Antinociceptive interactions between anandamide and endomorphin-1 at the spinal level.
1. Although it is well known that the combined administration of synthetic or plant-originated opioids with cannabinoids (CB) results in synergistic antinociception, the effects of combined administration of endogenous ligands acting at micro-opioid and CB receptors are not known. The aim of the present study was to determine the interaction between anandamide (AEA; a CB(1) receptor agonist) and endomorphin-1 (EM-1; a micro-opioid receptor agonist) after intrathecal administration. 2. Nociception was assessed by the paw-withdrawal test after carrageenan-induced inflammation in male Wistar rats. 3. Endomorphin-1 (16.4 pmol to 16.4 nmol) and AEA (4.3-288 nmol) alone dose-dependently decreased carrageenan-induced thermal hyperalgesia, although the highest dose of AEA also exhibited pain-inducing potential. The potency of AEA was approximately 59-fold lower than that of EM-1 (35% effective dose (ED(35)) 194.4 vs 3.3 nmol, respectively). Coadministration of these ligands revealed that combinations of 16.4 pmol EM-1 plus 28.8 or 86.5 nmol AEA were more effective than either drug alone, but other combinations were no more effective than the administration of EM-1 itself. Therefore, coadministration of AEA did not significantly shift the dose-response curve to EM-1. 4. The results of the present study indicate that the coadministration of AEA and EM-1 results in potentiated antihyperalgesia only for a combination of specific doses. Because AEA activates other receptor types (e.g. TRPV1) in addition to CB(1) receptors, the results of the present suggest that, after the coadministration of EM-1 and AEA, complex interactions ensue that may lead to different outcomes compared with those seen following the injection of exogenous ligands.
Tuboly
Gabor
G
Department of Physiology, Faculty of Medicine, University of Szeged, Szeged, Hungary.
Mecs
Laszlo
L
Benedek
György
G
Horvath
Gyöngyi
G
D000700:Analgesics / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D001095:Arachidonic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D002351:Carrageenan; D004338:Drug Combinations; D004353:Drug Evaluation, Preclinical; D004347:Drug Interactions; D063388:Endocannabinoids; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy*; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D007278:Injections, Spinal; D008297:Male; D009842:Oligopeptides / Q000008:administration & dosage / Q000494:pharmacology*; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D053284:Polyunsaturated Alkamides / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013131:Spine / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors
D000700:Analgesics; D001095:Arachidonic Acids; D004338:Drug Combinations; D063388:Endocannabinoids; D009842:Oligopeptides; D053284:Polyunsaturated Alkamides; C105293:endomorphin 1; D002351:Carrageenan; C078814:anandamide