HUMAN PHARMACOLOGY OF THE OPIOID NEUROPEPTIDE DYNORPHIN A(1-13)

We evaluated the human pharmacology of dynorphin A(1-13) and determine d whether this peptide can modulate naloxone-precipitated withdrawal e ffects. Such information could help determine its receptor mechanism o f action and whether dynorphin is useful for treating opioid dependenc e. Six opioid-experienced subjects participated in a within-subject, p lacebo-controlled design. There were two phases, each with four test. sessions. In phase 1, volunteers who were not physically dependent wer e administered 0, 0.1, 0.32 and 1 mg/kg dynorphin (15-min i.v. infusio n) in ascending order, and subjective, observer-rated and physiologica l effects were monitored. Dynorphin produced brief, dose-related incre ases in drug effect ratings with both good and bad drug effects report ed by different subjects. There were no significant changes in pupil s ize, respiratory rate, skin temperature, heart rate or blood pressure. These data are consistent with preclinical findings that dynorphin ha s a short duration of action and does not primarily exert its direct e ffects through mu-opioid receptors. In four separate sessions of phase 2, acute morphine pretreatment (45 mg/70 kg i.m.) was followed 15 or 18 hr later by dynorphin (0 vs. 1 mg/kg, 15-min i.v.) and then naloxon e (1 or 3 vs. 10 mg/70 kg, 5-min i.v.). Under these conditions, dynorp hin weakly potentiated naloxone-precipitated withdrawal. These data co ntrast with those of previous preclinical studies showing dependence-a ttenuating effects of dynorphin and fail to support its use as an anti withdrawal agent in humans.