Dynorphin A(1-13) causes elevation of serum levels of prolactin through anopioid 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-op ioid receptors. This study was conducted to determine whether dynorphin pep tides act to lower dopaminergic tone in the tuberoinfundibular system, resu lting in elevated serum prolactin revels and, if so, whether such an effect is mediated by the opioid receptors. Dose-related increases in serum prola ctin levels were observed after dynorphin A(1-13) was administered i.v. in doses of 120 and 500 mu g/kg to healthy human volunteers with no history of drug or alcohol abuse. Studies were then conducted to determine whether th is effect is opioid receptor mediated and, if so, whether at kappa- or mu t ypes. 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 A(1-13)-stimulated increases in serum prolactin l evels than pretreatment with similarly high doses of naloxone, an antagonis t with lower affinity for both mu- and kappa-opioid receptors. These result s suggest dynorphin A(1-13) lowers tuberoinfundibular dopaminergic tone thr ough action at kappa- and possibly mu-opioid receptors. Female subjects wer e significantly more responsive to the prolactin effects of dynorphin than were male subjects. Dynorphin gene expression, dynorphin peptides, and kapp a-opioid receptor gene expression and binding have been shown to be altered in response to cocaine administration. Also, both dynorphin peptides and s ynthetic kappa-opioid agonists have been shown to lower dopamine levels in the nucleus accumbens and to attenuate cocaine-induced surges in dopamine l evels. Thus, a dynorphin-like compound capable of reaching critical mesolim bic-mesocortical and nigrostriatal dopaminergic systems may be effective in the management of cocaine addiction.