Narcotic analgesics (i.e. opiates such as morphine) and endogenous opioid peptides bind to the three types of opioid receptors (mu, delta, kappa) with varying affinities and activate these receptors to different extents. Opioid receptor function is modulated by multiple mechanisms;the long-term objective of the project is to understand the contribution of these mechanisms to receptor activity. This application is focused on exploring a recently recognized mechanism of 'receptor dimerization/oligomerization'in modulating opioid receptor function. We and others have previously shown that mu receptors dimerize with delta receptors and this changes receptor properties. Recently we generated mu-delta heterodimer-selective antibodies. Using these we have found that levels of mu-delta heterodimers can be differentially regulated by opiates in vivo. The functional consequences of this regulation and the molecular mechanisms involved are not known. In this application we propose studies to directly address this important question.
Specific Aim # 1 is to examine the novel signaling pathways activated by the mu-delta heterodimer using classic biochemical techniques.
Aim # 2 is to investigate the distinct maturation/assembly and trafficking properties of the heterodimer using cell biological and imaging techniques.
Aim #3 is to study the distribution and regulation of the heterodimer by morphine in vivo using immunohistochemical techniques.
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