Lobeline, a potential pharmacotherapy for drug addiction, binds to μ opioid receptors and diminishes the effects of opioid receptor agonists

Dennis K. Miller, John R. Lever, Kelli R. Rodvelt, James A. Baskett, Matthew J. Will, George R. Kracke

Research output: Contribution to journalArticlepeer-review

Abstract

Lobeline diminishes the behavioral and neurochemical effects of nicotine and amphetamines, and is considered a potential pharmacotherapy for drug abuse and addiction. Lobeline has high affinity for nicotinic acetylcholine receptors and inhibits the function of vesicular monoamine and dopamine transporters. The present study investigated the less-explored interaction of lobeline and the endogenous opioid system. In guinea pig brain homogenates, lobeline displaced (Ki = 0.74 μM) the binding of [3H]DAMGO [(D-Ala2, N-ME-Phe4, Gly5-ol)-enkephalin]. In a functional assay system comprised of MOR-1 μ opioid receptors and GIRK2 potassium channels expressed in Xenopus oocytes, lobeline had no effect on the resting current, but maximally inhibited (IC50 = 1.1 μM) morphine- and DAMGO-activated potassium current in a concentration-dependent manner. In a second functional assay, lobeline-evoked [3H]overflow from rat striatal slices preloaded with [3H]dopamine was not blocked by naltrexone. Importantly, concentrations of lobeline (0.1-0.3 μM) that did not have intrinsic activity attenuated (∼50%) morphine-evoked [3H]overflow. Overall, the results suggest that lobeline functions as a μ opioid receptor antagonist. The ability of lobeline to block psychostimulant effects may be mediated by opioid receptor antagonism, and lobeline could be investigated as a treatment for opiate addiction.

Original languageEnglish (US)
Pages (from-to)282-291
Number of pages10
JournalDrug and alcohol dependence
Volume89
Issue number2-3
DOIs
StatePublished - Jul 10 2007
Externally publishedYes

Keywords

  • DAMGO
  • Dopamine
  • Dopamine transporter
  • Lobeline morphine
  • Opioid receptor
  • Striatum

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology
  • Psychiatry and Mental health
  • Pharmacology (medical)

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