Trends in Neurosciences
Volume 21, Issue 12, 1 December 1998, Pages 521-528
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Endocannabinoids: endogenous cannabinoid receptor ligands with neuromodulatory action

https://doi.org/10.1016/S0166-2236(98)01283-1Get rights and content

Abstract

The existence of an endogenous cannabinoid system was demonstrated conclusively with the discovery of endogenous brain constituents capable of activating the cannabinoid receptors functionally. These compounds are synthesized by neuronal cells and inactivated through re-uptake and enzymatic hydrolysis by both neurons and astrocytes. In analogy with the endorphins they can be referred to as endocannabinoids. Apart from the identification of their metabolic pathways, research carried out in the past six years has focused on the possible cellular and molecular targets for the actions of endocannabinoids. These studies have confirmed a similarity between the endocannabinoids and the psychoactive substance in marijuana, Δ9(−)-tetrahydrocannabinol, and have suggested a role for endocannabinoids in the modulation of neurotransmitter action and release.

Section snippets

Endocannabinoids and the endogenous cannabinoid system

In 1992, the first endogenous ligand of CB1 receptors was identified in porcine brain[8]. This substance is the amide of arachidonic acid (AA) with ethanolamine, and was named anandamide from the Sanskrit word `ananda' meaning `bliss'. This brain component was able to reproduce the most typical behavioural effects of THC in rodents, that is, inhibition of locomotor activity in open-field and ring-immobility tests, analgesia on a hot plate, and rectal hypothermia[9]. Moreover, anandamide

How the brain makes and disposes of endocannabinoids

After the discovery of anandamide and its cannabimimetic properties, the first step towards establishing its possible neurophysiological role was to find mechanisms for its biosynthesis and inactivation in the CNS (Fig. 2). Studies carried out in the rat[22]showed that the synthesis and release of anandamide, whose basal levels in brain are low compared to most neurotransmitters[23], could be stimulated in intact cortical and striatal neurones (but not astrocytes) by treatment with

Cannabinoid-receptor-mediated actions of endocannabinoids in neurones and astrocytes

In the nervous system, endocannabinoids exert most of their pharmacological actions by activating the CB1 receptor, which is preferentially expressed in neurones of specific brain regions7, 21. In transfected cells, the interaction with overexpressed CB1 receptors and the subsequent activation of pertussis toxin-sensitive G-proteins allows anandamide to modulate negatively adenylate cyclase and voltage-sensitive Ca2+ channels and to activate the inwardly rectifying K+ channel12, 13, 41(Fig. 3).

Endocannabinoids as neuromodulators: where, when and why?

Some of the intracellular actions outlined above strongly suggest a role for endocannabinoids as modulators of neurotransmitter release and action (Fig. 3, Table 1). Their inhibitory effect on presynaptic voltage-sensitive Ca2+ channels might counteract the depolarization-induced release of neurotransmitters, whereas the facilitatory action on inwardly rectifying K+ channels could reduce the likelihood of pre- and postsynaptic depolarization and of action potential generation15, 21. Presynaptic

What is behind the endogenous cannabinoid system?

Six years of intensive research on endocannabinoids have not yet succeeded in identifying the key physiological function of the endogenous cannabinoid system. Reports of the actions of anandamide and 2-AG in non-nervous tissues, namely in the reproductive and immune systems, have not been discussed in this article and widen the range of the possible roles played by these metabolites (for a review see Ref. [74]). Three of the typical behavioural effects of marijuana smoking, appetite

Acknowledgements

The authors are grateful to Dr John R. Tippins, Imperial College of Science, Technology and Medicine, London, UK and Dr Nicola De Marchi, Institute of Psychiatry, II Faculty of Medicine, University of Naples, Italy for critically reviewing the manuscript, and to Mr R. Turco for the artwork. The author's research was partly supported by the Human Frontier Science Program Organization (RG 26/95 to V.D.M.).

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