Essential role of mu opioid receptor in the regulation of delta opioid receptor-mediated antihyperalgesia.
Analgesic effects of delta opioid receptor (DOR) -selective agonists are enhanced during persistent inflammation and arthritis. Although the underlying mechanisms are still unknown, membrane density of DOR was shown to be increased 72 h after induction of inflammation, an effect abolished in mu opioid receptor (MOR) -knockout (KO) mice [Morinville A, Cahill CM, Kieffer B, Collier B, Beaudet A (2004b) Mu-opioid receptor knockout prevents changes in delta-opioid receptor trafficking induced by chronic inflammatory pain. Pain 109:266-273]. In this study, we demonstrated a crucial role of MOR in DOR-mediated antihyperalgesia. Intrathecal administration of the DOR selective agonist deltorphin II failed to induce antihyperalgesic effects in MOR-KO mice, whereas it dose-dependently reversed thermal hyperalgesia in wild-type mice. The antihyperalgesic effects of deltorphin II were blocked by naltrindole but not d-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH(2) (CTOP) suggesting that this agonist was mainly acting through DOR. SNC80-induced antihyperalgesic effects in MOR-KO mice were also attenuated as compared with littermate controls. In contrast, kappa opioid receptor knockout did not affect deltorphin II-induced antihyperalgesia. As evaluated using mice lacking endogenous opioid peptides, the regulation of DOR's effects was also independent of beta-endorphin, enkephalins, or dynorphin opioids known to be released during persistent inflammation. We therefore conclude that DOR-mediated antihyperalgesia is dependent on MOR expression but that activation of MOR by endogenous opioids is probably not required.
Gendron
L
L
Department of Pharmacology, Health Sciences Building, University of Washington, Seattle, WA 98195-7280, USA. Louis.Gendron@USherbrooke.ca
Pintar
J E
JE
Chavkin
C
C
D000818:Animals; D004305:Dose-Response Relationship, Drug; D004399:Dynorphins / Q000172:deficiency; D004745:Enkephalins / Q000172:deficiency; D005620:Freund's Adjuvant; D006930:Hyperalgesia / Q000188:drug therapy* / Q000209:etiology; D007249:Inflammation / Q000139:chemically induced / Q000150:complications; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D009271:Naltrexone / Q000008:administration & dosage; D009292:Narcotic Antagonists / Q000008:administration & dosage; D009842:Oligopeptides / Q000008:administration & dosage; D010147:Pain Measurement; D011498:Protein Precursors / Q000172:deficiency; D011930:Reaction Time / Q000187:drug effects; D017465:Receptors, Opioid, delta / Q000378:metabolism*; D017473:Receptors, Opioid, kappa / Q000172:deficiency; D017450:Receptors, Opioid, mu / Q000172:deficiency / Q000502:physiology*; D013004:Somatostatin / Q000008:administration & dosage / Q000031:analogs & derivatives; D001615:beta-Endorphin / Q000172:deficiency
D004745:Enkephalins; D009292:Narcotic Antagonists; D009842:Oligopeptides; D011498:Protein Precursors; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; C029992:proenkephalin; C049352:phenylalanyl-cyclo(cysteinyltyrosyl-tryptophyl-ornithyl-threonyl-penicillamine)threoninamide; C060209:deltorphin II, Ala(2)-; D013004:Somatostatin; D009271:Naltrexone; D001615:beta-Endorphin; D004399:Dynorphins; D005620:Freund's Adjuvant