Opioid tolerance and the emergence of new opioid receptor-coupled signaling |
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Authors: | Alan R Gintzler Sumita Chakrabarti |
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Institution: | (1) Department of Biochemistry, State University of New York Health Science Center at Brooklyn, 11203 Brooklyn, NY |
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Abstract: | Multiple cellular adaptations are elicited by chronic exposure to opioids. These include diminution of spare opioid receptors,
decreased opioid receptor density, and G-protein content and coupling thereof. All imply that opioid tolerance is a manifestation
of a loss of opioid function, i.e., desensitization. Recent observations challenge the exclusiveness of this formulation and
indicate that opioid tolerance also results from qualitative changes in opioid signaling. In this article, Gintzler and Chakrabarti
discuss the evidence that suggests that opioid tolerance results not only from impaired opioid receptor functionality, but
also from altered consequences of coupling. Underlying the latter are fundamental changes in the nature of effectors that
are coupled to the opioid receptor/G-protein signaling pathway. These molecular changes include the upregulation of adenylyl
cyclase isoforms of the type II family as well as a substantial increase in their phosphorylation state. As a result, there
is a shift in opioid receptor/G-protein signaling from predominantly Giα inhibitory to Gβγ stimulatory following chronic in vivo morphine exposure. These adaptations to chronic morphine indicate the plasticity of
opioid-signal transduction mechanisms and the ability of chronic morphine to augment new signaling strategies. |
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Keywords: | Opioid tolerance adenylyl cyclase phosphorylation plasticity isoforms |
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