Review

Targeting the endocannabinoid system: to enhance or reduce?

  • Nature Reviews Drug Discovery 7, 438455 (2008)
  • doi:10.1038/nrd2553
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Abstract

As our understanding of the endocannabinoids improves, so does the awareness of their complexity. During pathological states, the levels of these mediators in tissues change, and their effects vary from those of protective endogenous compounds to those of dysregulated signals. These observations led to the discovery of compounds that either prolong the lifespan of endocannabinoids or tone down their action for the potential future treatment of pain, affective and neurodegenerative disorders, gastrointestinal inflammation, obesity and metabolic dysfunctions, cardiovascular conditions and liver diseases. When moving to the clinic, however, the pleiotropic nature of endocannabinoid functions will require careful judgement in the choice of patients and stage of the disorder for treatment.

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IUPHAR Receptor Database

  1. CB1

    • CB2

      Acknowledgements

      The author wishes to thank A. Ligresti and S. Petrosino at the Endocannabinoid Research Group for their help with preparing the manuscript. This article is dedicated to the memory of the highly esteemed scientists and friends Professor Santosh Nigam, who passed away on 2 October 2007, and Professor Michael J. Walker, who passed away 5 January 2008.

      Author information

      Affiliations

      1. Endocannabinoid Research Group, Institute of Biomolecular Chemistry, National Research Council (CNR), Via Campi Flegrei 34, 80078, Pozzuoli, Naples, Italy.

        • Vincenzo Di Marzo

      Authors

      1. Search for Vincenzo Di Marzo in:

      Competing interests

      The author receives research grants from Allergan, Sanofi–Aventis and GW Pharmaceuticals. He has been in the speakers' bureau for Sanofi–Aventis. The author is co-inventor of several patents on endocannabinoid-based molecules.

      Glossary

      Cannabinoids

      Natural lipophilic products from the flower of Cannabis sativa, most of which have a typical bicyclic or tricyclic structure and a common biogenetic origin from olivetol.

      Cannabinoid receptors

      G-protein-coupled receptors for Δ9-tetrahydrocannabinol, so far identified in most vertebrate phyla. Two subtypes are known: CB1 and CB2.

      Endocannabinoids

      Endogenous agonists of cannabinoid receptors in animals.

      Δ9-Tetrahydrocannabinol

      The major psychotropic component of Cannabis sativa, and one of about 66 'cannabinoids' found in the flowers of this plant.

      2-arachidonoylglycerol

      (2-AG). The second most-studied endocannabinoid after anandamide. It is thought to be the most selective endogenous agonist of cannabinoid 1 and 2 (CB1 and CB2) receptors, and the one most often involved in CB1-mediated retrograde signalling.

      Hyperphagia

      A state characterized by an exaggerated drive for food consumption and subsequent enhanced food-intake.

      Gliosis

      Proliferation of astrocytes in damaged areas of the central nervous system, often associated with anoxic injury and neuronal death, and found in certain brain regions during various neurodegenerative disorders.

      Retrograde signalling

      A mechanism whereby a chemical signal is released from the postsynaptic neuron, travels in the synaptic space and activates presynaptic receptors to modulate the release of neurotransmitters, thereby influencing synaptic plasticity.

      Superoxide dismutase 1

      (SOD1). One of the enzymes that converts the superoxide anion in oxygen and hydrogen peroxide. Gain-of-function mutations in the Cu,Zn-SOD1 gene are implicated in progressive motor neuron death and paralysis in one form of inherited amyotrophic lateral sclerosis.

      Conditioned fear

      An animal defensive behaviour (for example, immobility or 'freezing') that is induced by exposure to aversive stimuli (for example, a non-noxious electrical shock) coupled to a non-aversive one (for example, a light or an acoustic tone). This behaviour can later be reinstated by simply re-exposing the animal to the non-aversive stimulus.

      Non-alcoholic steatosis

      Also known as non-alcoholic fatty liver disease, this is the inflammatory accumulation of fat in the liver when this is not due to excessive alcohol use. It is related to insulin resistance.

      Osteoblasts and osteoclasts

      Osteoblasts are mononucleate cells that are responsible for bone formation. They produce osteoid, which is composed mainly of type I collagen, and are responsible for mineralization of the osteoid matrix. Bones are constantly being reshaped by osteoblasts, which build bone, for example in its endocortical region, and osteoclasts, which resorb bone, for example in its trabecular region.

      Direct and indirect pathways of locomotor control

      Neuronal circuitries in the basal ganglia involving medium spiny GABA (γ-aminobutyric acid)ergic neurons of the dorsal striatum terminating onto other GABAergic neurons in either the substantia nigra reticulata or external layer of the globus pallidus, and ultimately causing stimulation or inhibition of locomotion, respectively.

      TRPV1

      A six-transmembrane-domain non-selective cation channel that is activated by either physical or chemical stimuli. Stimuli include thermosensation, sensory transduction, taste, flow-sensing, and the detection of obnoxious and irritant compounds.

      Theiler's virus

      Theiler's murine encephalo-myelitis virus (TMEV) is a single-stranded RNA picornavirus that persistently infects the mouse central nervous system, recently reclassified into the cardiovirus group. In the wild it produces a gastrointestinal infection that may be complicated by concomitant infection of the nervous system.