The cannabinoid agonist Win55,212-2 inhibits calcium channels by receptor-mediated and direct pathways in cultured rat hippocampal neurons

Brain Res. 1998 Feb 2;783(1):77-84. doi: 10.1016/s0006-8993(97)01195-5.


The effects of the cannabinoid receptor agonist Win55,212 on Ca2+ channels were studied in rat hippocampal neurons grown in primary culture. Win55,212-2 inhibited whole-cell Ba2+ currents through Ca2+ channels by both CB1 receptor-mediated and direct mechanisms. The concentration dependent inhibition of the current showed two clear phases, a high-affinity receptor-mediated phase (IC50=14+/-2 nM) that was stereoselective and sensitive to a CB1 receptor antagonist, 300 nM SR141716, and a non-saturating phase that was neither stereoselective nor inhibited by SR141716. These concentration-dependent effects were paralleled by Win55212-induced inhibition of glutamatergic synaptic transmission. Win55,212-2 (100 nM) inhibited both omega-agatoxin IVA- and omega-conotoxin GVIA-sensitive currents. Thus, activation of cannabinoid receptors inhibits N- and P/Q-type Ca2+ channels. Activation of cannabinoid receptors inhibited only a fraction of the whole-cell Ca2+ channel current (17+/-2%) even though more than half of the whole-cell Ba2+ current was carried by N- and P/Q-type Ca2+ channels. Concentrations of agonist greater than 1 microM inhibited Ca2+ channels directly.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Analgesics / pharmacology*
  • Animals
  • Benzoxazines
  • Calcium Channel Blockers / pharmacology*
  • Cannabinoids / metabolism*
  • Cells, Cultured
  • Hippocampus / cytology
  • Hippocampus / drug effects*
  • Hippocampus / metabolism
  • Morpholines / pharmacology*
  • Naphthalenes / pharmacology*
  • Neural Pathways / physiology
  • Neurons / drug effects
  • Neurons / metabolism
  • Patch-Clamp Techniques
  • Rats
  • Receptors, Cannabinoid
  • Receptors, Drug / agonists*


  • Analgesics
  • Benzoxazines
  • Calcium Channel Blockers
  • Cannabinoids
  • Morpholines
  • Naphthalenes
  • Receptors, Cannabinoid
  • Receptors, Drug
  • (3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone