The kinin B1 receptor antagonist SSR240612 reverses tactile and cold allodynia in an experimental rat model of insulin resistance.

Abstract

BACKGROUND AND PURPOSE:

Diabetes causes sensory polyneuropathy with associated pain in the form of tactile allodynia and thermal hyperalgesia which are often intractable and resistant to current therapy. This study tested the beneficial effects of the non-peptide and orally active kinin B(1) receptor antagonist SSR240612 against tactile and cold allodynia in a rat model of insulin resistance.

EXPERIMENTAL APPROACH:

Rats were fed with 10% D-glucose for 12 weeks and effects of orally administered SSR240612 (0.3-30 mg kg(-1)) were determined on the development of tactile and cold allodynia. Possible interference of SSR240612 with vascular oxidative stress and pancreatic function was also addressed.

KEY RESULTS:

Glucose-fed rats exhibited tactile and cold allodynia, increases in systolic blood pressure and higher plasma levels of insulin and glucose, at 12 weeks. SSR240612 blocked tactile and cold allodynia at 3 h (ID(50)=5.5 and 7.1 mg kg(-1), respectively) in glucose-fed rats but had no effect in control rats. The antagonist (10 mg kg(-1)) had no effect on plasma glucose and insulin, insulin resistance (HOMA index) and aortic superoxide anion production in glucose-fed rats.

CONCLUSIONS AND IMPLICATIONS:

We provide the first evidence that the B(1) receptors are involved in allodynia in an experimental rat model of insulin resistance. Allodynia was alleviated by SSR240612 most likely through a direct inhibition of B(1) receptors affecting spinal cord and/or sensory nerve excitation. Thus, orally active non-peptide B(1) receptor antagonists should have clinical therapeutic potential in the treatment of sensory polyneuropathy.

• Authors: J P Dias, M A Ismael, M Pilon, J de Champlain, B Ferrari, P Carayon, R Couture
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 152 Issue 2 Pg. 280-7 (Sep 2007) ISSN: 0007-1188 [Print] England
• PMID: 17618300 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 2-((3-(1,3-benzodioxol-5-yl)-3-(((6-methoxy-2-naphthyl)sulfonyl)amino)propanoyl)amino)-3-(4-((2,6-dimethylpiperidinyl)methyl)phenyl)-N-isopropyl-N-methylpropanamide
• Analgesics, Non-Narcotic
• Blood Glucose
• Bradykinin B1 Receptor Antagonists
• Dioxoles
• Insulin
• Sulfonamides
• Superoxides

Topics

• Analgesics, Non-Narcotic (therapeutic use)
• Animals
• Aorta, Thoracic (metabolism)
• Blood Glucose (analysis)
• Bradykinin B1 Receptor Antagonists
• Cold Temperature
• Dioxoles (therapeutic use)
• Disease Models, Animal
• Hot Temperature
• Hyperalgesia (drug therapy)
• Insulin (blood)
• Insulin Resistance (physiology)
• Male
• Oxidative Stress (drug effects)
• Pain (drug therapy, metabolism, physiopathology)
• Rats
• Rats, Sprague-Dawley
• Sulfonamides (therapeutic use)
• Superoxides (metabolism)
• Touch