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Cited by 608Cannabis and Cannabinoid ResearchNeuroscience and Neuropharmacology ResearchReceptor Mechanisms and Signaling

Cannabinoid physiology and pharmacology: 30 years of progress

Howlett, Allyn C., Breivogel, Christopher S., Childers, Steven R., Deadwyler, Samuel A., Hampson, Robert E., Porrino, Linda J.·2004·Neuropharmacology
DOI 10.1016/j.neuropharm.2004.07.030
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Abstract

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.

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Crossref · 10.1016/j.neuropharm.2004.07.030

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  • Activation of CB1 suppresses neuronal activity by reducing Ca2+ entry via Cav2.2 channels and potassium efflux through KCC2 following presynaptic vesicle release.

    “Activation of CB1 suppresses neuronal activity by reducing Ca2+ entry via Cav2.2 channels and potassium efflux through KCC2 following presynaptic vesicle release (155).”

    From Nociplastic pain: the prominent role of non-neuronal cells in central and peripheral sensitization (2026) · cites this paper as [155]

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Authors
Howlett, A. C., Breivogel, C. S., Childers, S. R., Deadwyler, S. A., Hampson, R. E., & Porrino, L. J.
Affiliations
  • Campbell University (US)
  • Wake Forest University Health Sciences (US)
ORCID
Venue
Neuropharmacology
Publisher
Elsevier BV
Published
2004-01
Volume
47
Pages
345-358
ISSN
0028-3908 (ISSN-L)
DOI
10.1016/j.neuropharm.2004.07.030
OpenAlex
W2165518874
Cited by
608
References
9
Citations by year
2026: 9 · 2025: 10 · 2024: 8 · 2023: 15 · 2022: 13 · 2021: 18 · 2020: 19 · 2019: 21 · 2018: 23 · 2017: 27 · 2016: 23 · 2015: 24 · 2014: 21 · 2013: 26 · 2012: 48
FWCI
5.32
Type
journal article
Language
en
Open access
closed
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Neuropharmacology (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institute on Drug Abuse (R01DA006784, DA 06784, DA03502, DA00182, T32DA007246, R01DA008549, DA-00119, DA03690, P50DA006634, DA-12385, DA07246, DA 06634, U24DA012385, DA-08549, DA07624, R01DA003690, K05DA000182)
Topics
  • Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
Keywords
endocannabinoid system, cannabinoid receptors, CB1 receptor, CB2 receptor, delta-9-tetrahydrocannabinol, rimonabant, SR144528, CP55,940, WIN 55,212-2, anandamide, 2-arachidonoylglycerol, G protein-coupled receptors, retrograde signaling, depolarization-induced suppression of inhibition, GABA release, tolerance (pharmacology and immunology), drug design
MeSH terms
Animals, Cannabinoids, Cannabis, Humans, Research, Signal Transduction, Receptors, Cannabinoid, Cannabinoid Receptor Modulators, Cannabinoid Receptor Agonists

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