AbstractKisspeptin neurons located in the arcuate nucleus (ARN) coexpress dynorphin and neurokinin B (NKB) and may interact to influence gonadotropin secretion. Using a kisspeptin-green fluorescent protein mouse model, the present study examined whether the neuropeptides kisspeptin, dynorphin, and NKB modulate the electrical activity of ARN kisspeptin neurons in the adult male mouse. Cell-attached recordings showed that kisspeptin itself had no effect on kisspeptin neuron firing. Dynorphin and the κ-opioid receptor agonist U50-488 evoked a potent suppression of all ARN kisspeptin neuron firing that was blocked completely by the κ-opioid receptor antagonist nor-Binaltorphimine. Both NKB and Senktide, a neurokinin 3 receptor agonist, exerted a potent stimulatory action on ∼95% of ARN kisspeptin neurons. Although the selective neurokinin 3 receptor antagonists SB222200 and SR142801 blocked the effects of Senktide on kisspeptin neurons, they surprisingly had no effect on NKB activation of firing. Studies with selective neurokinin 1 receptor (SDZ-NKT343) and neurokinin 2 receptor (GR94800) antagonists revealed that the activation of kisspeptin neurons by NKB was only blocked completely by a cocktail of antagonists against all 3 tachykinin receptors. Whole-cell recordings revealed that individual kisspeptin neurons were activated directly by all 3 tachykinins substance, P, neurokinin A, and NKB. These experiments show that dynorphin and NKB have opposing actions on the electrical activity of kisspeptin neurons supporting the existence of an interconnected network of kisspeptin neurons in the ARN. However, the effects of NKB result from an unexpected activation of multiple tachykinin receptors.

01 Aug 2012·Neurogastroenterology & MotilityQ3 · MEDICINE

Origin and modulation of circular smooth muscle layer contractions in the porcine esophagus

Q3 · MEDICINE

Article

Author: Ricard Farre ; P Clavé ; D Gallego ; B Lecea

AbstractBackground The origin and modulation mechanisms controlling timing and amplitude of esophageal body peristalsis are not fully understood. We aimed to characterize the neurotransmitters involved in the origin and modulation of circular smooth muscle esophageal body (EB) contractions.Methods Responses of porcine EB strips to electrical stimulation of motor neurons (MNs) were assessed in organ baths and with microelectrodes. The effect of antagonists of inhibitory (L‐NAME 1 mmol L−1, MRS2179 10 μmol L−1) and excitatory neurotransmitters (atropine 1 μmol L−1; SR140333 1 μmol L−1‐NK1ra‐, GR94800 1 μmol L−1‐NK2ra‐) and of ganglionic neurotransmitters (hexamethonium 100 μmol L−1, ondansetron 1 μmol L−1, NF279 10 μmol L−1) were characterized.Key Results Electrical field stimulation (EFS) induced a frequency‐dependent off‐contraction (16.8 ± 0.8 g) following a latency period. Latency was significantly reduced by L‐NAME (−66.1 ± 4.1%) and MRS2179 (−25.9 ± 5.6%), and strongly increased by atropine (+36.8 ± 5.8%). Amplitude was reduced by L‐NAME (−69.9 ± 10.4%), MRS2179 (−34.1 ± 6.0%), atropine (−42.3 ± 4.7%), hexamethonium (−18.9 ± 3.3%), NF279 (−20.7 ± 3.5%), ondansetron (−16.3 ± 3.2%), GR94800 (−28.0 ± 4.8%) SR140333 (−20.9 ± 7.1%), and α‐chymotrypsin (−31.3 ± 7.0%). The EFS induced a monophasic nitrergic inhibitory junction potential.Conclusions & Inferences Our results suggest that timing (latency) and amplitude of esophageal contractions are determined by a balance of complex interactions between excitatory and inhibitory MNs. Latency depends on the activation of inhibitory MNs releasing NO and a minor purinergic contribution through P2Y1 receptors, and excitatory MNs releasing ACh. Amplitude depends on a major contribution of excitatory MNs releasing ACh and tachykinins, and also on inhibitory MNs releasing NO, ATP or related purines, and peptidergic neurotransmitters acting as strong modulators of the excitatory neuroeffector transmission.

01 Apr 2011·Acta Pharmacologica SinicaQ1 · MEDICINE

Contractile effect of tachykinins on rabbit small intestine

Q1 · MEDICINE

Article

Author: Miguel Ángel Plaza ; Laura Grasa ; Marta Sofía Valero ; Diego Santos Fagundes ; María Divina Murillo ; María Pilar Arruebo

AIMTo study the role of the tachykinin receptors in spontaneous contractions of longitudinal and circular smooth muscle from rabbit small intestine and to determine the mechanism of action of Substance P (SP).METHODSRabbit duodenum, jejunum and ileum segments were prepared. The spontaneous contractions of longitudinal and circular smooth muscle were recorded using a computer via an isometric force transducer. The specific agonists and antagonists of tachykinin receptors were added into the organ bath.RESULTSThe agonists of tachykinin NK1 receptor (SP and [Sar9] SP), NK2 receptor (NKA and (β-Ala8)-NKA), and NK3 receptor (NKB and Senktide) all induced contractions in the small intestine. The contractions were diminished by NK1 receptor antagonist L-733,060, NK2 receptor antagonist GR-94800, and NK3 receptor antagonist SB 218795. Contractions caused by SP were also reduced by atropine, verapamil, PKC inhibitor staurosporine, and PLC inhibitor U73122.CONCLUSIONTtachykinin NK1, NK2, and NK3 receptors mediate the contractions of the smooth muscle in rabbit intestine. Furthermore, SP acts directly on smooth muscle cells through the tachykinin NK1 receptor.

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Indication	Highest Phase	Country/Location	Organization	Date
Gastrointestinal motility disorder	Discovery	GB	Glaxo Group Ltd.	-

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