The findings of many reports have led us to hypothesize that tolerance and dependence on an opioid may induce vast qualitative changes in the selectivity and the dynamics of the opioid receptor populations. It has been shown that morphine-induced analgesia is antagonized by dynorphin in the naive rat, but paradoxically augmented in morphine-tolerance mice. Naive monkeys were found not to self-administer ketocyclazocine and ethylketocyclazocine. In our laboratory, rats made tolerant and dependent on morphine readily self-administered ketocyclazocine, ethylketocyclazocine and dynorphin as substitutes for morphine. Changes in properties of the opioid receptor populations will be delineated by studying EEG, EEG power spectra and behavior in the naive vs. the morphine tolerant and dependent rat. Female Sprague-Dawley rats will be surgically prepared with cortical EEG and temporalis EMG electrodes and permanent indwelling i.v. and i.vt. cannulae. The dose-response effects of morphine (mu agonist), ethylketocyclazocine and dynorphin (kappa agonists), (-)-SKF 10,047 (sigma agonist) and DADLE and DTLET (delta agonists) on EEG, EEG power spectra and behavior will be determined and compared in the naive rat. Dose-response effects of the same agonists will be determined in rats made tolerant to morphine. Whereas qualitative differences between naive and morphine-tolerant rats in the EEG and EEG power spectra effects will represent qualitative changes in receptor properties, quantitative changes will reflect degree of tolerance. We will also assess the reinforcing properties of selective mu, kappa, sigma and delta opioid agonists in naive rats (primary dependence), vs the dependent rat self-administering morphine. The differences in the reinforcing properties of the various opioids in the naive vs the morphine dependent rat should reflect qualitative changes in receptor characteristics secondary to the dependence state. We intend to perform in vitro receptor-binding studies in parallel rats similarly subjected to the above opioid treatments. Changes in receptor affinity and modifications in receptor selectivity towards ligands of different classes of opioid will be determined.
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