authors: Vladimir P Zagorodnyuk, Carlo Alberto Maggi, Paolo Santicioli, Antonio GiachettiAbstract:Abstract 1. In the presence of atropine (1 microM), guanethidine (3 microM), indomethacin (3 microM), nifedipine (1 microM), L-nitroarginine (L-NOARG, 100 microM), and the selective tachykinin NK1 and NK2 receptor antagonists, SR 140,333 and GR 94,800, respectively (0.1 microM each), a single pulse of electrical field stimulation (EFS) produced a monophasic non-adrenergic non-cholinergic (NANC) inhibitory Junction Potential (i.j.p., about 10 mV in amplitude) in the circular muscle of guinea-pig proximal colon, recorded by the modified single sucrose gap technique. 2. The P2 purinoceptor agonist, alpha, beta methylene ATP (alpha, beta mATP, 100 microM) and the pituitary adenylyl cyclase activating peptide (PACAP, 1 microM) both produced hyperpolarization (11 +/- 0.8 mV, n = 14 and 10.2 +/- 0.8 mV, n = 19, respectively) and relaxation (1.1 +/- 0.2 mV, n = 14 and 1.5 +/- 0.2 mN, n = 19, respectively) of the circular muscle. 3. Apamin (0.1 microM) nearly abolished (about 90% inhibition) the NANC i.j.p. and the alpha, beta mATP-induced hyperpolarization, markedly reduced the alpha, beta mATP-induced relaxation (73% inhibition) and the PACAP-induced hyperpolarization (65% inhibition), while the PACAP-induced relaxation was unaffected. 4. Tetraethylammonium (TEA, 10 mM) increased the EFS-evoked i.j.p. and revealed an Excitatory Junction Potential (e.j.p.). In the presence of TEA, alpha, beta mATP induced a biphasic response: transient depolarization and contraction followed by hyperpolarization and relaxation. The hyperpolarization to PACAP was reduced by TEA (45% inhibition) but the relaxation was unaffected. 5. The combined application of apamin (0.1 microM) and TEA (10 mM) abolished the i.j.p. and single pulse EFS evoked a pure e.j.p. with latency three times longer than that of the i.j.p. In the majority of strips tested, alpha, beta mATP and PACAP elicited a biphasic response : depolarization and small contraction followed by hyperpolarization and relaxation. 6. The P2 purinoceptor antagonist, pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS) inhibited the NANC i.j.p. in concentration-dependent manner and inhibited the alpha, beta mATP-induced hyperpolarization and relaxation, without affecting the hyperpolarization and relaxation induced by PACAP. On the other hand, the P2 purinoceptor antagonist, suramin (100 microM) inhibited to a similar extent (60-80%) the NANC i.j.p. and the hyperpolarization and relaxation induced by alpha, beta mATP or PACAP. 7. PPADS and suramin reduced the NANC e.j.p. evoked by a single pulse EFS in the presence of apamin and TEA (100 microM of PPADS and 300 microM of suramin inhibited the e.j.p. by about 40%). 8. We conclude that ATP, but not PACAP, mediates the apamin-sensitive NANC i.j.p. in the circular muscle of the guinea-pig colon. After blockade of the NANC i.j.p., ATP may act as an Excitatory transmitter by activating Excitatory P2 purinoceptors. The subtypes of P2 purinoceptor involved in the inhibitory and Excitatory responses remain to be established. The data suggest that Excitatory P2 purinoceptors may be located extraJunctionally.
Vladimir P Zagorodnyuk - One of the best experts on this subject based on the ideXlab platform.
-
antimuscarinic calcium channel blocker and tachykinin nk2 receptor antagonist actions of otilonium bromide in the circular muscle of guinea pig colon
Naunyn-schmiedebergs Archives of Pharmacology, 1999Co-Authors: Paolo Santicioli, Vladimir P Zagorodnyuk, Anna Rita Renzetti, Carlo Alberto MaggiAbstract:We have analyzed, by the sucrose gap method, the action of otilonium bromide, a quaternary ammonium derivative in use for the symptomatic therapy of irritable bowel syndrome, on the electrical and mechanical responses initiated by different stimuli in the circular muscle of the guinea-pig proximal colon. Otilonium bromide produced a concentration-dependent inhibition of membrane depolarization (IC50 4.1 µM), action Potentials (APs) and contraction (IC50 3.7 µM) produced by the muscarinic receptor agonist, methacholine. It also produced a concentration-dependent inhibition of APs and accompanying contraction (IC50 31 µM) produced by KCl (30 mM), and had a biphasic effect on the cholinergic Excitatory Junction Potential (e.j.p.) produced by single pulse electrical field stimulation: at low concentrations (0.1–0.3 µM) otilonium bromide enhanced the e.j.p. and, at higher concentrations (IC50 22 µM and 16 µM toward depolarization and contraction), produced a concentration-dependent inhibition. Otilonium bromide eliminated the APs superimposed on the depolarization induced by the tachykinin NK1 receptor agonist, [Sar9]substance P-sulphone and suppressed the corresponding contraction (IC50 43 µM) but had little effect on the sustained membrane depolarization induced by this agonist. On the other hand, otilonium bromide produced a similar inhibitory effect on both membrane depolarization and contraction (IC50 38 µM and 45 µM, respectively) induced by the tachykinin NK2 receptor agonist [βAla8]neurokinin A (4–10). When tested in the presence of nifedipine (1 µM), otilonium bromide had no effect on the membrane depolarization induced by [Sar9]substance P-sulphone but inhibited in a concentration-dependent manner the depolarization induced by [βAla8]neurokinin A (4–10) (IC50 41 µM). In contrast, the blocker of receptor-operated cation channels, SKF 96365, inhibited with similar potency the depolarization induced by both [Sar9]substance P-sulphone and [βAla8]neurokinin A (4–10) (IC50 60 µM and 54 µM, respectively). In radioligand binding experiments otilonium bromide produced a concentration-dependent inhibition of the binding of both an agonist ([125I]neurokinin A, K i 7.2 µM) and an antagonist ([3H]SR 48968, K i 2.2 µM) to membranes of Chinese hamster ovary cells transfected with the human tachykinin NK2 receptor. In conclusion, the present findings demonstrate that, in the µM range of concentrations, otilonium bromide acts as a muscarinic and tachykinin NK2 receptor antagonist and as a calcium channel blocker. The latter property is likely to account for its ability to suppress contraction initiated by the tachykinin NK1 receptor agonist. Therefore multiple mechanisms of action account for the ability of otilonium bromide to reduce stimulated motility of intestinal smooth muscle.
-
tachykinin nk1 and nk2 receptors mediate non adrenergic non cholinergic Excitatory neuromuscular transmission in the guinea pig stomach
Neuroscience, 1997Co-Authors: Vladimir P Zagorodnyuk, Carlo Alberto MaggiAbstract:Abstract By using selective tachykinin NK 1 and NK 2 receptor antagonists and agonists, we studied the Excitatory non-adrenergic non-cholinergic transmission to the circular muscle of the corpus of guinea-pig stomach by the sucrose-gap method. After elimination of inhibitory Junction Potentials by apamin (0.1 μM), l -nitroarginine (30 μM) and tetraethylammonium (10 mM), electrical field stimulation (10 Hz) in the presence of atropine (1 μM) and nifedipine (1 μM) evoked a pure Excitatory Junction Potential and contraction. The selective tachykinin NK 2 receptor antagonist, MEN 11420, concentration-dependently inhibited the non-adrenergic non-cholinergic Excitatory Junction Potential (EC 50 =0.09 μM) and contraction (EC 50 =0.04 μM) evoked by electrical field stimulation. On the other hand, the selective NK 1 receptor antagonist GR 82334 (3 μM) only slightly (by about 30%) inhibited the Excitatory Junction Potential while leaving the contraction unaffected. The combined administration of GR 82334 (1 μM) and MEN 11420 (0.3 μM) produced an additive inhibition of the Excitatory Junction Potential, significantly larger than that produced by each antagonist alone. In the presence of both GR 82334 (1 μM) and MEN 11420 (0.3 μM), the P 2 purinoreceptor antagonist pyridoxalphosphate-6-azophenyl-2′,4′-disulphonic acid (30 μM) remarkably inhibited the fast component of the Excitatory Junction Potential. In the presence of atropine (1 μM), indomethacin (3 μM) and guanethidine (3 μM) either the selective NK 2 receptor agonist, [ β Ala 8 ]neurokinin A (4–10) (0.01 μM), or the selective NK 1 receptor agonist, [Sar 9 ]substance P sulfone (0.3 μM), produced tetrodotoxin-(1 μM) and nifedipine-(1 μM) resistant depolarization and contraction. The [Sar 9 ]substance P sulfone (0.3 μM)-induced contraction, but not that induced by [ β Ala 8 ]neurokinin A (4–10) (0.01 μM), was potentiated by apamin (0.1 μM) plus l -nitroarginine (30 μM). In the presence of atropine (1 μM), indomethacin (3 μM), guanethidine (3 μM), apamin (0.1 μM) and l -nitroarginine (30 μM), the selective tachykinin NK 2 and NK 1 receptor agonists, [ β Ala 8 ]neurokinin A (4–10) and [Sar 9 ]substance P sulfone, both produced a concentration-dependent depolarization and contraction of the circular muscle. MEN 11420 inhibited the responses to [ β Ala 8 ]neurokinin A (4–10) without affecting the responses to [Sar 9 ]substance P sulfone, while GR 82334 inhibited the responses to [Sar 9 ]substance P sulfone but not that to [ β Ala 8 ]neurokinin A (4–10). These data provide evidence that tachykinin NK 2 receptors predominantly mediate the non-adrenergic non-cholinergic Excitatory transmission to the circular muscle of the corpus of guinea-pig stomach. In addition, after blocking the non-adrenergic non-cholinergic inhibitory Junction Potential by apamin, l -nitroarginine and tetraethylammonium, the fast component of the non-adrenergic non-cholinergic Excitatory Junction Potential could be mediated by adenosine triphosphate.
-
tachykinin nk1 and nk2 receptors mediate non adrenergic noncholinergic Excitatory neuromuscular transmission in the human ileum
Neuropeptides, 1997Co-Authors: Vladimir P Zagorodnyuk, P Santicioli, Damiano Turini, Carlo Alberto MaggiAbstract:Abstract Tachykinin NK 1 and NK 2 receptor selective antagonists and agonists were used to study Excitatory nonadrenergic non-cholinergic (NANC) transmission in circular muscle strips from human ileum by the sucrose-gap method. In the presence of atropine (1 μM), guanethidine (3 μM), indomethacin (3 μM), apamin (0.1 μM) and N ω -nitro-L-arginine (L-NOARG, 30 μM), electrical field simulation (EFS) produced a NANC inhibitory Junction Potential (i.j.p.) followed by NANC Excitatory Junction Potential (e.j.p.) with superimposed action Potentials and contraction of the circular muscle of human ileum. The selective tachykinin NK 1 receptor antagonist, GR 82334 (0.1–3 μM) produced a concentration-dependent inhibition of the EFS-evoked NANC e.j.p. (IC 50 = 0.21 μM) and contraction (IC 50 = 0.21 μM). The selective tachykinin NK 2 receptor antagonist, MEN 10627 (0.01–1 μM), likewise produced a concentration-dependent inhibition of the EFS-evoked NANC e.j.p. (IC 50 = 0.07 μM) and contraction (IC 50 = 0.03 μM). Either antagonist was more effective in inhibiting the mechanical than the electrical response to EFS. Neither GR 82334 nor MEN 10627 had any effect on the apamin- and L-NOARG-resistant NANC i.j.p. Activation of the NK 1 or NK 2 receptors by the selective receptor agonists, [Sar 9 ]substance P (SP) sulfone and [βAla 8 ]neurokinin A (NKA) (4–10), respectively (0.3 μM for 20 s each), produced depolarization with superimposed action Potentials and contractions. GR 82334 selectively inhibited the responses to [Sar 9 ]]SP sulfone, without affecting the responses to [βAla 8 ]NKA (4–10). MEN 10627 inhibited the responses to [βAla 8 ]NKA (4–10), without affecting the responses to [Sar 9 ]SP sulfone. We conclude that both tachykinin NK 1 and NK 2 receptors co-operate in producing NANC excitation and contraction of the circular muscle in human ileum.
-
the possible role of atp and pacap as mediators of apamin sensitive nanc inhibitory Junction Potentials in circular muscle of guinea pig colon
British Journal of Pharmacology, 1996Co-Authors: Vladimir P Zagorodnyuk, Carlo Alberto Maggi, Paolo Santicioli, Antonio GiachettiAbstract:Abstract 1. In the presence of atropine (1 microM), guanethidine (3 microM), indomethacin (3 microM), nifedipine (1 microM), L-nitroarginine (L-NOARG, 100 microM), and the selective tachykinin NK1 and NK2 receptor antagonists, SR 140,333 and GR 94,800, respectively (0.1 microM each), a single pulse of electrical field stimulation (EFS) produced a monophasic non-adrenergic non-cholinergic (NANC) inhibitory Junction Potential (i.j.p., about 10 mV in amplitude) in the circular muscle of guinea-pig proximal colon, recorded by the modified single sucrose gap technique. 2. The P2 purinoceptor agonist, alpha, beta methylene ATP (alpha, beta mATP, 100 microM) and the pituitary adenylyl cyclase activating peptide (PACAP, 1 microM) both produced hyperpolarization (11 +/- 0.8 mV, n = 14 and 10.2 +/- 0.8 mV, n = 19, respectively) and relaxation (1.1 +/- 0.2 mV, n = 14 and 1.5 +/- 0.2 mN, n = 19, respectively) of the circular muscle. 3. Apamin (0.1 microM) nearly abolished (about 90% inhibition) the NANC i.j.p. and the alpha, beta mATP-induced hyperpolarization, markedly reduced the alpha, beta mATP-induced relaxation (73% inhibition) and the PACAP-induced hyperpolarization (65% inhibition), while the PACAP-induced relaxation was unaffected. 4. Tetraethylammonium (TEA, 10 mM) increased the EFS-evoked i.j.p. and revealed an Excitatory Junction Potential (e.j.p.). In the presence of TEA, alpha, beta mATP induced a biphasic response: transient depolarization and contraction followed by hyperpolarization and relaxation. The hyperpolarization to PACAP was reduced by TEA (45% inhibition) but the relaxation was unaffected. 5. The combined application of apamin (0.1 microM) and TEA (10 mM) abolished the i.j.p. and single pulse EFS evoked a pure e.j.p. with latency three times longer than that of the i.j.p. In the majority of strips tested, alpha, beta mATP and PACAP elicited a biphasic response : depolarization and small contraction followed by hyperpolarization and relaxation. 6. The P2 purinoceptor antagonist, pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS) inhibited the NANC i.j.p. in concentration-dependent manner and inhibited the alpha, beta mATP-induced hyperpolarization and relaxation, without affecting the hyperpolarization and relaxation induced by PACAP. On the other hand, the P2 purinoceptor antagonist, suramin (100 microM) inhibited to a similar extent (60-80%) the NANC i.j.p. and the hyperpolarization and relaxation induced by alpha, beta mATP or PACAP. 7. PPADS and suramin reduced the NANC e.j.p. evoked by a single pulse EFS in the presence of apamin and TEA (100 microM of PPADS and 300 microM of suramin inhibited the e.j.p. by about 40%). 8. We conclude that ATP, but not PACAP, mediates the apamin-sensitive NANC i.j.p. in the circular muscle of the guinea-pig colon. After blockade of the NANC i.j.p., ATP may act as an Excitatory transmitter by activating Excitatory P2 purinoceptors. The subtypes of P2 purinoceptor involved in the inhibitory and Excitatory responses remain to be established. The data suggest that Excitatory P2 purinoceptors may be located extraJunctionally.
Mohammad Bashashati - One of the best experts on this subject based on the ideXlab platform.
-
targeting fatty acid amide hydrolase and transient receptor Potential vanilloid 1 simultaneously to modulate colonic motility and visceral sensation in the mouse a pharmacological intervention with n arachidonoyl serotonin aa 5 ht
Neurogastroenterology and Motility, 2017Co-Authors: Mohammad Bashashati, Jakub Fichna, Fabiana Piscitelli, Raffaele Capasso, Angelo A Izzo, A Sibaev, J P Timmermans, Nicolas CenacAbstract:BackgroundEndocannabinoid anandamide (AEA) inhibits intestinal motility and visceral pain, but it may also be proalgesic through transient receptor Potential vanilloid-1 (TRPV1). AEA is degraded by fatty acid amide hydrolase (FAAH). This study explored whether dual inhibition of FAAH and TRPV1 reduces diarrhea and abdominal pain. MethodsImmunostaining was performed on myenteric plexus of the mouse colon. The effects of the dual FAAH/TRPV1 inhibitor AA-5-HT on electrically induced contractility, Excitatory Junction Potential (EJP) and fast (f) and slow (s) inhibitory Junction Potentials (IJP) in the mouse colon, colonic propulsion and visceromotor response (VMR) to rectal distension were studied. The colonic levels of endocannabinoids and fatty acid amides were measured. Key ResultsCB1-positive neurons exhibited TRPV1;only some TRPV1 positive neurons did not express CB1. CB1 and FAAH did not colocalize. AA-5-HT (100nM-10M) decreased colonic contractility by similar to 60%;this effect was abolished by TRPV1 antagonist 5-IRTX, but not by CB1 antagonist, SR141716. AA-5-HT (1M-10M) inhibited EJP by similar to 30% and IJPs by similar to 50%. The effects of AA-5-HT on Junction Potentials were reversed by SR141716 and 5`-IRTX. AA-5-HT (20mg/kg;i.p.) inhibited colonic propulsion by similar to 30%;SR141716 but not 5`-IRTX reversed this effect. AA-5-HT decreased VMR by similar to 50%-60%;these effects were not blocked by SR141716 or 5`-IRTX. AA-5-HT increased AEA in the colon. Conclusions and InferencesThe effects of AA-5-HT on visceral sensation and colonic motility are differentially mediated by CB1, TRPV1 and non-CB1/TRPV1 mechanisms, possibly reflecting the distinct neuromodulatory roles of endocannabinoid and endovanilloid FAAH substrates in the mouse intestine.
-
Regulation of the Enteric Neuromotor and Sensory Functions in the Mouse With N-Arachidonoyl-Serotonin (AA-5-HT), a Dual Fatty Acid Amide Hydrolase (FAAH) Inhibitor and TRPV1 Antagonist
'Elsevier BV', 2016Co-Authors: Mohammad Bashashati, Jakub Fichna, Fabiana Piscitelli, Raffaele Capasso, Angelo A Izzo, A Sibaev, J P Timmermans, Nicolas Cenac, Nathalie Vergnolle, Vincenzo Di MarzoAbstract:Background: Endocannabinoid N-arachidonoylethanolamine (AEA, anandamide) is a double- edged sword: it inhibits intestinal motility and visceral pain through its neuroinhibitory effects, but may also have proalgesic or proinflammatory effects by activating transient receptor Potential vanilloid-1 (TRPV1). AEA levels may be increased by inhibition of fatty acid amide hydrolase (FAAH). We hypothesize that N-arachidonoyl-serotonin (AA-5-HT), as a dual FAAH inhibitor and TRPV1 antagonist, enhances the beneficial effects of AEA by: (1) increasing its endogenous levels and (2) blocking TRPV1. Dual FAAH and TRPV1 blockade may be a Potential treatment for GI hypermotility and visceral hyperalgesia. Methods: Male CD1 mice were used in this study. Whole-mount preparations of the colonic myenteric plexus were immunostained for cannabinoid-1 (CB1) receptor, TRPV1 and FAAH. The effects of AA-5-HT on the following parameters were studied: (1) colonic contractility induced by electrical field stimulation (EFS; 4 Hz); in vitro, (2) Excitatory Junction Potential (EJP) and fast (f) and slow (s) inhibitory Junction Potential (IJP); in vitro, (3) colonic expulsion of a bead; in vivo, (4) visceral hyperalgesia to distensive stimuli and visceromotor response (VMR) induced by intra-colonic administration of the protease-activated receptor-2 activating peptide SLIGRL (20μg/mouse); in vivo and (5) colonic levels of AEA, 2-AG, palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), measured by mass spectrometry. Results: CB1-immunoreactive enteric neurons exhibited TRPV1 immunoreactivity. Only some TRPV1-positive neurons also expressed CB1 receptors, which were not co-localized with FAAH. AA-5-HT (100nM- 10μM) decreased EFS induced colonic longitudinal muscle contractility by ~60% at the highest concentration. These effects were abolished by the TRPV1 antagonist, 5` -IRTX (75nM), but not by the CB1 antagonist, SR141716 (100nM). Electrical stimulation of the enteric neurons induced EJP followed by fIJP and sIJP. AA-5-HT inhibited EJP at 1μM by ~30% and fIJP and sIJP at 10μM by ~50%. Both SR141716 (1μM) and 5` - IRTX (1μM) reversed the effects of AA-5-HT on the Junction Potentials. AA-5-HT (20mg/ kg i.p.) inhibited colonic propulsion by ~30 %. This effect was blocked by SR141716 (1mg/ kg), but not by 5` -IRTX (0.75mg/kg). AA-5-HT (20mg/kg) decreased VMR by ~50-60% at distention levels of 30-60mmHg. This effect was not sensitive to SR141716 or5` -IRTX. AA- 5-HT (20mg/kg) significantly increased colonic AEA, but not 2-AG, PEA or OEA levels. Conclusion: Dual inhibition of FAAH and TRPV1 channels has neuromodulatory effects in the mouse intestine. The effects of AA-5-HT on visceral sensation and intestinal motility parameters are differentially mediated by CB1, TRPV1 and non-CB1/TRPV1-mediated mechanisms
Fabiana Piscitelli - One of the best experts on this subject based on the ideXlab platform.
-
targeting fatty acid amide hydrolase and transient receptor Potential vanilloid 1 simultaneously to modulate colonic motility and visceral sensation in the mouse a pharmacological intervention with n arachidonoyl serotonin aa 5 ht
Neurogastroenterology and Motility, 2017Co-Authors: Mohammad Bashashati, Jakub Fichna, Fabiana Piscitelli, Raffaele Capasso, Angelo A Izzo, A Sibaev, J P Timmermans, Nicolas CenacAbstract:BackgroundEndocannabinoid anandamide (AEA) inhibits intestinal motility and visceral pain, but it may also be proalgesic through transient receptor Potential vanilloid-1 (TRPV1). AEA is degraded by fatty acid amide hydrolase (FAAH). This study explored whether dual inhibition of FAAH and TRPV1 reduces diarrhea and abdominal pain. MethodsImmunostaining was performed on myenteric plexus of the mouse colon. The effects of the dual FAAH/TRPV1 inhibitor AA-5-HT on electrically induced contractility, Excitatory Junction Potential (EJP) and fast (f) and slow (s) inhibitory Junction Potentials (IJP) in the mouse colon, colonic propulsion and visceromotor response (VMR) to rectal distension were studied. The colonic levels of endocannabinoids and fatty acid amides were measured. Key ResultsCB1-positive neurons exhibited TRPV1;only some TRPV1 positive neurons did not express CB1. CB1 and FAAH did not colocalize. AA-5-HT (100nM-10M) decreased colonic contractility by similar to 60%;this effect was abolished by TRPV1 antagonist 5-IRTX, but not by CB1 antagonist, SR141716. AA-5-HT (1M-10M) inhibited EJP by similar to 30% and IJPs by similar to 50%. The effects of AA-5-HT on Junction Potentials were reversed by SR141716 and 5`-IRTX. AA-5-HT (20mg/kg;i.p.) inhibited colonic propulsion by similar to 30%;SR141716 but not 5`-IRTX reversed this effect. AA-5-HT decreased VMR by similar to 50%-60%;these effects were not blocked by SR141716 or 5`-IRTX. AA-5-HT increased AEA in the colon. Conclusions and InferencesThe effects of AA-5-HT on visceral sensation and colonic motility are differentially mediated by CB1, TRPV1 and non-CB1/TRPV1 mechanisms, possibly reflecting the distinct neuromodulatory roles of endocannabinoid and endovanilloid FAAH substrates in the mouse intestine.
-
Regulation of the Enteric Neuromotor and Sensory Functions in the Mouse With N-Arachidonoyl-Serotonin (AA-5-HT), a Dual Fatty Acid Amide Hydrolase (FAAH) Inhibitor and TRPV1 Antagonist
'Elsevier BV', 2016Co-Authors: Mohammad Bashashati, Jakub Fichna, Fabiana Piscitelli, Raffaele Capasso, Angelo A Izzo, A Sibaev, J P Timmermans, Nicolas Cenac, Nathalie Vergnolle, Vincenzo Di MarzoAbstract:Background: Endocannabinoid N-arachidonoylethanolamine (AEA, anandamide) is a double- edged sword: it inhibits intestinal motility and visceral pain through its neuroinhibitory effects, but may also have proalgesic or proinflammatory effects by activating transient receptor Potential vanilloid-1 (TRPV1). AEA levels may be increased by inhibition of fatty acid amide hydrolase (FAAH). We hypothesize that N-arachidonoyl-serotonin (AA-5-HT), as a dual FAAH inhibitor and TRPV1 antagonist, enhances the beneficial effects of AEA by: (1) increasing its endogenous levels and (2) blocking TRPV1. Dual FAAH and TRPV1 blockade may be a Potential treatment for GI hypermotility and visceral hyperalgesia. Methods: Male CD1 mice were used in this study. Whole-mount preparations of the colonic myenteric plexus were immunostained for cannabinoid-1 (CB1) receptor, TRPV1 and FAAH. The effects of AA-5-HT on the following parameters were studied: (1) colonic contractility induced by electrical field stimulation (EFS; 4 Hz); in vitro, (2) Excitatory Junction Potential (EJP) and fast (f) and slow (s) inhibitory Junction Potential (IJP); in vitro, (3) colonic expulsion of a bead; in vivo, (4) visceral hyperalgesia to distensive stimuli and visceromotor response (VMR) induced by intra-colonic administration of the protease-activated receptor-2 activating peptide SLIGRL (20μg/mouse); in vivo and (5) colonic levels of AEA, 2-AG, palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), measured by mass spectrometry. Results: CB1-immunoreactive enteric neurons exhibited TRPV1 immunoreactivity. Only some TRPV1-positive neurons also expressed CB1 receptors, which were not co-localized with FAAH. AA-5-HT (100nM- 10μM) decreased EFS induced colonic longitudinal muscle contractility by ~60% at the highest concentration. These effects were abolished by the TRPV1 antagonist, 5` -IRTX (75nM), but not by the CB1 antagonist, SR141716 (100nM). Electrical stimulation of the enteric neurons induced EJP followed by fIJP and sIJP. AA-5-HT inhibited EJP at 1μM by ~30% and fIJP and sIJP at 10μM by ~50%. Both SR141716 (1μM) and 5` - IRTX (1μM) reversed the effects of AA-5-HT on the Junction Potentials. AA-5-HT (20mg/ kg i.p.) inhibited colonic propulsion by ~30 %. This effect was blocked by SR141716 (1mg/ kg), but not by 5` -IRTX (0.75mg/kg). AA-5-HT (20mg/kg) decreased VMR by ~50-60% at distention levels of 30-60mmHg. This effect was not sensitive to SR141716 or5` -IRTX. AA- 5-HT (20mg/kg) significantly increased colonic AEA, but not 2-AG, PEA or OEA levels. Conclusion: Dual inhibition of FAAH and TRPV1 channels has neuromodulatory effects in the mouse intestine. The effects of AA-5-HT on visceral sensation and intestinal motility parameters are differentially mediated by CB1, TRPV1 and non-CB1/TRPV1-mediated mechanisms
