The goal of this proposal is to study the effects of the opioid peptide dynorphin in heroin abusers during acute abstinence. Dynorphin is self- administered by morphine dependent mice and suppresses morphine withdrawal but has little or no antinociceptive activity by itself and produced no withdrawal syndrome of its own after chronic administration. This spectrum of activity is unique among opiate receptor ligands. In humans, initial studies suggest that dynorphin has analgesic potentiating activity and that a single dose may transiently reduce the severity of opiate withdrawal. These actions suggest that investigation of the effects of dynorphin in humans may provide insights into the mechanisms of opiate addiction and lead to new approaches to its treatment. The proposed study is a phase I/II clinical trial aimed at obtaining preliminary information about the duration of action, safety, and short- term efficacy of dynorphin in heroin addicts. The hypotheses to be tested are that dynorphin is safe, suppresses withdrawal, and reduced craving for heroin. Subjects will be hospitalized and allowed to develop signs and symptoms of opiate withdrawal. Each subject will then receive a single dose of placebo or 50, 150 or 500 ug/kg dynorphin i.v. Because the higher doses exceed those previously studied in humans, an initial 6 subjects will be studied unblinded. Four groups of 8 subjects will then receive each treatment using a randomized, double blinded protocol. Behavioral and physiologic parameters will be monitored for 24 h. This study will provide a preliminary assessment of whether the actions of dynorphin in humans are similar to its actions in animals, and whether dynorphin or dynorphin-like drugs may be useful in the management of opiate addiction. It is intended to be a preliminary investigation, to be followed by studies of longer term dynorphin administration if the single dose is shown to be effective.
| Specker, S; Wananukul, W; Hatsukami, D et al. (1998) Effects of dynorphin A(1-13) on opiate withdrawal in humans. Psychopharmacology (Berl) 137:326-32 |
| Pentel, P R; Wananukul, W; Hooke, L P et al. (1995) Effects of high intravenous doses of dynorphin A(1-13) on tail flick latency and central nervous system histology in rats. Pharmacol Biochem Behav 51:387-90 |
