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


CONCLUSIONS
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.
Mecs
Laszlo
L
Department of Orthopedics, University of Szeged, Szeged, Hungary.
Tuboly
Gabor
G
Nagy
Endre
E
Benedek
Gyorgy
G
Horvath
Gyongyi
G
D000701:Analgesics, Opioid / Q000008:administration & dosage*; D000818:Animals; D018771:Arthralgia / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D001522:Behavior, Animal / Q000187:drug effects; D002351:Carrageenan; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D004487:Edema / Q000209:etiology; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage*; D006930:Hyperalgesia / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D007270:Injections, Intra-Articular; D007279:Injections, Subcutaneous; D007736:Kynurenic Acid / Q000008:administration & dosage*; D008024:Ligands; D008297:Male; D009271:Naltrexone / Q000008:administration & dosage; D009292:Narcotic Antagonists / Q000008:administration & dosage; D009842:Oligopeptides / Q000008:administration & dosage*; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011957:Receptors, Opioid / Q000819:agonists* / Q000378:metabolism; D013997:Time Factors
D000701:Analgesics, Opioid; D018691:Excitatory Amino Acid Antagonists; D008024:Ligands; D009292:Narcotic Antagonists; D009842:Oligopeptides; D016194:Receptors, N-Methyl-D-Aspartate; D011957:Receptors, Opioid; C105293:endomorphin 1; D009271:Naltrexone; D002351:Carrageenan; D007736:Kynurenic Acid