The molecular mechanism for morphine tolerance has not been firmly established yet. The current model of[j-opioid receptor (MOR) desensitization via the &-Arrestin pathway cannot account for the numerousobservations that other neurotransmitter receptor activities, such as NMDA, could contribute to morphinetolerance. The activity of other opioid receptors, such as the 6-opioid receptor (DOR), could be implicated inmorphine tolerance development also. Since morphine can activate and desensitize DOR during prolongedtreatment, our working hypothesis is that the post-signaling events occurring within the DOR-containingneurons during morphine treatment contribute to tolerance development. Our working hypothesis also is thatmorphine has post-signaling events distinct from those of other opioid agonists. In order to demonstratethese hypotheses, agonist-dependent signaling events will be established for morphine activation of DOR. Inour studies with MOR signaling, we have demonstrated that morphine differs from other agonists in itspathway to activate ERK1/2. Agonists such as etorphine activate ERK1/2 via the B-Arrestin-dependentpathway, while morphine activates ERK1/2 via the PKC-dependent pathway. This divergent activation resultsin differential translocation of the activated ERK1/2 and the transcripts produced. Therefore, the signalingpathway and the post-signaling events of morphine in cell models expressing DOR will be established. Thepossible involvement of the PKC-dependent pathway on morphine-mediated DOR activation of ERK1/2 willbe studied. The specific PKC subtypes involved will be defined. The reasons for the differences amongagonists in selecting a pathway will be investigated by monitoring protein-protein interactions using a novelprotease assay system. Parallel studies will be conducted with primary neuronal cultures. The blockade ofspecific PKC subtypes in DOR-expressing neurons on in vivo morphine tolerance development will beexplored. By selectively inactivating the morphine signaling pathway, and subsequently its post-signalingevents in DOR-containing neurons, possible blockade of morphine tolerance without altering morphineactivities in MOR containing neuron could be accomplished.
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