Opioids comprise a broad range of compounds, from classical morphine-like agonists to pure antagonists. Between those extremes are drugs with varying spectra of agonist and antagonist properties, probably as a consequence of interactions with multiple subtypes of opiate receptors. Abuse potential also varies considerably among the different types of opioids. Experiments are proposed that will continue an ongoing research program aimed at characterizing systematically and comprehensively the behavioral effects of opioids having different spectra of activities in order to identify and study components of drug action relevant to abuse potential, and to gain insights into the neuronal substrates subserving those components of action. Emphasis will be placed on clarifying the role of endogenous opioid peptides in the diverseness of the behavioral effects of opioid antagonists and agonists. Behavioral effects of opioid peptides will be determined following intracerebroventricular (icv) administration, their effects compared to those of prototypic opioid alkaloids, and interactions studied between opioid peptides administered icv and opioid antagonists and agonists administered systemically. Tests will usually be performed in two animal species (rat and squirrel monkey), and in several behavioral procedures in order to assess the generality of experimental findings. Principal studies will include: a) characterizing the discriminative stimulus effects of opioid peptides and their interactions with various opioid antagonists and agonists in animals trained to discriminate saline from prototypic agonists (e.g., morphine, ethylketocyclazocine, SKF 10,047) of proposed receptor subtypes; b) determining if the discrimination of saline from diprenorphine by monkeys is based on stimuli associated with a blockade of endogenous opioid peptide systems; c) assessing the effects of antagonists, agonists and opioid peptides alone and in combination on schedule-controlled behavior (punishment paradigm) in rats and monkeys, and on motor activity in rats. Experiments will also be continued to elucidate the fole of endogenous opioid peptides in the regulation of appetitive behaviors by testing pure opioid antagonists and peptides administered centrally to rats and monkeys.
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