Cannabinoid physiology and pharmacology: 30 years of progress.
Delta9-Tetrahydrocannabinol from Cannabis sativa is mimicked by cannabimimetic analogs such as CP55940 and WIN55212-2, and antagonized by rimonabant and SR144528, through G-protein-coupled receptors, CB1 in the brain, and CB2 in the immune system. Eicosanoids anandamide and 2-arachidonoylglycerol are the "endocannabinoid" agonists for these receptors. CB1 receptors are abundant in basal ganglia, hippocampus and cerebellum, and their functional activity can be mapped during behaviors using cerebral metabolism as the neuroimaging tool. CB1 receptors couple to G(i/o) to inhibit cAMP production, decrease Ca2+ conductance, increase K+ conductance, and increase mitogen-activated protein kinase activity. Functional activation of G-proteins can be imaged by [35S]GTPgammaS autoradiography. Post-synaptically generated endocannabinoids form the basis of a retrograde signaling mechanism referred to as depolarization-induced suppression of inhibition (DSI) or excitation (DSE). Under circumstances of sufficient intracellular Ca2+ (e.g., burst activity in seizures), synthesis of endocannabinoids releases a diffusible retrograde messenger to stimulate presynaptic CB1 receptors. This results in suppression of gamma-aminobutyric acid (GABA) release, thereby relieving the post-synaptic inhibition. Tolerance develops as neurons adjust both receptor number and cellular signal transduction to the chronic administration of cannabinoid drugs. Future therapeutic drug design can progress based upon our current understanding of the physiology and pharmacology of CB1, CB2 and related receptors. One very important role for CB1 antagonists will be in the treatment of craving in the disease of substance abuse.
Howlett
Allyn C
AC
Neuroscience of Drug Abuse Research Program, Julius L. Chambers Biomedical/Biotechnology Research Institute, North Carolina Central University, Durham, NC 27707, USA. ahowlett@wpo.nccu.edu
Breivogel
Christopher S
CS
Childers
Steven R
SR
Deadwyler
Samuel A
SA
Hampson
Robert E
RE
Porrino
Linda J
LJ
D000818:Animals; D063386:Cannabinoid Receptor Agonists; D063385:Cannabinoid Receptor Modulators / Q000502:physiology; D002186:Cannabinoids / Q000494:pharmacology*; D002188:Cannabis / Q000737:chemistry; D006801:Humans; D043882:Receptors, Cannabinoid / Q000187:drug effects / Q000502:physiology*; D012106:Research; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D063386:Cannabinoid Receptor Agonists; D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids; D043882:Receptors, Cannabinoid