5-HT(2B) receptors modulate visceral hypersensitivity in a stress-sensitive animal model of brain-gut axis dysfunction.
BACKGROUND
Irritable bowel syndrome (IBS) is associated with an enhanced perception to visceral stimuli and exaggerated stress response. The serotonergic neurotransmitter system has been strongly implicated as a key player in the manifestation of IBS symptomatology including visceral hypersensitivity. However the role of 5-HT(2B) receptors in visceral pain, although speculated, is currently unclear. Thus we assessed the impact of a selective 5-HT(2B) receptor antagonist, RS-127445, on visceral hypersensitivity in a model of brain gut axis dysfunction the Wistar Kyoto (WKY) rat.


METHODS
Colorectal distension (CRD) was used to assess the visceral sensitivity of the WKY rat compared to normosensitive Sprague Dawley (SD) rats. Once we verified the visceral sensitivity of the WKY rat we assessed the efficacy of RS-127445 in pain signalling from the colorectum. We administered the compound peripherally (i.p.) and centrally (i.c.v.) in order to ascertain the site of action of RS 127445. Behavioural responses to colorectal distention were then monitored.


RESULTS
The WKY rats were more viscerally hypersensitive than the SD as previously shown. RS-127445 (5 mg kg(-1), i.p.) significantly reversed visceral hypersensitivity in WKY animals. Moreover, when administered intracerebroventricularly RS-127445 (100 nM) also decreased the number of pain behaviours during noxious CRD in the WKY animals.


CONCLUSIONS
Taken together, blockade of 5-HT(2B) receptors offers an exciting novel therapeutic target for pain relief in stress-related gastrointestinal disorders such as IBS.
O'Mahony
S M
SM
Laboratory of Neurogastroenterology, Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland. somahony@ucc.ie
Bulmer
D C
DC
Coelho
A-M
AM
Fitzgerald
P
P
Bongiovanni
C
C
Lee
K
K
Winchester
W
W
Dinan
T G
TG
Cryan
J F
JF
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004195:Disease Models, Animal; D006930:Hyperalgesia / Q000378:metabolism* / Q000503:physiopathology; D007420:Intestine, Large / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D043183:Irritable Bowel Syndrome / Q000378:metabolism* / Q000503:physiopathology; D010146:Pain / Q000378:metabolism* / Q000503:physiopathology; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D011921:Rats, Inbred WKY; D017207:Rats, Sprague-Dawley; D044403:Receptor, Serotonin, 5-HT2B / Q000378:metabolism*; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists / Q000494:pharmacology
D011743:Pyrimidines; D044403:Receptor, Serotonin, 5-HT2B; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists; C121466:2-amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine