The 5-HT(3) receptor antagonist alosetron inhibits the colorectal distention induced depressor response and spinal c-fos expression in the anaesthetised rat.
BACKGROUND
Noxious intestinal distention elicits a reflex depressor response in the sodium pentobarbitone anaesthetised rat, which can be used as an index of visceral nociception. 5-HT(3) receptor antagonists inhibit this reflex. Repeated colorectal distention (CRD) induces Fos like immunoreactivity (Fos-LI) in the rat spinal cord.


OBJECTIVE
To examine the effect of the 5-HT(3) receptor antagonist alosetron on the depressor response to CRD, and on Fos expression in the lumbosacral spinal cord.


METHODS
Male rats were anaesthetised with sodium pentobarbitone, and mean arterial blood pressure monitored during repeated colorectal balloon inflation before and after treatment with alosetron or saline. Rats anaesthetised with urethane and treated with alosetron or saline underwent a repeated CRD paradigm, after which the lumbosacral spinal cord was removed and processed for visualisation of Fos-LI.


RESULTS
CRD elicited reproducible, volume dependent falls in arterial blood pressure, and repeated distention-effect curves were constructed. Alosetron (1-100 microg/kg intravenously) inhibited the depressor response to CRD in a dose related manner, with an ID(50) value of 3.0 microg/kg. Following repeated CRD, numbers of Fos-LI neurones were significantly increased to 1246 (total in 12 sections at 120 microm intervals from L6 to S1) compared with 49 in sham distended animals. Pretreatment with alosetron (100 microg/kg) significantly reduced numbers of Fos-LI neurones to 479.8.


CONCLUSIONS
The 5-HT(3) receptor antagonist alosetron inhibits the depressor response to CRD in a potent and dose dependent manner. It also inhibits CRD induced Fos-LI in the spinal cord. These results suggest that 5-HT(3) receptors are involved in visceral nociceptive transmission, perhaps located on primary afferent or spinal neurones.
Kozlowski
C M
CM
Neuroscience Unit, GlaxoWellcome Research and Development, Stevenage SG1 2NY, UK.
Green
A
A
Grundy
D
D
Boissonade
F M
FM
Bountra
C
C
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002243:Carbolines / Q000494:pharmacology*; D002404:Catheterization; D003106:Colon / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects; D016762:Genes, fos / Q000187:drug effects*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D012007:Rectum / Q000187:drug effects*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013116:Spinal Cord / Q000378:metabolism
D002243:Carbolines; D012702:Serotonin Antagonists; C090840:alosetron