Peristalsis is impaired in the small intestine of mice lacking the P2X3 subunit

Bian, Xiaochun; Ren, Jianhua; Vries, Matt De; Schnegelsberg, Birthe; Cockayne, Debra A.; Ford, Anthony; Galligan, James J.

doi:10.1111/j.1469-7793.2003.00309.x

Cited by 19 publications

(30 citation statements)

References 38 publications

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“…Although immunohistochemistry failed to show P2X1 receptor reactivity in the myenteric plexus of the mouse ileum (Vial and Evans, 2001; Giaroni et al. , 2002), there is functional evidence for the presence of pre‐synaptic P2X1 receptors in the mouse enteric nervous system (Vial and Evans, 2001) and P2X3 receptors regulate intestinal peristalsis in the mouse (Bian et al. , 2003).…”

Section: Discussionmentioning

confidence: 99%

Interaction between cannabinoid CB₁ receptors and endogenous ATP in the control of spontaneous mechanical activity in mouse ileum

Baldassano

Zizzo

Serio

et al. 2009

British J Pharmacology

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Background and purpose:Although it is well accepted that cannabinoids modulate intestinal motility by reducing cholinergic neurotransmission mediated by CB1 receptors, it is not known whether the endocannabinoids are involved in more complex circuits and if they interact with other systems. The aim of the present study was to examine possible interactions between cannabinoid CB1 receptors and purines in the control of spontaneous contractility of longitudinal muscle in mouse ileum. Experimental approach: The mechanical activity of longitudinally oriented ileal segments from mice was recorded as isometric contractions. Key results: The selective CB1 receptor agonist, N-(2-chloroethyl)5,8,11,14-eicosaetraenamide (ACEA) reduced, concentration dependently, spontaneous contractions in mouse ileum. This effect was almost abolished by tetrodotoxin (TTX) or atropine. Inhibition by ACEA was not affected by theophylline (P1 receptor antagonist) or by P2Y receptor desensitization with adenosine 5′[b-thio]diphosphate trilithium salt, but was significantly reversed by pyridoxal phosphate-6-azo(benzene-2,4-disulphonic acid) (P2 receptor antagonist), by P2X receptor desensitization with a,b-methyleneadenosine 5′-triphosphate lithium salt (a,b-MeATP) or by 8,8′-[carbonylbis(imino-4,1-phenylenecarbonylimino-4,1-phenylenecarbonylimino) bis(1,3,5-naphthalenetrisulphonic acid)] (P2X receptor antagonist). Contractile responses to a,b-MeATP (P2X receptor agonist) were virtually abolished by TTX or atropine, suggesting that they were mediated by acetylcholine released from neurones, and significantly reduced by ACEA. Conclusion and implications:In mouse ileum, activation of CB1 receptors, apart from reducing acetylcholine release from cholinergic nerves, was able to modulate negatively, endogenous purinergic effects, mediated by P2X receptors, on cholinergic neurons. Our study provides evidence for a role of cannabinoids in the modulation of interneuronal purinergic transmission.

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Section: Discussionmentioning

confidence: 99%

Interaction between cannabinoid CB₁ receptors and endogenous ATP in the control of spontaneous mechanical activity in mouse ileum

Baldassano

Zizzo

Serio

et al. 2009

British J Pharmacology

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“…Reduction of P2X3 receptor expression through intrathecal administration of P2X3‐selective antisense or siRNA also causes a significant decrease in behavioural signs of chronic inflammatory and neuropathic pain in mice (Barclay et al ., 2002; Honore et al ., 2002a; Dorn et al ., 2004). The role of the P2X3 protein in the function of visceral organs, such as the urinary bladder and small intestine, is suggested by the sensory deficits observed in P2X3 receptor‐KO mice, that included urinary and intestinal hyporeflexia (Cockayne et al ., 2000; Bian et al ., 2003; Ren et al ., 2003). Thus, it appears that P2X3 protein subunits are involved in sensitization of many types of somatic and visceral afferent circuits.…”

Section: Introductionmentioning

confidence: 99%

AF‐353, a novel, potent and orally bioavailable P2X3/P2X2/3 receptor antagonist

Gever

Soto

Henningsen

et al. 2010

British J Pharmacology

113

109

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Background and purpose: Purinoceptors containing the P2X3 subunit (P2X3 homotrimeric and P2X2/3 heterotrimeric) are members of the P2X family of ion channels gated by ATP and may participate in primary afferent sensitization in a variety of pain-related diseases. The current work describes the in vitro pharmacological characteristics of AF-353, a novel, orally bioavailable, highly potent and selective P2X3/P2X2/3 receptor antagonist. Experimental approach: The antagonistic potencies (pIC50) of AF-353 for rat and human P2X3 and human P2X2/3 receptors were determined using methods of radioligand binding, intracellular calcium flux and whole cell voltage-clamp electrophysiology. Key results: The pIC50 estimates for these receptors ranged from 7.3 to 8.5, while concentrations 300-fold higher had little or no effect on other P2X channels or on an assortment of receptors, enzymes and transporter proteins. In contrast to A-317491 and TNP-ATP, competition binding and intracellular calcium flux experiments suggested that AF-353 inhibits activation by ATP in a non-competitive fashion. Favourable pharmacokinetic parameters were observed in rat, with good oral bioavailability (%F = 32.9), reasonable half-life (t1/2 = 1.63 h) and plasma-free fraction (98.2% protein bound). Conclusions and implications:The combination of a favourable pharmacokinetic profile with the antagonist potency and selectivity for P2X3 and P2X2/3 receptors suggests that AF-353 is an excellent in vivo tool compound for study of these channels in animal models and demonstrates the feasibility of identifying and optimizing molecules into potential clinical candidates, and, ultimately, into a novel class of therapeutics for the treatment of pain-related disorders.

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“…Moreover, P2X 3 ‐deficient mice have reduced urinary bladder reflexes (Cockayne et al 2000). Within the gastrointestinal tract, ATP and α,β‐meATP excite extrinsic (Kirkup et al 1999; Wynn et al 2003) and intrinsic (Burnstock, 2001; Bertrand & Bornstein, 2002; Bian et al 2003) afferents, and P2X 3 ‐deficient mice have impaired peristalsis (Bian et al 2003).…”

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confidence: 99%

P2X₂ knockout mice and P2X₂/P2X₃ double knockout mice reveal a role for the P2X₂ receptor subunit in mediating multiple sensory effects of ATP

Cockayne

Dunn

Zhong

et al. 2005

The Journal of Physiology

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345

314

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Extracellular ATP plays a role in nociceptive signalling and sensory regulation of visceral function through ionotropic receptors variably composed of P2X 2 and P2X 3 subunits. P2X 2 and P2X 3 subunits can form homomultimeric P2X 2 , homomultimeric P2X 3 , or heteromultimeric P2X 2/3 receptors. However, the relative contribution of these receptor subtypes to afferent functions of ATP in vivo is poorly understood. Here we describe null mutant mice lacking the P2X 2 receptor subunit (P2X 2 −/− ) and double mutant mice lacking both P2X 2 and P2X 3 subunits (P2X 2 /P2X 3 Dbl−/− ), and compare these with previously characterized P2X 3 −/− mice. In patch-clamp studies, nodose, coeliac and superior cervical ganglia (SCG) neurones from wild-type mice responded to ATP with sustained inward currents, while dorsal root ganglia (DRG) neurones gave predominantly transient currents. Sensory neurones from P2X 2 −/− mice responded to ATP with only transient inward currents, while sympathetic neurones had barely detectable responses. Neurones from P2X 2 /P2X 3 Dbl−/− mice had minimal to no response to ATP. These data indicate that P2X receptors on sensory and sympathetic ganglion neurones involve almost exclusively P2X 2 and P2X 3 subunits. P2X 2 −/− and P2X 2 /P2X 3 Dbl−/− mice had reduced pain-related behaviours in response to intraplantar injection of formalin. Significantly, P2X 3 −/− , P2X 2 −/− , and P2X 2 /P2X 3 Dbl−/− mice had reduced urinary bladder reflexes and decreased pelvic afferent nerve activity in response to bladder distension. No deficits in a wide variety of CNS behavioural tests were observed in P2X 2 −/− mice. Taken together, these data extend our findings for P2X 3 −/− mice, and reveal an important contribution of heteromeric P2X 2/3 receptors to nociceptive responses and mechanosensory transduction within the urinary bladder.

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Peristalsis is impaired in the small intestine of mice lacking the P2X3 subunit

Cited by 19 publications

References 38 publications

Interaction between cannabinoid CB₁ receptors and endogenous ATP in the control of spontaneous mechanical activity in mouse ileum

Interaction between cannabinoid CB₁ receptors and endogenous ATP in the control of spontaneous mechanical activity in mouse ileum

AF‐353, a novel, potent and orally bioavailable P2X3/P2X2/3 receptor antagonist

P2X₂ knockout mice and P2X₂/P2X₃ double knockout mice reveal a role for the P2X₂ receptor subunit in mediating multiple sensory effects of ATP

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Peristalsis is impaired in the small intestine of mice lacking the P2X3 subunit

Cited by 19 publications

References 38 publications

Interaction between cannabinoid CB1 receptors and endogenous ATP in the control of spontaneous mechanical activity in mouse ileum

Interaction between cannabinoid CB1 receptors and endogenous ATP in the control of spontaneous mechanical activity in mouse ileum

AF‐353, a novel, potent and orally bioavailable P2X3/P2X2/3 receptor antagonist

P2X2 knockout mice and P2X2/P2X3 double knockout mice reveal a role for the P2X2 receptor subunit in mediating multiple sensory effects of ATP

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Product

Resources

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Interaction between cannabinoid CB₁ receptors and endogenous ATP in the control of spontaneous mechanical activity in mouse ileum

Interaction between cannabinoid CB₁ receptors and endogenous ATP in the control of spontaneous mechanical activity in mouse ileum

P2X₂ knockout mice and P2X₂/P2X₃ double knockout mice reveal a role for the P2X₂ receptor subunit in mediating multiple sensory effects of ATP