Interactions between dynorphin A-(1--13) and morphine: In vivo effects on EEG, in vitro effects on tritium-morphine binding, and correlations between them in naive and morphine tolerant rats

Abstract

Utilizing an in vivo EEG functional assay and in vitro receptor binding techniques, the mechanisms of the modulatory effects of dynorphin A-(1-13) on morphine-induced EEG effects and receptor binding in naive vs. morphine-tolerant rats were studied. In naive rats, dynorphin A-(1-13) i.c.v. pretreatment significantly attenuated cumulative i.v. morphine-induced EEG spectral power and the maximal response, although dynorphin A-(1-13) alone produced little or no EEG bursting activity. Dynorphin A-(1-13) also significantly decreased the maximal binding (B{dollar}\sb{lcub}\rm max{rcub}{dollar}) for ({dollar}\sp3{dollar}H) -morphine without altering the affinity constant (K{dollar}\sb{lcub}\rm d{rcub}{dollar}) in rat cortical membranes. A significant linear correlation between in vivo EEG spectral power increases and in vitro receptor binding was found. These data suggest that the regulatory effects of dynorphin A-(1-13) on morphine-induced responses are non-competitive in nature. The linear correlation between in vivo and in vitro data suggests that the antagonism by dynorphin A-(1-13) on morphine-induced EEG changes may occur at the receptor level in naive rats. In morphine-tolerant rats, dynorphin A-(1-13) i.c.v. pretreatment produced opposite effects to those found in naive rats. Instead of antagonizing morphine-induced EEG spectral power, dynorphin A-(1-13) pretreatment significantly increased cumulative i.v. morphine-induced EEG spectral power and the maximal response. The effects of dynorphin A-(1-13) on ({dollar}\sp3{dollar}H) -morphine binding were complex in cortical membrane preparations from morphine-tolerant rats. While dynorphin A-(1-13) inhibited ({dollar}\sp3{dollar}H) -morphine binding at lower morphine concentrations, it was unable to inhibit ({dollar}\sp3{dollar}H) -morphine binding at higher morphine concentrations. Significant logarithmic correlations between in vivo EEG spectral power increases and in vitro receptor binding data were found. These findings suggest that while dynorphin A-(1-13) behaved as a non-competitive antagonist in naive rats, there may be positive cooperativity between morphine and dynorphin A-(1-13) at relatively lower affinity morphine binding sites in morphine-tolerant rats. Dynorphin A-(1-13) was also found to modulate morphine-induced qualitative EEG properties differently in naive vs. morphine-tolerant rats. While dynorphin A-(1-13) pretreatment qualitatively shifted the relative distribution of cumulative i.v. morphine-induced spectral power to predominantly faster frequencies in naive rats, it had no effects on the relative distribution of EEG spectral power in morphine-tolerant rats. These data suggest that dynorphin-induced quantitative and qualitative EEG changes of morphine may reflect different underlying processes. (Abstract shortened by UMI.)