Chronic use of morphine results in tolerance to and dependence on the drug. One mechanism underlying cellular tolerance is an uncoupling of the opioid receptor from effects such that greater receptor occupancy is required to obtain a given response. This uncoupling mechanism has been studied using effectors that include; potassium and calcium conductances and the inhibition of adenylyl cyclase. A similar phenomenon is observed with acute opioid desensitization. Acute desensitization is thought to involve at least two linked processes, receptor uncoupling through an arresting dependent mechanism and removal of receptors from the plasma membrane through an internalization mechanism. Unlike more protracted forms of tolerance, acute desensitization is reversible within minutes and therefore easier to study in vitro. One goal of this proposal is to define the events that mediate the initiation and recovery from acute opioid desensitization. This goal has two parts, one is to characterize acute desensitization and determine the role of receptor internalization in that process. Given that receptor trafficking is an important form of receptor regulation, the second goal is to characterize how chronic morphine treatment alters desensitization and internalization of the opioid receptor. With a better understanding of the events that mediate desensitization and internalization the processes leading to long term tolerance may be more easily identified. The second goal is to identify post-synaptic cellular adaptations to chronic opioid treatment. These adaptations oppose the initial effect of opioid such that normal function is attained even in the continued presence of morphine. Thus adaptive mechanisms underlie an important form of tolerance. Two cell types will be examined the neurons in the locus coeruleus and interneurons of the VTA. There is an extensive knowledge of opioid actions in these areas, however, the identification and characterization of a post-synaptic adaptive mechanism studied in isolation has yet to be presented. Knowledge of alterations in regulation of ion channels during withdrawal form morphine may help in the development of more efficient protocols for the prevention of relapse to drug use.
Showing the most recent 10 out of 52 publications
