EFFECTS OF SYSTEMICALLY ADMINISTERED DYNORPHINS

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Kappa (k)- opioid ligands have received renewed attention due to their potential in the treatment of painful conditions, and their ability to attenuate the effects of psychostimulants (e.g., cocaine). The objective of these studies is to test the Central Hypothesis that dynorphin A(I-17) (an endogenous agonist at k-receptors), and E-2078 (a stable dynorphin A(1-8) analog), are high efficacy, peripherally selective agonists at the proposed "k," subtype opioid receptors, after systemic administration in rhesus monkeys. Several studies have focused on dynorphin pharmacology after central administration in rodents. In contrast, the effects of systemically administered dynorphins in monkeys have not been widely studied, and may be of particular clinical relevance, due to qualitative and quantitative similarities between k-receptor populations in non-human primates and humans. Studies to date reveal that systemically administered dynorphins produce some, but not all the effects commonly associated with non-peptidic k-agonists in primates, including humans. This is of particular interest, because clinical use of selective non-peptidic k-agonists has been limited by their undesirable effects (e.g., sedation and dysphoric subjective effects). The dynorphins may produce clinically relevant effects (e.g., anti-allodynia), with fewer or less severe undesirable effects. The agonist actions of intravenously administered dynorphin A(I-17) and E-2078 will therefore be characterized in assays ofthermal antinociception and capsaicin-induced thermal allodynia, and in a neuroendocrine endpoint, increases in serum prolactin levels. Prolactin levels can be used as a sensitive, quantitative marker of systemic dynorphin pharmacology in human and non-human primates. The receptor mediation of dynorphin effects in all the above assays will be initially studied by pretreatment with opioid antagonists (naltrexone and its peripherally selective analog, quaternary naltrexone). Overall, dynorphin A(I-I 7) and E-2078 will be compared to the non-opioid fragment, dynorphin A(2-17), to subtype-selective k-opioid ligands (U69,593 and bremazocine) and to a partial k-agonist (nalorphine). Specifically, we aim to determine whether the dynorphins'apparent efficacy, their proposed peripheral selectivity and their proposed k-subtype selectivity may be relevant to their in vivo profile in primates (and thus their clinical potential).