Activation of colonic mucosal 5-HT(4) receptors accelerates propulsive motility and inhibits visceral hypersensitivity.
OBJECTIVE
5-hydroxytryptamine receptor (5-HT(4)R) agonists promote gastrointestinal motility and attenuate visceral pain, but concerns about adverse reactions have restricted their availability. We tested the hypotheses that 5-HT(4) receptors are expressed in the colonic epithelium and that 5-HT(4)R agonists can act intraluminally to increase motility and reduce visceral hypersensitivity.


METHODS
Mucosal expression of the 5-HT(4)R was evaluated by reverse-transcriptase polymerase chain reaction and immunohistochemical analysis of tissues from 5-HT(4)R(BAC)-enhanced green fluorescent protein mice. Amperometry, histology, and short-circuit current measurements were used to study 5-HT, mucus, and Cl(-) secretion, respectively. Propulsive motility was measured in guinea pig distal colon, and visceromotor responses were recorded in a rat model of colonic hypersensitivity. 5-HT(4)R compounds included cisapride, tegaserod, naronapride, SB204070, and GR113808.


RESULTS
Mucosal 5-HT(4) receptors were present in the small and large intestines. In the distal colon, 5-HT(4) receptors were expressed by most epithelial cells, including enterochromaffin and goblet cells. Stimulation of 5-HT(4)Rs evoked mucosal 5-HT release, goblet cell degranulation, and Cl(-) secretion. Luminal administration of 5-HT(4)R agonists accelerated propulsive motility; a 5-HT(4)R antagonist blocked this effect. Bath application of 5-HT(4)R agonists did not affect motility. Oral or intracolonic administration of 5-HT(4)R agonists attenuated visceral hypersensitivity. Intracolonic administration was more potent than oral administration, and was inhibited by a 5-HT(4)R antagonist.


CONCLUSIONS
Mucosal 5-HT(4) receptor activation can mediate the prokinetic and antinociceptive actions of 5-HT(4)R agonists. Colon-targeted, intraluminal delivery of 5-HT(4)R agonists might be used to promote motility and alleviate visceral pain, while restricting systemic bioavailability and resulting adverse side effects.
Department of Anatomy & Neurobiology, University of Vermont, Burlington, Vermont 05405, USA.
Jill M
JM
Hoffman
Karl
K
Tyler
Sarah J
SJ
MacEachern
Onesmo B
OB
Balemba
Anthony C
AC
Johnson
Elice M
EM
Brooks
Hong
H
Zhao
Greg M
GM
Swain
Peter L
PL
Moses
James J
JJ
Galligan
Keith A
KA
Sharkey
Beverley
B
Greenwood-Van Meerveld
Gary M
GM
Mawe
D000284:Administration, Oral; D000700:Analgesics / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D002712:Chlorides / Q000378:metabolism; D022202:Chromosomes, Artificial, Bacterial; D003106:Colon / Q000187:drug effects* / Q000294:innervation / Q000378:metabolism; D004195:Disease Models, Animal; D004759:Enterochromaffin Cells / Q000187:drug effects / Q000378:metabolism; D005765:Gastrointestinal Agents / Q000008:administration & dosage / Q000494:pharmacology*; D005769:Gastrointestinal Motility / Q000187:drug effects*; D020397:Goblet Cells / Q000187:drug effects / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006168:Guinea Pigs; D006801:Humans; D006930:Hyperalgesia / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000294:innervation / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009093:Mucus / Q000378:metabolism; D010146:Pain / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D017288:Pain Threshold / Q000187:drug effects; D011312:Pressure; D051381:Rats; D017207:Rats, Sprague-Dawley; D044422:Receptors, Serotonin, 5-HT4 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012701:Serotonin / Q000378:metabolism; D058828:Serotonin 5-HT4 Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology*
D000700:Analgesics; D002712:Chlorides; D005765:Gastrointestinal Agents; D058828:Serotonin 5-HT4 Receptor Agonists; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D044422:Receptors, Serotonin, 5-HT4; D012701:Serotonin