Dynorphin A1-13 causes elevation of serum levels of prolactin through an opioid receptor mechanism in humans: gender differences and implications for modulation of dopaminergic tone in the treatment of addictions.
Dynorphin peptides act preferentially at kappa- as well as mu- and delta-opioid receptors. This study was conducted to determine whether dynorphin peptides act to lower dopaminergic tone in the tuberoinfundibular system, resulting in elevated serum prolactin levels and, if so, whether such an effect is mediated by the opioid receptors. Dose-related increases in serum prolactin levels were observed after dynorphin A1-13 was administered i.v. in doses of 120 and 500 micrograms/kg to healthy human volunteers with no history of drug or alcohol abuse. Studies were then conducted to determine whether this effect is opioid receptor mediated and, if so, whether at kappa- or mu types. Pretreatment with the opioid antagonist nalmefene (30 mg i.v.), which has high affinity at both mu- and kappa-opioid receptors, caused a greater attenuation in dynorphin A1-13-stimulated increases in serum prolactin levels than pretreatment with similarly high doses of naloxone, an antagonist with lower affinity for both mu- and kappa-opioid receptors. These results suggest dynorphin A1-13 lowers tuberoinfundibular dopaminergic tone through action at kappa- and possibly mu-opioid receptors. Female subjects were significantly more responsive to the prolactin effects of dynorphin than were male subjects. Dynorphin gene expression, dynorphin peptides, and kappa-opioid receptor gene expression and binding have been shown to be altered in response to cocaine administration. Also, both dynorphin peptides and synthetic kappa-opioid agonists have been shown to lower dopamine levels in the nucleus accumbens and to attenuate cocaine-induced surges in dopamine levels. Thus, a dynorphin-like compound capable of reaching critical mesolimbic-mesocortical and nigrostriatal dopaminergic systems may be effective in the management of cocaine addiction.
Kreek
M J
MJ
Laboratory of the Biology of Addictive Diseases, The Rockefeller University, New York, New York, USA.
Schluger
J
J
Borg
L
L
Gunduz
M
M
Ho
A
A
D000328:Adult; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology*; D000704:Analysis of Variance; D019970:Cocaine-Related Disorders / Q000097:blood / Q000628:therapy; D004305:Dose-Response Relationship, Drug; D004399:Dynorphins / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009270:Naloxone / Q000494:pharmacology; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology*; D011388:Prolactin / Q000032:analysis / Q000097:blood*; D011954:Receptors, Dopamine / Q000187:drug effects / Q000378:metabolism; D011957:Receptors, Opioid / Q000378:metabolism*; D017473:Receptors, Opioid, kappa / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000187:drug effects / Q000378:metabolism; D012727:Sex Characteristics; D013997:Time Factors
D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D010446:Peptide Fragments; D011954:Receptors, Dopamine; D011957:Receptors, Opioid; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D009270:Naloxone; D009271:Naltrexone; C026843:dynorphin (1-13); D004399:Dynorphins; D011388:Prolactin; C038981:nalmefene