Demonstration of functional neuronal beta3-adrenoceptors within the enteric nervous system.
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.
Cellek
Selim
S
Neurology and Gastrointestinal Centre of Excellence in Drug Discovery, GlaxoSmithKline, Harlow, United Kingdom. Selim.2.Cellek@gsk.com <Selim.2.Cellek@gsk.com>
Thangiah
Ramkumar
R
Bassil
Anna K
AK
Campbell
Colin A
CA
Gray
Karen M
KM
Stretton
Jennifer L
JL
Lalude
Olutunde
O
Vivekanandan
Shanmugam
S
Wheeldon
Alan
A
Winchester
Wendy J
WJ
Sanger
Gareth J
GJ
Schemann
Michael
M
Lee
Kevin
K
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
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