- 期刊
Alteration of the Interaction of Mu-Opioid Receptor and G Protein after Chronic PL017 Treatment in Rats
並列摘要
Alteration in ligand-receptor interaction during chronic drug treatment has been suggested as a possible mechanism underlying opioid tolerance. However, our previous studies found that chronic PL017 (a selective μ-opioid agonist) treatment of adult animals resulted in down regulation of μ opioid receptor levels only after 5 days of PL017 treatment although tolerance had significantly developed after 3 days of PL017 treatment. Since G protein seems to be involved in regulation of opioid receptors, we suspect that opioid receptor-G protein interaction may be altered after chronic PL017 treatment before down-regulation of opioid receptors occurrs. Our investigation proceeded first, by measuring the ability of Gpp(NH)p to alter t-opioid agonist: [(superscript 3)H]DAMGO binding; and second, by measuring the opioid agonist-stimulated GTPase activity before and after crhonic PL017 treatment for 1 or 3 days when tolerance has developed but without down-regulation. We found that after 1 day and 3 days of PL017 treatment, rats produced 1.9 and 7.4 fold degree of tolerance. In receptor binding assay, we found the B(subscript max) values did not show significant difference before and after chronic PL017 treatment. On the other hand, 10μM Gpp(NH)p (a stable GTP analogue) significantly increased the K(subscript d) of the control midbrain by 2.59 ± 0.21 fold but only increased the K(subscript d) by 1.92±0.11 fold after 3 days of PL017 treatment. Furthermore, the EC50 and maximal effect of DAMGO on stimulating low Km GTPase activity for control midbrain are 1.2±0.3 10^(-8)M and 21.7±0.6%, respectively; in the experimental group, after 3 days PL017 treatment, the EC50 has increased to 7.3±2.7×10^(-8)M and maximal stimulation decreased to 16.6±1.1%. The present findings indicate that after 3 days chronic PL017 treatment: (1) The effect of Gpp(NH)p on the affinity of μ-opioid receptor and DAMGO has been diminished. (2) The effect of DAM GO on stimulating low Km GTPase activity of G protein has been decreased. Therefore, it seems that the interaction between opioid receptor and G protein has been altered after chronic PL017 treatment. This phenomenum happens before down-regulation, and it may be one of the mechanisms for opioid tolerance.
延伸閱讀
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