Involvement of spinal calcitonin gene-related peptide in the development of acute visceral hyperalgesia in the rat.
This study aimed to characterize the role of the neuropeptide calcitonin gene-related peptide (CGRP) in the development of mechanically induced visceral hyperalgesia. Tonic colorectal distension (CRD) was performed in fasted, conscious male Sprague-Dawley rats. The visceromotor reflex associated with noxious CRD was determined as the number of contractions during each of two consecutive tonic distensions (10 min at 60 mmHg), which were separated by a series of phasic distensions (repeated 15-s distensions to 80 mmHg at 30-s intervals). The effect of the CGRP receptor antagonist h-CGRP8-37 given intrathecally (i.t.) (0.03-3 nmol rat-1) or intravenously (i.v.) (20 microg kg-1 bodyweight [bw]) on the visceromotor response was evaluated. The dose for i.v. administration was chosen based on previous results from similar studies. In addition, the effect of a CGRP monoclonal antibody (6 mg kg-1 bw) given intravenously was evaluated. Compared to the baseline response, a significant increase in the number of abdominal contractions was observed during the second tonic distension. The i.t. application of h-CGRP8-37 dose-dependently reduced the numbers of abdominal contractions both during the first and the second tonic distension period, with a maximum effect observed at a peptide concentration of 3 nmol. Intravenous administration of h-CGRP8-37 or of the CGRP antiserum produced a small reduction of the visceromotor response induced by the second tonic distension and had no effect on colonic compliance. The development of mechanically induced colorectal hyperalgesia by repeated tonic distension involves the spinal release of CGRP, while peripheral release of CGRP plays only a minor role.
Gschossmann
J M
JM
CURE Digestive Diseases Research Center/Neuroenteric Disease Program and Animal Models Core, Departments of Medicine and Physiology and Brain Research Institute, UCLA School of Medicine, and VA Wadsworth Medical Center, Los Angeles, CA 90073, USA.
Coutinho
S V
SV
Miller
J C
JC
Huebel
K
K
Naliboff
B
B
Wong
H C
HC
Walsh
J H
JH
Mayer
E A
EA
D000208:Acute Disease; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015740:Calcitonin Gene-Related Peptide / Q000276:immunology / Q000494:pharmacology*; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D002404:Catheterization; D003106:Colon / Q000294:innervation / Q000502:physiology*; D005769:Gastrointestinal Motility / Q000187:drug effects / Q000502:physiology; D006930:Hyperalgesia / Q000503:physiopathology*; D007275:Injections, Intravenous; D007278:Injections, Spinal; D008297:Male; D008916:Miotics / Q000494:pharmacology*; D009130:Muscle, Smooth / Q000294:innervation / Q000502:physiology; D010446:Peptide Fragments / Q000276:immunology / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000378:metabolism; D013116:Spinal Cord / Q000502:physiology*; D017833:Visceral Afferents / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D008916:Miotics; D010446:Peptide Fragments; D018015:Receptors, Calcitonin Gene-Related Peptide; C058636:calcitonin gene-related peptide (8-37); D015740:Calcitonin Gene-Related Peptide