The peripheral antinociceptive effects of endomorphin-1 and kynurenic acid in the rat inflamed joint model

Anesth Analg. 2009 Oct;109(4):1297-304. doi: 10.1213/ane.0b013e3181b21c5e.

Abstract

Background: Several data suggest that both opioid and N-methyl-d-aspartate (NMDA) receptors are localized at the peripheral level, and drugs acting on these receptors may produce antinociception after topical administration; however, the antinociceptive effect of endogenous ligands at these receptors is poorly clarified. Our goal in this study was to determine the antinociceptive potency of the endogenous opioid peptide, endomorphin-1 (EM1), and the endogenous NMDA receptor antagonist, kynurenic acid (KYNA), and their interaction at the peripheral level in the rat inflamed joint model.

Methods: Mechanical hypersensitivity was produced by injection of carrageenan (300 microg/20 microL) into the tibiotarsal joint of the right hind leg. The mechanical pain threshold was assessed by von Frey filaments (0.064-110 g). EM1 (30, 100, and 200 microg), KYNA (30, 100, 200, and 400 microg), and their combinations in a fixed-dose ratio (1:1) were injected into the inflamed joint, and the pain threshold was determined repeatedly for 75 min after the drug administrations.

Results: Neither EM1 nor KYNA administered to the inflamed joint influenced the pain threshold at the noninflamed side. Both ligands produced dose-dependent antihyperalgesia, and the highest doses caused a prolonged effect. EM1 had higher potency (30% effective dose [ED(30)] and 50% effective dose [ED(50)] values were 112 microg [confidence interval {CI}: 80-146] and 167 microg [CI: 135-220], respectively) compared with KYNA (ED(30) and ED(50) values were 204 microg [CI: 160-251] and 330 microg [CI: 280-407], respectively). The antinociceptive effect of EM1 was prevented by subcutaneous naltrexone pretreatment. The coadministration of EM1 with KYNA caused an enhanced and/or prolonged antinociceptive effect. The ED(30) and ED(50) values of the combination were 141 microg [CI: 83-182] and 231 microg [CI: 190-293], respectively, which did not differ significantly from the theoretically additive values (ED(30) and ED(50) values were 145 microg [CI: 68-237] and 220 microg [CI: 144-230], respectively), thus the interaction between these ligands is additive. None of the treatments caused any sign of side effects.

Conclusion: Peripherally administered endogenous opioid agonist and NMDA receptor antagonist ligands might be beneficial in inflammatory pain. Because both drugs barely cross the blood-brain barrier, their local administration causes no central side effects.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics, Opioid / administration & dosage*
  • Animals
  • Arthralgia / etiology
  • Arthralgia / metabolism
  • Arthralgia / physiopathology
  • Arthralgia / prevention & control*
  • Arthritis, Experimental / chemically induced
  • Arthritis, Experimental / complications
  • Arthritis, Experimental / drug therapy*
  • Arthritis, Experimental / metabolism
  • Arthritis, Experimental / physiopathology
  • Behavior, Animal / drug effects
  • Carrageenan
  • Dose-Response Relationship, Drug
  • Drug Therapy, Combination
  • Edema / etiology
  • Excitatory Amino Acid Antagonists / administration & dosage*
  • Hyperalgesia / etiology
  • Hyperalgesia / metabolism
  • Hyperalgesia / physiopathology
  • Hyperalgesia / prevention & control*
  • Injections, Intra-Articular
  • Injections, Subcutaneous
  • Kynurenic Acid / administration & dosage*
  • Ligands
  • Male
  • Naltrexone / administration & dosage
  • Narcotic Antagonists / administration & dosage
  • Oligopeptides / administration & dosage*
  • Pain Measurement
  • Pain Threshold / drug effects
  • Rats
  • Rats, Wistar
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors*
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Receptors, Opioid / agonists*
  • Receptors, Opioid / metabolism
  • Time Factors

Substances

  • Analgesics, Opioid
  • Excitatory Amino Acid Antagonists
  • Ligands
  • Narcotic Antagonists
  • Oligopeptides
  • Receptors, N-Methyl-D-Aspartate
  • Receptors, Opioid
  • endomorphin 1
  • Naltrexone
  • Carrageenan
  • Kynurenic Acid