Endogenous neuropeptide Y depresses the afferent signaling of gastric acid challenge to the mouse brainstem via neuropeptide Y type Y2 and Y4 receptors.
Vagal afferents signal gastric acid challenge to the nucleus tractus solitarii of the rat brainstem. This study investigated whether nucleus tractus solitarii neurons in the mouse also respond to gastric acid challenge and whether this chemonociceptive input is modified by neuropeptide Y acting via neuropeptide Y receptors of type Y2 or Y4. The gastric mucosa of female mice was exposed to different concentrations of HCl or saline, excitation of neurons in the nucleus tractus solitarii visualized by c-Fos immunohistochemistry, gastric emptying deduced from the gastric volume recovery, and gastric lesion formation evaluated by planimetry. Relative to saline, intragastric HCl (0.15-0.35 M) increased the number of c-Fos-expressing cells in the nucleus tractus solitarii in a concentration-dependent manner, inhibited gastric emptying but failed to cause significant hemorrhagic injury in the stomach. Mice in which the Y2 or Y4 receptor gene had been deleted responded to gastric acid challenge with a significantly higher expression of c-Fos in the nucleus tractus solitarii, the increases amounting to 39 and 31%, respectively. The HCl-induced inhibition of gastric emptying was not altered by deletion of the Y2 or Y4 receptor gene. BIIE0246 ((S)-N2-[[1-[2-[4-[(R,S)-5,11-dihydro-6(6H)-oxodibenz[b,e] azepin-11-yl]-1-piperazinyl]-2-oxoethyl]cyclopentyl] acetyl]-N-[2-[1,2-dihydro-3,5 (4H)-dioxo-1,2-diphenyl-3H-1,2,4-triazol-4-yl]ethyl]-argininamide; 0.03 mmol/kg s.c.), a Y2 receptor antagonist which does not cross the blood-brain barrier, did not modify the c-Fos response to gastric acid challenge. The Y2 receptor agonist peptide YY-(3-36) (0.1 mg/kg intraperitoneally) likewise failed to alter the gastric HCl-evoked expression of c-Fos in the nucleus tractus solitarii. BIIE0246, however, prevented the effect of peptide YY-(3-36) to inhibit gastric acid secretion as deduced from measurement of intragastric pH. The current data indicate that gastric challenge with acid concentrations that do not induce overt injury but inhibit gastric emptying is signaled to the mouse nucleus tractus solitarii. Endogenous neuropeptide Y acting via Y2 and Y4 receptors depresses the afferent input to the nucleus tractus solitarii by a presumably central site of action.
Wultsch
T
T
Department of Experimental and Clinical Pharmacology, Medical University of Graz, Universitätsplatz 4, A-8010 Graz, Austria.
Painsipp
E
E
Thoeringer
C K
CK
Herzog
H
H
Sperk
G
G
Holzer
P
P
D000704:Analysis of Variance; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001552:Benzazepines / Q000494:pharmacology; D001933:Brain Stem / Q000166:cytology / Q000502:physiology*; D002452:Cell Count; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D050580:Excitatory Amino Acid Transporter 3 / Q000378:metabolism; D005260:Female; D005744:Gastric Acid / Q000502:physiology*; D005746:Gastric Emptying; D005753:Gastric Mucosa / Q000187:drug effects / Q000294:innervation* / Q000473:pathology; D006851:Hydrochloric Acid / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D007150:Immunohistochemistry / Q000379:methods; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000502:physiology; D009478:Neuropeptide Y / Q000502:physiology*; D010446:Peptide Fragments; D019894:Peptide YY / Q000494:pharmacology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D017476:Receptors, Neuropeptide Y / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000502:physiology*
D001552:Benzazepines; D050580:Excitatory Amino Acid Transporter 3; D009478:Neuropeptide Y; D010446:Peptide Fragments; D016760:Proto-Oncogene Proteins c-fos; D017476:Receptors, Neuropeptide Y; C493399:Slc1a1 protein, mouse; C095889:neuropeptide Y2 receptor; D019894:Peptide YY; C061785:peptide YY (3-36); C109491:neuropeptide Y4 receptor; D001120:Arginine; C403256:BIIE 0246; D006851:Hydrochloric Acid