Involvement of a non-CB1/CB2 cannabinoid receptor in the aqueous humor outflow-enhancing effects of abnormal-cannabidiol

Exp Eye Res. 2012 Jul;100:59-64. doi: 10.1016/j.exer.2012.05.001. Epub 2012 May 8.

Abstract

The purpose of this study was to investigate the effects of abnormal-cannabidiol (abn-cbd), a non-psychoactive cannabinoid agonist, on aqueous humor outflow via the trabecular meshwork (TM) of porcine eye, and to examine the involvement of a non-CB1/CB2 cannabinoid receptor and the p42/44 mitogen-activated protein kinase (p42/44 MAPK) pathway. The effects of abn-cbd on aqueous humor outflow were measured using a porcine anterior segment perfused organ culture model. The activation of p42/44 MAPK by abn-cbd was determined in cultured TM cells with western blot analysis using an anti-phospho-p42/44 MAPK antibody. Administration of abn-cbd caused a concentration-dependent enhancement of aqueous humor outflow facility with a maximum effect (155.0 ± 11.7% of basal outflow facility) after administration of 30 nM abn-cbd. Pretreatment with 1 μM of O-1918, a cannabidiol analog that acts as a selective antagonist at the non-CB1/CB2 receptor, produced a full antagonism of 30 nM abn-cbd induced increase of aqueous humor outflow facility. Pretreatment with 1 μM of CB1 antagonist SR141716A partially blocked, whereas pretreatment with either 1 μM of CB1 antagonist AM251 or 1 μM of CB2 antagonist SR144528 had no effect on abn-cbd induced enhancement of outflow facility. Treatment of TM cells with 30 nM of abn-cbd activated p42/44 MAPK, which was blocked completely by pretreatment with O-1918, and partially by pretreatment with SR141716A, but not by either AM251 or SR144528. In addition, PD98059, an inhibitor of p42/44 MAPK pathway, blocked completely the abn-cbd induced p42/44 MAPK activation and blocked partially the abn-cbd induced enhancement of outflow facility. In conclusion, the results from this study demonstrate that abn-cbd increases aqueous humor outflow through the TM pathway of the eye, and this effect is mediated by a non-CB1/CB2 cannabinoid receptor, with an involvement of p42/44 MAPK signaling pathway.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Anisoles / pharmacology
  • Aqueous Humor / metabolism*
  • Blotting, Western
  • Cannabinoids / antagonists & inhibitors
  • Cells, Cultured
  • Cyclohexanes / pharmacology
  • Dose-Response Relationship, Drug
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Organ Culture Techniques
  • Piperidines / pharmacology
  • Pyrazoles / pharmacology
  • Receptor, Cannabinoid, CB1 / antagonists & inhibitors
  • Receptor, Cannabinoid, CB1 / metabolism*
  • Receptor, Cannabinoid, CB2 / antagonists & inhibitors
  • Receptor, Cannabinoid, CB2 / metabolism*
  • Resorcinols / pharmacology*
  • Rimonabant
  • Swine
  • Trabecular Meshwork / drug effects*
  • Trabecular Meshwork / metabolism

Substances

  • 1,3-dimethoxy-5-methyl-2-(3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl)benzene
  • 4-(3-3,4-p-menthadien-(1,8)-yl)olivetol
  • Anisoles
  • Cannabinoids
  • Cyclohexanes
  • Piperidines
  • Pyrazoles
  • Receptor, Cannabinoid, CB1
  • Receptor, Cannabinoid, CB2
  • Resorcinols
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Rimonabant