Cannabinoid Receptor Agonists Inhibit Ca²⁺ Influx to Synaptosomes from Rat Brain

Abstract

We examined the effects of cannabinoid receptor agonists on ⁴⁵Ca²⁺ uptake in rat brain synaptosomes. A cannabinoid receptor agonist, (R)-(+)-[2,3-dihydro-5-methyl-3-[(4-merpholino)methyl]pyrrolo-[1,2,3-de]-1,4-benzoxazin-6-yl](1-naphthyl)methanone (WIN 55212-2) dose-dependently inhibited ⁴⁵Ca²⁺ uptake in rat synaptosomes. Only an endogenous cannabinoid receptor agonist, anandamide, dose-dependently inhibited ⁴⁵Ca²⁺ uptake in rat synaptosomes, but not an endogenous cannabinoid receptor agonist, palmitoylethanolamide. Only a cannabinoid CB1 antagonist, [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamidehydrochloride] (SR 141716A), reversed the inhibitory effect of these WIN 55212-2 and anandamide on ⁴⁵Ca²⁺ uptake in rat synaptosomes, but not a cannabinoid CB2 receptor antagonist, [N-[(1S)-endo-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)pyrazole-3-carboxamide] (SR 144528). The inhibitory effects of WIN 55212–2 and anandamide on ⁴⁵Ca²⁺ uptake in rat synaptosomes were reversed by the pretreatment of a voltage-sensitive A-type K⁺ channel blocker, dendrotoxin, but no other type of K⁺ channel blockers, i.e. iberiotoxin, charybdotoxin or glibenclamide. These findings suggest that cannabinoid receptors inhibit Ca²⁺ influx into rat brain nerves via the activation of CB1 receptors and the opening of voltage-sensitive A-type K⁺ channels.

Prejunctional and peripheral effects of the cannabinoid CB1 receptor inverse agonist rimonabant (SR 141716)

“…Interestingly, such Ca 2+ elevations may involve G q rather than G i proteins and also a phospholipase C (Lauckner et al 2005). Rimonabant can also antagonize the cannabinoid-induced inhibition of Ca 2+ uptake into rat brain synaptosomes or NG108-15 cells, possibly also independent of G i proteins (Rubovitch et al 2002;Yoshihara et al 2006). Rimonabant also inhibited the cannabinoid-induced activation of protein kinase B in prostate cancer cells (Sanchez et al 2003a) and extracellular signal-regulated kinase in 3T3 F442A murine preadipocytes (Gary-Bobo et al 2006), rat arteries (Su and Vo 2007), and human endothelial cells (Liu et al 2000).…”

The cannabinoid receptor antagonist AM251 increases paraoxon and chlorpyrifos oxon toxicity in rats

“…Once released into the synapse, eCB signaling is affected primarily by activation of presynaptic G-protein coupled cannabinoid CB1 receptors, with modulation of neurotransmitter release coupled to inhibition of calcium influx or facilitation of potassium efflux. Other signal transduction pathways may also play a role (Maingret et al 2001; Brown et al 2004; van der Steldt and Di Marzo 2005; Yoshihara et al 2006). …”

Therapeutic utility of palmitoylethanolamide in the treatment of neuropathic pain associated with various pathological conditions: a case series

“…PEA also has affinity to cannabinoid-like G protein-coupled receptors GPR55 and GPR119 8. PEA can influence ion channels (eg, potassium channels) that play a role in pain 9. Furthermore, PEA might desensitize transient receptor potential cation channel subfamily V member 1 channels on sensory neurons 10,11…”