Regulation of δ-Opioid Receptor Trafficking via μ-Opioid Receptor Stimulation: Evidence from μ-Opioid Receptor Knock-Out Mice

Abstract

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.

Morphine priming in rats with chronic inflammation reveals a dichotomy between antihyperalgesic and antinociceptive properties of deltorphin

“…We previously demonstrated that prolonged treatment of rodents with OR agonists including morphine induced a selective increase in cell surface density of ␦OR (Cahill et al, 2001b;Morinville et al, 2003) and internalization of ␦OR agonists in neurons of layers I-VI of the lumbar spinal cord (Morinville et al, 2004a). We also showed that chronic inflammation resulting from the injection of CFA into the rat hind paw similarly enhanced, bilaterally, the membrane density of ␦OR in neurons of the dorsal horn .…”

“…The CFA-induced up-regulation of cell surface ␦OR in spinal cord neurons involves the participation of OR as it can no longer be elicited in OR knockout mice (Morinville et al, 2004b). The effect of chronic inflammation on ␦OR trafficking is therefore akin to that of prolonged treatment with OR-preferring agonists (including morphine, fentanyl, methadone and etorphine), which was shown to induce a selective membrane recruitment of ␦OR in neurons of layers I-VI of the rat lumbar spinal cord (Cahill et al, 2001b;Morinville et al, 2003). As in animals with chronic inflammation, this increased density of cell surface ␦OR translates into a potentiation of the antinociceptive properties of deltorphin II injected intrathecally (i.t.)…”

“…As in animals with chronic inflammation, this increased density of cell surface ␦OR translates into a potentiation of the antinociceptive properties of deltorphin II injected intrathecally (i.t.) (Cahill et al, 2001b;Morinville et al, 2003). However, it is unclear whether chronic inflammation and sustained morphine treatment affect the same neuronal populations in the lumbar spinal cord and whether their effects are independent or cumulative.…”

神经细胞中多巴胺d1和d5受体不同亚细胞分布和胞内转运的特性

“…The heterodimerization of different GPCRs can result in the modulation of their function and/or the redistribution of their subcellular locations [17][18][19][20] . It was documented that 2-adrenergic agonist isoproterenol could induce the internalization of opioid receptors through the hetero-dimer of 2-adrenergic receptor and opioid receptor [20] .…”

“…3.4 D1R and D5R co-expressed in the same cell kept their distinct trafficking properties Dopamine D1 receptors can not only form the homodimer [16,17] , but also form the heterodimer with other GPCRs [17,18] . The heterodimerized GPCRs can result in the mutual modulation of their function and/or the redistribution of their subcellular locations [17][18][19][20] .…”