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

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

Research output: Contribution to journalArticle

29 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)257-265
Number of pages9
JournalPain
Volume151
Issue number2
DOIs
StatePublished - Nov 2010

Fingerprint

Interleukin-6 Receptors
Pancreatitis
Interleukin-6
Pain
Spinal Ganglia
Chronic Pain
Nociceptors
20,21-epoxyresibufogenin-3-formate
Calcitonin Gene-Related Peptide
Capsaicin
Chronic Pancreatitis
Analgesics
Pancreas
Hypersensitivity
Inflammation
Neurons
Injections

Keywords

  • Interleukin-6
  • Mechanisms
  • Pain
  • Pancreatitis

ASJC Scopus subject areas

  • Clinical Neurology
  • Anesthesiology and Pain Medicine
  • Neurology
  • Pharmacology

Cite this

Reversal of pancreatitis-induced pain by an orally available, small molecule interleukin-6 receptor antagonist. / Vardanyan, Marina; Melemedjian, Ohannes K.; Price, Theodore J.; Ossipov, Michael H.; Lai, Josephine; Roberts, Ed; Boos, Terrence L.; Deschamps, Jeffrey R.; Jacobson, Arthur E.; Rice, Kenner C.; Porreca, Frank.

In: Pain, Vol. 151, No. 2, 11.2010, p. 257-265.

Research output: Contribution to journalArticle

Vardanyan, M, Melemedjian, OK, Price, TJ, Ossipov, MH, Lai, J, Roberts, E, Boos, TL, Deschamps, JR, Jacobson, AE, Rice, KC & Porreca, F 2010, 'Reversal of pancreatitis-induced pain by an orally available, small molecule interleukin-6 receptor antagonist', Pain, vol. 151, no. 2, pp. 257-265. https://doi.org/10.1016/j.pain.2010.05.022
Vardanyan M, Melemedjian OK, Price TJ, Ossipov MH, Lai J, Roberts E et al. Reversal of pancreatitis-induced pain by an orally available, small molecule interleukin-6 receptor antagonist. Pain. 2010 Nov;151(2):257-265. https://doi.org/10.1016/j.pain.2010.05.022
Vardanyan, Marina ; Melemedjian, Ohannes K. ; Price, Theodore J. ; Ossipov, Michael H. ; Lai, Josephine ; Roberts, Ed ; Boos, Terrence L. ; Deschamps, Jeffrey R. ; Jacobson, Arthur E. ; Rice, Kenner C. ; Porreca, Frank. / Reversal of pancreatitis-induced pain by an orally available, small molecule interleukin-6 receptor antagonist. In: Pain. 2010 ; Vol. 151, No. 2. pp. 257-265.
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