Reversal of pancreatitis-induced pain by an orally available, small molecule interleukin-6 receptor antagonist.

Abstract

Pancreatic pain resulting from chronic inflammation of the pancreas is often intractable and clinically difficult to manage with available analgesics reflecting the need for more effective therapies. The mechanisms underlying pancreatitis pain are not well understood. Here, the possibility that interleukin-6 (IL-6) may promote pancreatitis pain was investigated with TB-2-081 (3-O-formyl-20R,21-epoxyresibufogenin, EBRF), a small molecule IL-6 receptor antagonist that was semi-synthetically derived from natural sources. The potential activity and mechanism of TB-2-081 were investigated following the induction of persistent pancreatitis using dibutyltin dichloride (DBTC) in rats. TB-2-081 displaces the binding of IL-6 to the human recombinant soluble IL-6 receptor with apparent high affinity and inhibits IL-6 mediated cell growth. Systemic or oral, but not intrathecal, administration of TB-2-081 reversed DBTC-induced abdominal hypersensitivity in a dose- and time-dependent manner. IL-6 levels were significantly up-regulated in the dorsal root ganglia (DRG) of rats with pancreatitis on day 6 after DBTC injection. IL-6-enhanced capsaicin-evoked release of calcitonin gene-related peptide from cultured DRG neurons was blocked by TB-2-081. Our data demonstrate that TB-2-081 acts as a systemically available and orally active small molecule IL-6 receptor antagonist. TB-2-081 effectively reduces pancreatitis-induced pain through peripheral mechanisms that are likely due to (a) increased expression of IL-6 in the DRG and (b) IL-6-mediated sensitization of nociceptive neurons. The activity of TB-2-081 implicates an important role for IL-6 in sustaining pancreatitis pain. Strategies targeting IL-6 actions through small molecule antagonists may offer novel approaches to improve the therapy of chronic pancreatitis and other chronic pain states.

• Authors: Marina Vardanyan, Ohannes K Melemedjian, Theodore J Price, Michael H Ossipov, Josephine Lai, Ed Roberts, Terrence L Boos, Jeffrey R Deschamps, Arthur E Jacobson, Kenner C Rice, Frank Porreca
• Journal: Pain (Pain) Vol. 151 Issue 2 Pg. 257-265 (Nov 2010) ISSN: 1872-6623 [Electronic] United States
• PMID: 20599324 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural)
• Copyright: Copyright © 2010 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Chemical References

• 20,21-epoxyresibufogenin-3-formate
• Bufanolides
• Interleukin-6
• Organotin Compounds
• Receptors, Interleukin-6
• dibutyldichlorotin
• Calcitonin Gene-Related Peptide

Topics

• Abdominal Pain (drug therapy, etiology)
• Administration, Oral
• Animals
• Binding, Competitive (drug effects)
• Bufanolides (administration & dosage)
• Calcitonin Gene-Related Peptide (metabolism)
• Cell Line, Transformed
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Enzyme-Linked Immunosorbent Assay (methods)
• Ganglia, Spinal (drug effects)
• Gene Expression Regulation (drug effects)
• Humans
• Hyperalgesia (drug therapy, etiology)
• Interleukin-6 (metabolism, pharmacology)
• Male
• Organotin Compounds
• Pancreatitis (chemically induced, complications)
• Rats
• Rats, Sprague-Dawley
• Receptors, Interleukin-6 (antagonists & inhibitors)
• Time Factors
• Tissue Culture Techniques