Mk. Greenwald et al., HUMAN PHARMACOLOGY OF THE OPIOID NEUROPEPTIDE DYNORPHIN A(1-13), The Journal of pharmacology and experimental therapeutics, 281(3), 1997, pp. 1154-1163
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.