Abstract
Our hypothesis is that heterologous tolerance following chronic treatment with morphine is an adaptive process mediated by alterations in one or more cellular signaling proteins. This lab has previously characterized a time course for the onset and decay of tolerance following subcutaneous (sc) injection by assessing tolerance using paw pressure testing and the response of the longitudinal muscle/myenteric plexus (LM/MP) to DAMGO and 2‐CADO after various schedules of treatment. Western blot protein analysis in LM/MP homogenates from those animals revealed no change in the number of μ, A1, or A2a receptors, indicating that the tolerance observed in that tissue cannot be explained by a decrease in receptor abundance. Because the brainstem is involved in the analgesic effect produced by morphine, we examined the abundance of several proteins in tissue homogenates obtained from the same animals used for the previous time course study. Western blot analysis of brainstem homogenates also revealed no change in the abundance of μ, A1, and A2a receptors at all time points examined. In addition, the α2b receptor was also largely unchanged. Previous studies have shown that the α3 subunit of the Na+/K+ ATPase decreased as tolerance develops and returned to baseline as tolerance decays in the LM/MP. We therefore determined the abundance of the α1, α3, and β1 subunits of the Na+/K+ ATPase. Unlike results obtained from the LM/MP, we observed no change in any of these subunits in the brainstem. We also examined PKCγ and PKCɛ and observed that PKCγ decreases in concentration as tolerance develops and that this change reverses as tolerance decays. PKCγ is not present in the LM/MP and PKCɛ does not change significantly there. These data indicate that PKCγ may be an important mediator for the development of tolerance in the brainstem and that the cellular mechanism by which tolerance develops may be different between the LM/MP and brainstem.
Published Version
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