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 journalArticle

50 Citations (Scopus)

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
StatePublished - Aug 1 2000

Fingerprint

Nociception
Oligodeoxyribonucleotides
Opioid Receptors
Ala(2)-MePhe(4)-Gly(5)-enkephalin
Pain Measurement
Colon
Aptitude
Spinal Ganglia
Nerve Fibers
Down-Regulation
Western Blotting
asimadoline
Proteins

Keywords

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

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

κ-Opioid receptor agonists modulate visceral nociception at a novel, peripheral site of action. / Joshi, S. K.; Su, Xin; Porreca, Frank; Gebhart, G. F.

In: Journal of Neuroscience, Vol. 20, No. 15, 01.08.2000, p. 5874-5879.

Research output: Contribution to journalArticle

@article{981f707eb6ed45848e75f66969fa5988,
title = "κ-Opioid receptor agonists modulate visceral nociception at a novel, peripheral site of action",
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.",
keywords = "Antisense, Colorectal distension, Formalin test, Nociception, Peripheral opioids, Visceral pain",
author = "Joshi, {S. K.} and Xin Su and Frank Porreca and Gebhart, {G. F.}",
year = "2000",
month = "8",
day = "1",
language = "English (US)",
volume = "20",
pages = "5874--5879",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "15",

}

TY - JOUR

T1 - κ-Opioid receptor agonists modulate visceral nociception at a novel, peripheral site of action

AU - Joshi, S. K.

AU - Su, Xin

AU - Porreca, Frank

AU - Gebhart, G. F.

PY - 2000/8/1

Y1 - 2000/8/1

N2 - 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.

AB - 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.

KW - Antisense

KW - Colorectal distension

KW - Formalin test

KW - Nociception

KW - Peripheral opioids

KW - Visceral pain

UR - http://www.scopus.com/inward/record.url?scp=0034255006&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0034255006&partnerID=8YFLogxK

M3 - Article

C2 - 10908631

AN - SCOPUS:0034255006

VL - 20

SP - 5874

EP - 5879

JO - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

IS - 15

ER -