title: Demonstration of functional neuronal beta3-adrenoceptors within the enteric nervous system.
abstract: OBJECTIVE
  Although the beta(3)-adrenoceptor (AR) has been suggested to be involved in regulation of gut motility and visceral algesia, the precise mechanisms have been unknown. beta(3)-AR has been postulated to have a nonneuronal expression, being initially characterized in adipocytes and subsequently in the smooth muscle. We aimed to investigate the expression of beta(3)-AR in human enteric nervous system and its role in motility and visceral algesia.
  
  
  METHODS
  The expression of beta(3)-AR in human colon myenteric and submucosal plexus was investigated using immunohistochemistry. The effects of a beta(3)-AR agonist on nerve-evoked and carbachol-induced contractions as well as somatostatin release were investigated in strips of human colon. The effect of an agonist on diarrhea and visceral pain was investigated in vivo in rat models.
  
  
  RESULTS
  beta(3)-AR is expressed in cholinergic neurons in the myenteric plexus and submucosal plexus of human colon. Activation of beta(3)-AR causes the release of somatostatin from human isolated colon. In a rat model of visceral pain, beta(3)-AR agonist elicits somatostatin-dependent visceral analgesia. beta(3)-AR agonists inhibit cholinergically mediated muscle contraction of the human colon, as well as chemically induced diarrhea in vivo in a rat model.
  
  
  CONCLUSIONS
  This is the first demonstration of expression of beta(3)-AR in the enteric nervous system. Activation of these receptors results in inhibition of cholinergic contractions and enhanced release of somatostatin, which may lead to visceral analgesia and inhibition of diarrhea. Therefore, beta(3)-AR could be a novel therapeutic target for functional gastrointestinal disorders.
authors.affiliation: Neurology and Gastrointestinal Centre of Excellence in Drug Discovery, GlaxoSmithKline, Harlow, United Kingdom. Selim.2.Cellek@gsk.com <Selim.2.Cellek@gsk.com>
authors.forename: Selim
authors.initials: S
authors.lastname: Cellek
authors.forename: Ramkumar
authors.initials: R
authors.lastname: Thangiah
authors.forename: Anna K
authors.initials: AK
authors.lastname: Bassil
authors.forename: Colin A
authors.initials: CA
authors.lastname: Campbell
authors.forename: Karen M
authors.initials: KM
authors.lastname: Gray
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Stretton
authors.forename: Olutunde
authors.initials: O
authors.lastname: Lalude
authors.forename: Shanmugam
authors.initials: S
authors.lastname: Vivekanandan
authors.forename: Alan
authors.initials: A
authors.lastname: Wheeldon
authors.forename: Wendy J
authors.initials: WJ
authors.lastname: Winchester
authors.forename: Gareth J
authors.initials: GJ
authors.lastname: Sanger
authors.forename: Michael
authors.initials: M
authors.lastname: Schemann
authors.forename: Kevin
authors.initials: K
authors.lastname: Lee
mesh_terms: D015746:Abdominal Pain / Q000139:chemically induced / Q000378:metabolism; D058667:Adrenergic beta-3 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D002368:Castor Oil; D002400:Cathartics; D003106:Colon / Q000294:innervation*; D003967:Diarrhea / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D004149:Dioxoles / Q000494:pharmacology; D005769:Gastrointestinal Motility; D006801:Humans; D007150:Immunohistochemistry; D009149:Mustard Plant; D009197:Myenteric Plexus / Q000378:metabolism*; D010938:Plant Oils; D051381:Rats; D011919:Rats, Inbred Strains; D022702:Receptors, Adrenergic, beta-3 / Q000378:metabolism*; D013004:Somatostatin / Q000378:metabolism; D013368:Submucous Plexus / Q000378:metabolism*; D017833:Visceral Afferents / Q000378:metabolism
chemical_list: D058667:Adrenergic beta-3 Receptor Agonists; D000318:Adrenergic beta-Agonists; D002400:Cathartics; D004149:Dioxoles; D010938:Plant Oils; D022702:Receptors, Adrenergic, beta-3; C076126:disodium (R,R)-5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)-amino)propyl)-1,3-benzodioxole-2,3-dicarboxylate; D013004:Somatostatin; D002368:Castor Oil; C027793:mustard oil