κ-Opioid receptor agonists modulate visceral nociception at a novel, peripheral site of action

S. K. Joshi, Xin Su, Frank Porreca, G. F. Gebhart

Research output: Contribution to journalArticlepeer-review

50 Scopus citations

Abstract

κ-opioid receptor agonists (κ-ORAs) have been shown to modulate visceral nociception through an interaction with a peripheral, possibly novel, κ-opioid-like receptor. We used in the present experiments an antisense strategy to further explore the hypothesis that κ-ORA effects in the colon are produced at a site different from the cloned κ-opioid receptor (KOR). An antisense oligodeoxynucleotide (ODN) to the cloned rat KOR was administered intrathecally (12.5 μg, twice daily for 4 d) to specifically knock-down the cloned KOR. Efficacy of the KOR antisense ODN treatment was behaviorally evaluated by assessing the antinociceptive effects of peripherally administered κ- (EMD 61,753 and U 69,593), μ- (DAMGO) and δ- (deltorphin) ORAs in the formalin test. Intrathecal antisense, but not mismatch ODN blocked the actions of EMD 61,753 and U 69,593 without affecting the actions of DAMGO or deltorphin; a complete recovery of antinociceptive actions of the κ-ORA EMD 61,753 was observed 10 d after the termination of antisense ODN treatment. In contrast, the ability of EMD 61,753 to dose-dependently attenuate responses of pelvic nerve afferent fibers to noxious colonic distension was unaffected in the same rats in which the antisense ODN effectively knocked-down the KOR as assessed in the formalin test. Additionally, Western blot analysis demonstrated a significant downregulation of KOR protein in the L4-S1 dorsal root ganglia of antisense, but not mismatch ODN-treated rats. The present results support the existence of a non-κ-opioid receptor site of action localized in the colon.

Original languageEnglish (US)
Pages (from-to)5874-5879
Number of pages6
JournalJournal of Neuroscience
Volume20
Issue number15
DOIs
StatePublished - Aug 1 2000

Keywords

  • Antisense
  • Colorectal distension
  • Formalin test
  • Nociception
  • Peripheral opioids
  • Visceral pain

ASJC Scopus subject areas

  • Neuroscience(all)

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