title: The peripheral antinociceptive effects of endomorphin-1 and kynurenic acid in the rat inflamed joint model.
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.
  
  
  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.
authors.affiliation: Department of Orthopedics, University of Szeged, Szeged, Hungary.
authors.forename: Laszlo
authors.initials: L
authors.lastname: Mecs
authors.forename: Gabor
authors.initials: G
authors.lastname: Tuboly
authors.forename: Endre
authors.initials: E
authors.lastname: Nagy
authors.forename: Gyorgy
authors.initials: G
authors.lastname: Benedek
authors.forename: Gyongyi
authors.initials: G
authors.lastname: Horvath
mesh_terms: 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
chemical_list: 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