Peripheral antinociceptive effect of 2-arachidonoyl-glycerol and its interaction with endomorphin-1 in arthritic rat ankle joints.
1. Both cannabinoid and opioid receptors are localized at the peripheral level, and drugs acting on these receptors may produce antinociception after topical administration; however, the effect of endogenous ligands at these receptors is poorly understood. Our goal was to determine the antinociceptive potency of the endogenous cannabinoid 2-arachidonoyl-glycerol (2-AG), and its interaction with endomorphin-1 (EM1) at joint level in the rat inflammation model. 2. Mechanical hypersensitivity was produced by injection of carrageenan (300 microg/30 microL) into the tibiotarsal joint of the right hind leg. The mechanical threshold was assessed by von Frey filaments. 2-AG (3-200 microg), EM1 (100-300 microg) and their combinations in a fixed-dose ratio (1 : 10) were given into the inflamed joint, and the threshold was determined repeatedly for 105 min after the drug administrations. 3. Both ligands produced dose-dependent anti-hyperalgesia, and the highest doses caused prolonged effects, but they did not influence the degree of oedema and the withdrawal threshold at the non-inflamed side. EM1 had lower potency compared to 2-AG (ED(25): 233 (CI: 198-268) microg and 126 (CI: 88-162) microg, respectively; P < 0.05). The effects of EM1 and 2-AG were prevented by mu-opioid and cannabinoid 1 receptor antagonists, respectively. The ED(25) value for the combination (98 (CI: 80-112) microg) did not differ significantly from the value of 2-AG; however, the largest dose combination produced a significantly higher effect than the ligands by themselves. 4. Our data showed that 2-AG was an effective antinociceptive ligand at joint level, and its combination with EM1 produced long-lasting, effective antinociception.
Department of Physiology, University of Szeged, H-6701 Szeged, Hungary.
Laszlo
L
Mecs
Gabor
G
Tuboly
Kalman
K
Toth
Endre
E
Nagy
Tibor
T
Nyari
Gyorgy
G
Benedek
Gyöngyi
G
Horvath
D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001095:Arachidonic Acids / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000378:metabolism; D063385:Cannabinoid Receptor Modulators / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004487:Edema / Q000188:drug therapy / Q000378:metabolism; D063388:Endocannabinoids; D005989:Glycerides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D008024:Ligands; D008297:Male; D009292:Narcotic Antagonists / Q000494:pharmacology; D009842:Oligopeptides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D017288:Pain Threshold / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D043882:Receptors, Cannabinoid / Q000378:metabolism; D011957:Receptors, Opioid / Q000378:metabolism; D013640:Tarsal Joints / Q000187:drug effects* / Q000378:metabolism
D000701:Analgesics, Opioid; D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D005989:Glycerides; D008024:Ligands; D009292:Narcotic Antagonists; D009842:Oligopeptides; D043882:Receptors, Cannabinoid; D011957:Receptors, Opioid; C105293:endomorphin 1; C094503:glyceryl 2-arachidonate