The exposure of an opioid receptor to opioid peptides or opiate alkaloids initiates a biological response. A long-term or repeated exposure to opioids causes a decreased sensitivity to the drug, leading to a reduced cellular response; this desensitization is regulated by multiple mechanisms which have been implicated in the generalized development of tolerance and addiction. Acute opioid treatments result in a rapid desensitization by functional uncoupling of the receptor from the effector system. In addition, this treatment results in a rapid internalization of the receptor into intracellular compartments. Chronic opioid treatment results in longer desensitization due to receptor down-regulation with a net loss of binding sites from the cell. Relatively little is known about the molecular mechanisms underlying these events. The objective of the studies proposed here is to explore the agonist-mediated events that lead to receptor internalization and degradation. These studies propose to explore the molecular mechanisms of opioid receptor internalization and dimerization in order to understand the functional significance of these events.
The specific aims are: (i) to characterize kappa opioid receptor trafficking in neuronal cells, and (ii) to explore the role of dimerization in kappa opioid receptor function. This work will provide critical information about the early agonist-mediated events that modulate opioid receptor function. A thorough understanding of the cellular mechanisms involved in the modulation of receptor desensitization is crucial for the development of a therapeutic basis for drug addiction.
