Abstract
Dynorphin peptides act preferentially at κ- as well as μ- and δ-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 μg/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 κ- or μ types. Pretreatment with the opioid antagonist nalmefene (30 mg i.v.), which has high affinity at both μ- and κ-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 μ- and κ-opioid receptors. These results suggest dynorphin A1–13 lowers tuberoinfundibular dopaminergic tone through action at κ- and possibly μ-opioid receptors. Female subjects were significantly more responsive to the prolactin effects of dynorphin than were male subjects. Dynorphin gene expression, dynorphin peptides, and κ-opioid receptor gene expression and binding have been shown to be altered in response to cocaine administration. Also, both dynorphin peptides and synthetic κ-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.
Footnotes
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1 This work was conducted with support from a National Institutes of Health-National Institute on Drug Abuse Research Center Grant P50-DAO5130, a National Institutes of Health-National Institute on Drug Abuse Research Scientific Award Grant KO5-DA00049, a grant from the New York State Office of Alcoholism and Substance Abuse Services, and a General Clinical Research Center grant (M01-RR00102) from the National Center for Research Resources at the National Institutes of Health.
- Abbreviations:
- ANOVA
- analysis of variance
- GABA
- γ-aminobutyric acid
- Received January 7, 1998.
- Accepted August 4, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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