Regulation of delta-opioid receptor trafficking via mu-opioid receptor stimulation: evidence from mu-opioid receptor knock-out mice.
We recently demonstrated that prolonged treatment with morphine increases the antinociceptive potency of the delta-opioid receptor (deltaOR) agonist deltorphin and promotes cell surface targeting of deltaORs in neurons of the dorsal horn of the rat spinal cord (Cahill et al., 2001b). In the present study we examined whether these effects were mediated selectively via muOR. Using the same intermittent treatment regimen as for morphine, we found that methadone and etorphine, but not fentanyl, enhanced [D-Ala2]-deltorphin-mediated antinociception. However, continuous delivery of fentanyl for 48 hr resulted in augmented deltaOR-mediated antinociception when compared with saline-infused animals. Time course studies confirmed that a 48 hr treatment with morphine was necessary for the establishment of enhanced deltaOR-mediated antinociception. The observed increases in deltaOR agonist potency and deltaOR plasma membrane density were reversed fully 48 hr after discontinuation of morphine injections. Wild-type C57BL/6 mice pretreated with morphine for 48 hr similarly displayed enhanced deltaOR-mediated antinociception in a tonic pain paradigm. Accordingly, the percentage of plasma membrane-associated deltaOR in the dorsal horn of the spinal cord, as assessed by immunogold electron microscopy, increased from 6.6% in naive to 12.4% in morphine-treated mice. In contrast, morphine treatment of muOR gene knock-out (KO) mice did not produce any change in deltaOR plasma membrane density. These results demonstrate that selective activation of muOR is critical for morphine-induced targeting of deltaOR to neuronal membranes, but not for basal targeting of this receptor to the cell surface.
Morinville
Anne
A
Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada H3G 1Y6.
Cahill
Catherine M
CM
Esdaile
M James
MJ
Aibak
Haneen
H
Collier
Brian
B
Kieffer
Brigitte L
BL
Beaudet
Alain
A
D000818:Animals; D019540:Area Under Curve; D001522:Behavior, Animal / Q000187:drug effects; D002462:Cell Membrane / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005048:Etorphine / Q000494:pharmacology; D005260:Female; D005283:Fentanyl / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D008691:Methadone / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009020:Morphine / Q000494:pharmacology; D009294:Narcotics / Q000494:pharmacology; D010147:Pain Measurement / Q000187:drug effects; D020671:Posterior Horn Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017465:Receptors, Opioid, delta / Q000819:agonists / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D013995:Time; D015854:Up-Regulation / Q000187:drug effects
D009294:Narcotics; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D005048:Etorphine; D009020:Morphine; D008691:Methadone; D005283:Fentanyl