Cannabinoid physiology and pharmacology: 30 years of progress

doi:10.1016/j.neuropharm.2004.07.030

Neuropharmacology

Volume 47, Supplement 1, 2004, Pages 345-358

https://doi.org/10.1016/j.neuropharm.2004.07.030 Get rights and content

Abstract

Δ⁹-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]GTPγS 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 γ-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.

Section snippets

Plant-derived and synthetic cannabimimetic agents

Ingestion of Cannabis sativa preparations such as marijuana (leaves and flowering tops) or ganja (resin) results in an intoxication characterized by sedation, cognitive dysfunction, failure to consolidate short-term memory, alteration in time assessment, perceptual changes, motor incoordination and poor executive function (see Abood and Martin, 1992, Dewey, 1986, Hollister, 1986, Pertwee, 1988 for review). Cannabinoid compounds isolated from the plant C. sativa comprise a family of tricyclic

Radioreceptor ligand binding and in situ hybridizaton of CB₁ receptors

CB₁ receptors are among the most abundant G-protein-coupled receptors in brain, their densities being similar to levels of γ-aminobutyric acid (GABA)- and glutamate-gated ion channels. The distribution of cannabinoid receptors within the central nervous system was first described by Miles Herkenham in a landmark study using quantitative in vitro receptor autoradiography with the radioligand [³H]CP55940 (Herkenham et al., 1991). The distribution of CB₁ receptors is highly heterogeneous with the

Signal transduction mechanisms of cannabinoid receptors

Both CB1 and CB2 cannabinoid receptors are members of the superfamily of G-protein-coupled receptors, so the signal transduction properties of these receptors are mediated by the process of G-protein activation. The use of specific signal transduction assays was a critical turning point in the identification of specific cannabinoid receptors. After many years of speculation, the existence of cannabinoid receptors was confirmed when Howlett and colleagues showed that cannabinoids decreased cAMP

Functional consequences of cannabinoid receptor activation

Cannabinoid receptors are among the most ubiquitous neurotransmitter elements in the mammalian brain, as they are present in almost every brain region and on many different types of neurons (Moldrich and Wenger, 2000). The multiple consequences of cannabinoid receptor activation, i.e., a reduction in adenylyl cyclase, modulation of ion channels and reduction in intracellular Ca²⁺, provide an important basis for control of multiple cellular signaling processes within the brain (Breivogel et al.,

Chronic cannabinoid effects on receptors and signal transduction systems

Chronic administration of cannabinoid drugs to animals results in tolerance to many of the acute effects of Δ⁹-THC, including memory disruption (Deadwyler et al., 1995), decreased locomotion (Abood et al., 1993, Oviedo et al., 1993), hypothermia (Fan et al., 1996, Pertwee et al., 1993), neuroendocrine effects (Rodriguez de Fonseca et al., 1991), and analgesia (Adams and Martin, 1996). Both cannabinoid receptors and their signal transduction systems are significantly regulated by chronic agonist

The next 30 years of cannabinoid physiology and pharmacology

Cannabinoid receptor agonists were developed by the pharmaceutical industry as non-NSAID, non-opioid analgesics; however, their therapeutic utility was curtailed due to untoward side effects such as sedation and cognitive dysfunction (Johnson et al., 1981). Both beneficial and untoward effects were believed to be the result of CB₁ receptor activation. As the result of landmark studies in CB₁ −/− knock-out mice (DiMarzo et al., 2000, Breivogel et al., 2001), we now understand that the

Acknowledgements

This work was supported by National Institute on Drug Abuse grants DA03690, DA00182, DA12385 to A.C.H.; DA07246 to C.S.B.; DA06784 to S.R.C.; DA03502, DA07624, DA00119 to S.A.D.; DA08549 to R.E.H; and DA06634 to L.J.P.

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Cannabinoid physiology and pharmacology: 30 years of progress

Abstract

Section snippets

Plant-derived and synthetic cannabimimetic agents

Radioreceptor ligand binding and in situ hybridizaton of CB1 receptors

Signal transduction mechanisms of cannabinoid receptors

Functional consequences of cannabinoid receptor activation

Chronic cannabinoid effects on receptors and signal transduction systems

The next 30 years of cannabinoid physiology and pharmacology

Acknowledgements

Trends Pharmacol. Sci

Pharmacol. Biochem. Behav

FEBS Lett

Neuroimage

Pharmacol. Biochem. Behav

Biochem. Pharmacol

Biochem. Biophys. Res. Commun

J. Biol. Chem

Eur. J. Pharmacol

Eur. J. Pharmacol

Biochem. Biophys. Res. Commun

Biochem. Pharmacol

J. Neuroimmunol

Eur. J. Pharmacol

Neuron

Neuron

Brain Res

Brain Res

Neuroscience

Life Sci

Prog. Brain Res

Neurosci. Lett

Life Sci

Prostaglandins Other Lipid Mediat

Neuropharmacology

Eur. J. Pharmacol

Neuroscience

Eur. J. Pharmacol

Life Sci

Tetrahedron Lett

Cannabis: pharmacology and toxicology in animals and humans

Addiction

Pharmacokinetics and meta bolism of Δ1-tetrahydrocannabinol and other cannabinoids with emphasis on man

Pharmacol. Rev

Retrograde signaling in the regulation of synaptic transmission: focus on endocannabinoids

Prog. Neurobiol

Retrograde signalling in depolarization-induced suppression of inhibition in rat hippocampal CA1 cells

J. Physiol

The development of cannabinoid antagonists

Curr. Med. Chem

Transient suppression of GABA-A-receptor-mediated IPSPs after epileptiform burst discharges in CB1 pyramidal cells

J. Neurophysiol

Cannabinoid receptors and modulation of cyclic AMP accumulation in the rat brain

J. Neurochem

Cannabinoid receptor antagonists and obesity

Curr. Opin. Investig. Drugs

Activation of mitogen-activated protein kinases by stimulation of the central cannabinoid receptor CB1

Biochem. J

Signaling pathway associated with stimulation of CB2 peripheral cannabinoid receptor. Involvement of both mitogen-activated protein kinase and induction of Krox-24 expression

Eur. J. Biochem

Regional differences in cannabinoid receptor/G-protein coupling in rat brain

J. Pharmacol. Exp. Ther

Chronic Δ9-tetrahydrocannabinol treatment produces a time-dependent loss of cannabinoid receptors and cannabinoid receptor-activated G proteins in rat brain

J. Neurochem

Evidence for a new G protein-coupled cannabinoid receptor in mouse brain

Mol. Pharmacol

Memory consolidation during sleep: a neurophysiological perspective

J. Sleep Res

Biosynthesis of an endogenous cannabinoid precursor in neurons and its control by calcium and cAMP

J. Neurosci

Endocannabinoids facilitate the induction of LTP in the hippocampus

Nat. Neurosci

Cannabinoid receptor agonists inhibit Ca current in NG108-15 neuroblastoma cells via a pertussis toxin-sensitive mechanism

Br. J. Pharmacol

Cannabinoid receptors: G-protein-mediated signal transduction mechanisms

Biochem. Soc. Symp

SR141716, a central cannabinoid (CB) receptor antagonist, blocks the motivational and dopamine-releasing effects of nicotine in rats

Behav. Pharmacol

Aminoalkylindole analogs: cannabimimetic activity of a class of compounds structurally distinct from Δ9-tetrahydrocannabinol

J. Pharmacol. Exp. Ther

Radioreceptor ligand binding and in situ hybridizaton of CB₁ receptors

Pharmacokinetics and meta bolism of Δ¹-tetrahydrocannabinol and other cannabinoids with emphasis on man

Chronic Δ⁹-tetrahydrocannabinol treatment produces a time-dependent loss of cannabinoid receptors and cannabinoid receptor-activated G proteins in rat brain

Aminoalkylindole analogs: cannabimimetic activity of a class of compounds structurally distinct from Δ⁹-tetrahydrocannabinol