Mu-opioid receptor knockout prevents changes in delta-opioid receptor trafficking induced by chronic inflammatory pain.
Previous studies from our laboratory have demonstrated that both chronic inflammatory pain, induced by intraplantar injection of complete Freund's adjuvant (CFA), and prolonged (48 h) stimulation of mu-opioid receptors (muOR) by systemic administration of a variety of selective agonists, resulted in enhanced plasma membrane targeting of delta-opioid receptors (deltaOR) in neurons of the dorsal spinal cord. To determine whether deltaOR trafficking induced by chronic inflammation was dependent on the activation of muOR, we investigated by immunogold cytochemistry the effects of intraplantar CFA injection on the plasma membrane density of deltaOR in muOR knockout (KO) mice. In untreated wild-type (WT) mice, only a small proportion of deltaOR was associated with neuronal plasma membranes in the dorsal horn of the spinal cord. The CFA-induced inflammation produced a significantly higher ratio of plasma membrane to intracellular receptors, as well as a 75% increase in the membrane density of immunoreactive deltaOR, in dendrites of the ipsilateral dorsal horn as compared to untreated mice. This increase in the membrane density of deltaOR was likely due to a recruitment of receptors from intracellular stores since no difference in the overall deltaOR immunolabeling density was evident between CFA-treated and untreated mice. Most importantly, the CFA-induced changes in deltaOR plasma membrane insertion seen in WT animals were not present in the spinal cord of muOR KO mice. These results demonstrate that the integrity of muOR is necessary for CFA-induced changes in deltaOR trafficking to occur and suggest that these changes could be elicited by stimulation of muOR by endogenous opioids released in response to chronic inflammatory pain.
Morinville
Anne
A
Department of Neurology and Neurosurgery, Montreal Neurological Institute, Rm 896, McGill University, 3801 University Street, Montreal, Que., Canada H3A 2B4 Department of Pharmacology and Therapeutics, McGill University, 3655 Promenade Sir William Osler, Montreal, Que., Canada H3G 1Y6 IGBMC, CNRS/INSERM/ULP, 67404 Illkirch, France.
Cahill
Catherine M
CM
Kieffer
Brigitte
B
Collier
Brian
B
Beaudet
Alain
A
D000818:Animals; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D002908:Chronic Disease; D003712:Dendrites / Q000378:metabolism / Q000648:ultrastructure; D004195:Disease Models, Animal; D005260:Female; D005620:Freund's Adjuvant; D007839:Functional Laterality / Q000235:genetics; D007150:Immunohistochemistry; D007249:Inflammation / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008854:Microscopy, Electron; D010146:Pain / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D020671:Posterior Horn Cells / Q000378:metabolism / Q000648:ultrastructure; D021381:Protein Transport / Q000187:drug effects / Q000235:genetics; D017465:Receptors, Opioid, delta / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000172:deficiency / Q000235:genetics*; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D005620:Freund's Adjuvant