SYSTEMICALLY ADMINISTERED DYNORPHINS

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The dynorphins comprise both endogenous opioid peptides such as dynorphin A 1-17 and fragments of dynorphin A, as well as peptide analogs based on the dynorphin structure. Dynorphin A has been proposed as the endogenous ligand for the K type of opioid receptor, and many of the dynorphins do show K-selective profiles of action. Most studies examining the in vivo effects of the dynorphins have examined the effects of the central (eg. intracerebroventricular or intrathecal) administration of dynorphins in rodents; the effect of systemic administration of these compounds in other species, and especially in primates, has not been well studied. Such studies are important since 1) clinically-useful drugs are ideally active following systemic administration and 2)rodents are probably not the best species for the preclinical evaluation of potential K-selective compounds since they have been shown to possess populations of K receptors that are quantitatively and qualitatively distinct from those found in primates. The dynorphins have emerged as a set of compounds especially deserving of such scrutiny since preliminary experiments indicate that systemic (iv) administration of dynorphin 1-13 and the recently-developed dynorphin analog E-2078 may produce analgesic effects without the dysphoric subjective effects that have impeded the clinical application of the alkaloid K agonists. The proposed experiments will follow up on this lead by examining in detail the agonist effects of a series of systemically-administered dynorphins in rhesus monkeys in assays of antinociception (warm-water tail-dip procedure and prostaglandin E2-induced hyperalgesia/allodynia), drug discrimination (monkeys trained to discriminate E-2078 from saline or the K agonist U69,593 from saline), food-reinforced operant responding (monkeys trained to respond under FR3O schedule of food reinforcement), gross behavior (observational rating scales of muscle relaxation and sedation), diuresis (volume of urination during three-hour test sessions) and reinforcement (substitution in monkeys trained to self-administer alfentanil). Any agonist effects will be evaluated for susceptibility to antagonism by the mu-selective opioid antagonist quadazocine, the K-selective antagonist nor-binaltorphimine, and, if warranted, the delta-selective antagonist naltrindole. The results of the these studies should reveal the degree to which prototypical members of the dynorphin family share a similar profile of agonist effects with potential for clinical application. In addition, these studies will provide information relevant to identifying the structural requirements for systemic dynorphin activity, which will inform the design and synthesis of new compounds. Finally, these studies will determine the role of K opioid receptors in mediating the effects of systemically-administered dynorphins.