Dynorphin fragments, mu/delta ligands, delta ligands and certain nonopioid peptides regulate in vivo morphine-induced and beta-endorphin-induced effects. These data suggest complex interactions between these peptides and mu opioids or beta-endorphin. Thus, many endogenous peptides from diverse peptide families are most likely involved in opioid-related homeostatic processes. We are currently studying the in vivo effects of dynorphin-A-(1-13) on morphine-induced changes in EEG, EEG spectral parameters, and behavior in rats. We are proposing extensions of these ongoing studies with the following specific aims. (1.) Determine whether the antagonism of morphine-induced changes in EEG spectral parameters by dynorphin fragments, mu/delta ligands, delta ligands and certain nonopioid peptides is competitive or non-competitive. (2.) Determine whether the regulatory effects of these peptides are sensitive to reversal by selective antagonists. (3.) Determine whether the regulatory effects of these peptides are affected by the relative state of morphine tolerance. (4.) Determine whether the enhancing effects of the mu/delta peptide leucine enkephalin and the delta peptide DPDPE are sensitive to reversal by a selective delta antagonist. (5.) Determine whether the enhancing effects of these peptides are affected by the relative state of morphine tolerance. Assessments of pharmacological similarities and differences among the regulatory effects of these endogenous peptides and related synthetic opioids should contribute to further understanding of the functional roles of these endogenous peptides. Furthermore, extensive studies of the in vivo interactions between various endogenous peptides and structurally related synthetic peptides seem warranted because the acquired information might be beneficial for the clinical management of pain and the clinical treatment of opioid dependence and abuse. Morphine and related mu opioid agonists are extensively used clinically. These in vivo interactions can be effectively delineated in our EEG and EMG rat model in which effects of opioids or cortical EEG and associated behavior have been studied for several years. In the presently proposed studies, EEG spectral parameters will allow assessments and comparisons of quantitative and qualitative, regulatory effects of opioid and nonopioid neuroactive peptides on morphine-induced effects in non-tolerant and morphine-tolerant rats.
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