Guanylate cyclase C-mediated antinociceptive effects of linaclotide in rodent models of visceral pain.
BACKGROUND Linaclotide is a novel, orally administered investigational drug currently in clinical development for the treatment of constipation-predominant irritable bowel syndrome (IBS-C) and chronic idiopathic constipation. Visceral hyperalgesia is a major pathophysiological mechanism in IBS-C. Therefore, we investigated the anti-nociceptive properties of linaclotide in rodent models of inflammatory and non-inflammatory visceral pain and determined whether these pharmacological effects are linked to the activation of guanylate cyclase C (GC-C). METHODS Orally administered linaclotide was evaluated in non-inflammatory acute partial restraint stress (PRS) and acute water avoidance stress (WAS) models in Wistar rats, and in a trinitrobenzene sulfonic acid (TNBS)-induced inflammatory model in Wistar rats and GC-C null mice. KEY RESULTS In TNBS-induced colonic allodynia, linaclotide significantly decreased the number of abdominal contractions in response to colorectal distension without affecting the colonic wall elasticity change in response to distending pressures after TNBS. However, linaclotide had no effect on visceral sensitivity under basal conditions. In addition, linaclotide significantly decreased colonic hypersensitivity in the PRS and WAS models. In wild type (wt) and GC-C null mice, the instillation of TNBS induced similar hyperalgesia and allodynia. However, in post-inflammatory conditions linaclotide significantly reduced hypersensitivity only in wt mice, but not in GC-C null mice. CONCLUSIONS & INFERENCES These findings indicate that linaclotide has potent anti-nociceptive effects in several mechanistically different rodent models of visceral hypersensitivity and that these pharmacological properties of linaclotide are exerted through the activation of the GC-C receptor. Therefore, linaclotide may be capable of decreasing abdominal pain in patients suffering from IBS-C.
Eutamene
H
H
UMR INRA-Purpan Neuro-Gastroenterology and Nutrition Unit, Toulouse, France.
Bradesi
S
S
Larauche
M
M
Theodorou
V
V
Beaufrand
C
C
Ohning
G
G
Fioramonti
J
J
Cohen
M
M
Bryant
A P
AP
Kurtz
C
C
Currie
M G
MG
Mayer
E A
EA
Bueno
L
L
D000005:Abdomen / Q000503:physiopathology; D000704:Analysis of Variance; D000818:Animals; D003106:Colon / Q000187:drug effects / Q000503:physiopathology; D004567:Electrodes, Implanted; D004576:Electromyography; D005260:Female; D006162:Guanylate Cyclase / Q000235:genetics / Q000378:metabolism*; D006930:Hyperalgesia / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D010146:Pain / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D010455:Peptides / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012149:Restraint, Physical; D018709:Statistics, Nonparametric; D013312:Stress, Physiological / Q000187:drug effects* / Q000502:physiology; D013315:Stress, Psychological / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D014302:Trinitrobenzenesulfonic Acid
D010455:Peptides; D014302:Trinitrobenzenesulfonic Acid; D006162:Guanylate Cyclase; C523483:linaclotide