TY - JOUR
T1 - Evidence that (-)-7-hydroxy-4′-dimethylheptyl-cannabidiol activates a non-CB1, non-CB2, non-TRPV1 target in the mouse vas deferens
AU - Pertwee, Roger G.
AU - Thomas, Adèle
AU - Stevenson, Lesley A.
AU - Maor, Yehoshua
AU - Mechoulam, Raphael
PY - 2005/6
Y1 - 2005/6
N2 - Previous experiments showed that R-(+)-WIN55212-induced inhibition of electrically-evoked contractions of mouse vasa deferentia could be antagonized by cannabidiol in a manner that appeared to be competitive but not to involve direct competition for established cannabinoid receptors. We have now discovered that (-)-7-hydroxy-4′-dimethylheptyl-cannabidiol (7-OH-DMH-CBD) inhibits electrically-evoked contractions of the vas deferens (EC50 = 13.3 nM). This it appeared to do by acting on prejunctional neurones as 100 nM 7-OH-DMH-CBD did not attenuate contractile responses to phenylephrine or β,γ-methylene-ATP. Although 7-OH-DMH-CBD was antagonized by SR141716A, it was less susceptible to antagonism by this CB1 receptor antagonist than R-(+)-WIN55212. 7-OH-DMH-CBD was also antagonized by cannabidiol (1 μM; apparent KB = 222.2 nM) but not by the CB 2 receptor antagonist, SR144528 (32 nM), or by naloxone (300 nM), ruthenium red (1 μM) or capsazepine (10 μM). Yohimbine (100 nM) enhanced the ability of 7-OH-DMH-CBD to inhibit electrically-evoked contractions. R-(+)-WIN55212 was also potentiated by 100 nM yohimbine, possibly reflecting ongoing sequestration of Gi/o proteins from CB1 receptors by α2-adrenoceptors. Our results suggest that 7-OH-DMH-CBD may activate a neuronal target in the vas deferens that is not a CB1, CB2, TRPV1, opioid or α2-adrenergic receptor but do not exclude the possibility that it also activates CB1 receptors.
AB - Previous experiments showed that R-(+)-WIN55212-induced inhibition of electrically-evoked contractions of mouse vasa deferentia could be antagonized by cannabidiol in a manner that appeared to be competitive but not to involve direct competition for established cannabinoid receptors. We have now discovered that (-)-7-hydroxy-4′-dimethylheptyl-cannabidiol (7-OH-DMH-CBD) inhibits electrically-evoked contractions of the vas deferens (EC50 = 13.3 nM). This it appeared to do by acting on prejunctional neurones as 100 nM 7-OH-DMH-CBD did not attenuate contractile responses to phenylephrine or β,γ-methylene-ATP. Although 7-OH-DMH-CBD was antagonized by SR141716A, it was less susceptible to antagonism by this CB1 receptor antagonist than R-(+)-WIN55212. 7-OH-DMH-CBD was also antagonized by cannabidiol (1 μM; apparent KB = 222.2 nM) but not by the CB 2 receptor antagonist, SR144528 (32 nM), or by naloxone (300 nM), ruthenium red (1 μM) or capsazepine (10 μM). Yohimbine (100 nM) enhanced the ability of 7-OH-DMH-CBD to inhibit electrically-evoked contractions. R-(+)-WIN55212 was also potentiated by 100 nM yohimbine, possibly reflecting ongoing sequestration of Gi/o proteins from CB1 receptors by α2-adrenoceptors. Our results suggest that 7-OH-DMH-CBD may activate a neuronal target in the vas deferens that is not a CB1, CB2, TRPV1, opioid or α2-adrenergic receptor but do not exclude the possibility that it also activates CB1 receptors.
KW - (-)-7-hydroxy-4′-dimethylheptyl-cannabidiol (7-OH-DMH-CBD)
KW - Cannabidiol
KW - G protein sequestration
KW - Mouse vas deferens
KW - R-(+)-WIN55212
KW - Yohimbine
UR - http://www.scopus.com/inward/record.url?scp=19444386763&partnerID=8YFLogxK
U2 - 10.1016/j.neuropharm.2005.01.010
DO - 10.1016/j.neuropharm.2005.01.010
M3 - Article
C2 - 15910889
AN - SCOPUS:19444386763
VL - 48
SP - 1139
EP - 1146
JO - Neuropharmacology
JF - Neuropharmacology
SN - 0028-3908
IS - 8 SPEC. ISS.
ER -