title: Vagal afferent-dependent cholecystokinin modulation of visceral pain requires central amygdala NMDA-NR2B receptors in rats.
abstract: BACKGROUND
  Cholecystokinin (CCK), a gut hormone that is released during feeding, exerts gastrointestinal effects in part through vagal pathway. It is reported to be a potential trigger for increased postprandial visceral sensitivity in healthy subjects and, especially in patients with irritable bowel syndrome. NR2B-containing N-methyl-d-aspartate (NMDA) receptors in the central amygdala (CeA) participate in pain modulation. Systemically administered CCK activates the CeA-innervating neurons. Here, we investigated whether CCK modulation of visceral sensitivity is mediated through CeA NMDA-NR2B receptors and whether this modulation involves vagal pathway.
  
  
  METHODS
  We first examined the visceromotor response (VMR) to colorectal distention (CRD) following i.p. injection of CCK octapeptide (CCK-8) in a rat model. Next, the NR2B antagonist ifenprodil and the NR2A antagonist NVP-AAM077 were microinjected into the CeA before systemic CCK injection. NR2B phosphorylation was detected by Western blot. To down-regulate NR2B gene expression, NR2B-specific small interfering RNA (siRNA) was delivered into CeA neurons by electroporation. In addition, the effects of functional deafferentation by perivagal application of capsaicin and pretreatment with the CCK1 receptor antagonist devazepide were investigated.
  
  
  RESULTS
  CCK-8 increased VMR to CRD in a dose-dependent manner. This effect was blunted by intra-CeA administration of ifenprodil (but not NVP-AAM077) and was accompanied by phosphorylation of NR2B subunits in the CeA. CCK failed to increase VMR to CRD in NR2B siRNA-treated rats. Perivagal capsaicin application and pretreatment with devazepide prevented CCK-induced pronociception and CeA NR2B phosphorylation.
  
  
  CONCLUSIONS
  The pronociception induced by systemic CCK, which is vagal afferent-dependent, requires activation of CeA NMDA-NR2B receptors.
authors.affiliation: Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China.
authors.forename: E M
authors.initials: EM
authors.lastname: Wang
authors.affiliation: Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China.
authors.forename: W T
authors.initials: WT
authors.lastname: Li
authors.affiliation: Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China.
authors.forename: X J
authors.initials: XJ
authors.lastname: Yan
authors.affiliation: Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China.
authors.forename: X
authors.initials: X
authors.lastname: Chen
authors.affiliation: Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China.
authors.forename: C C
authors.initials: CC
authors.lastname: Feng
authors.affiliation: Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China.
authors.forename: Z J
authors.initials: ZJ
authors.lastname: Cao
authors.affiliation: Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China.
authors.forename: J Y
authors.initials: JY
authors.lastname: Fang
authors.affiliation: Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China.
authors.forename: S L
authors.initials: SL
authors.lastname: Chen
mesh_terms: D000009:Abdominal Muscles / Q000187:drug effects / Q000503:physiopathology; D000344:Afferent Pathways / Q000502:physiology; D000818:Animals; D066274:Central Amygdaloid Nucleus / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D006930:Hyperalgesia / Q000503:physiopathology; D008297:Male; D059225:Nociception / Q000187:drug effects / Q000502:physiology*; D010147:Pain Measurement; D010766:Phosphorylation; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000378:metabolism / Q000502:physiology*; D012844:Sincalide / Q000008:administration & dosage / Q000502:physiology*; D014628:Vagotomy; D014630:Vagus Nerve / Q000502:physiology*; D059265:Visceral Pain / Q000378:metabolism / Q000503:physiopathology*
chemical_list: C121001:NR2B NMDA receptor; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; D012844:Sincalide; C010739:ifenprodil
keywords: NR2B receptors; cholecystokinin; the central amygdala; vagal afferents; visceral pain