Article

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

Department of Orthopedics, University of Szeged, Szeged, Hungary.
Anesthesia and analgesia (impact factor: 3.08). 10/2009; 109(4):1297-304. DOI:10.1213/ane.0b013e3181b21c5e pp.1297-304
Source: PubMed

ABSTRACT 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.
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.
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.
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.

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Keywords

antinociceptive effect
 
central side effects
 
dose-dependent antihyperalgesia
 
endogenous ligands
 
endogenous NMDA receptor antagonist
 
endogenous opioid agonist
 
endogenous opioid peptide
 
highest doses
 
hind leg
 
inflamed joint
 
mechanical pain threshold
 
NMDA receptor antagonist ligands
 
noninflamed side
 
pain threshold
 
prolonged effect
 
rat inflamed joint model
 
subcutaneous naltrexone pretreatment
 
tibiotarsal joint
 
topical administration
 
von Frey filaments
 

Laszlo Mecs