In vivo evaluation of (+)-MR200 as a new selective sigma ligand modulating MOP, DOP and KOP supraspinal analgesia

Life Sci. 2006 Apr 18;78(21):2449-53. doi: 10.1016/j.lfs.2005.10.005. Epub 2005 Dec 1.

Abstract

The compound (+)-MR200 [(+)-methyl (1R,2S)-2-{[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]methyl}-1-phenylcyclopropanecarboxylate] is a sigma ligand with increased affinity and selectivity compared to the structurally related ligand haloperidol. From the results of a previous study on the modulation of a systemically injected KOP opioid agonist analgesia by (+)-MR200, we analysed the influence of this sigma ligand on the antinociceptive effect of centrally injected MOP, DOP, and KOP selective agonists using the tail-flick test in rats. The results obtained confirmed that systemic administration of (+)-MR200 (1mg/Kg s.c.) did not modify basal tail-flick latency. Pre-treatment with 1mg/Kg s.c. of (+)-MR200 provided a significant increase in the antinociceptive effect of DAMGO (100ng/rat i.c.v.) and DPDPE (20 microg/rat i.c.v.). Conversely to previous reports, pre-treatment with (+)-MR200 reversed, in these experimental conditions, U-50488H (100 microg/rat i.c.v.) analgesia. The mechanism involved in these effects was not clear, but provided additional data on a diverging modulator role of selective sigma-1 antagonists on KOP analgesia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / pharmacology
  • Analgesics, Opioid / pharmacology*
  • Animals
  • Cyclopropanes / pharmacology*
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / pharmacology
  • Enkephalin, D-Penicillamine (2,5)- / pharmacology
  • Injections, Intraventricular
  • Male
  • Pain Measurement / drug effects
  • Piperidines / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Opioid, delta / drug effects*
  • Receptors, Opioid, kappa / drug effects*
  • Receptors, Opioid, mu / drug effects*
  • Receptors, sigma / drug effects*

Substances

  • (+)-methyl 2-((4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl)methyl)-1-phenylcyclopropanecarboxylate
  • Analgesics, Opioid
  • Cyclopropanes
  • Piperidines
  • Receptors, Opioid, delta
  • Receptors, Opioid, kappa
  • Receptors, Opioid, mu
  • Receptors, sigma
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)-
  • 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer
  • Enkephalin, D-Penicillamine (2,5)-