Abstract
Herkinorin is the first μ-opioid receptor-selective ligand from the salvinorin A diterpenoid scaffold. Herkinorin has relative μ > κ > δ binding selectivity, and it can act as an agonist at both μ- and κ-receptors, in vitro. These studies were the first in vivo evaluation of the effects of herkinorin in nonhuman primates, using prolactin release, a neuroendocrine biomarker assay that is responsive to both μ- and κ-agonists, as well as to compounds with limited ability to cross the blood-brain barrier. In cumulative dosing studies (0.01–0.32 mg/kg i.v.), herkinorin produced only small effects in gonadally intact males (n = 4), but a more robust effect in females (n = 4). Time course studies with herkinorin (0.32 mg/kg) confirmed this greater effectiveness in females and revealed a fast onset after i.v. administration (e.g., by 5–15 min). Antagonism experiments with different doses of nalmefene (0.01 and 0.1 mg/kg) caused dose-dependent and complete prevention of the effect of herkinorin in females. This is consistent with a principal μ-agonist effect of herkinorin, with likely partial contribution by κ-agonist effects. The peripherally selective antagonist quaternary naltrexone (1 mg/kg s.c.) caused approximately 70% reduction in the peak effect of herkinorin (0.32 mg/kg) in females, indicating that this effect of herkinorin is prominently mediated outside the blood-brain barrier.
Footnotes
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This work was funded by National Institutes of Health-National Institute on Drug Abuse Grants DA017369 (to E.R.B.), DA018151 (to T.E.P.), and DA05130 (to M.J.K.).
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.108.140079.
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ABBREVIATIONS: ANOVA, analysis of variance.
- Received April 16, 2008.
- Accepted June 30, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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