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Review
, 58 (3), 389-462

The Endocannabinoid System as an Emerging Target of Pharmacotherapy

Review

The Endocannabinoid System as an Emerging Target of Pharmacotherapy

Pál Pacher et al. Pharmacol Rev.

Abstract

The recent identification of cannabinoid receptors and their endogenous lipid ligands has triggered an exponential growth of studies exploring the endocannabinoid system and its regulatory functions in health and disease. Such studies have been greatly facilitated by the introduction of selective cannabinoid receptor antagonists and inhibitors of endocannabinoid metabolism and transport, as well as mice deficient in cannabinoid receptors or the endocannabinoid-degrading enzyme fatty acid amidohydrolase. In the past decade, the endocannabinoid system has been implicated in a growing number of physiological functions, both in the central and peripheral nervous systems and in peripheral organs. More importantly, modulating the activity of the endocannabinoid system turned out to hold therapeutic promise in a wide range of disparate diseases and pathological conditions, ranging from mood and anxiety disorders, movement disorders such as Parkinson's and Huntington's disease, neuropathic pain, multiple sclerosis and spinal cord injury, to cancer, atherosclerosis, myocardial infarction, stroke, hypertension, glaucoma, obesity/metabolic syndrome, and osteoporosis, to name just a few. An impediment to the development of cannabinoid medications has been the socially unacceptable psychoactive properties of plant-derived or synthetic agonists, mediated by CB(1) receptors. However, this problem does not arise when the therapeutic aim is achieved by treatment with a CB(1) receptor antagonist, such as in obesity, and may also be absent when the action of endocannabinoids is enhanced indirectly through blocking their metabolism or transport. The use of selective CB(2) receptor agonists, which lack psychoactive properties, could represent another promising avenue for certain conditions. The abuse potential of plant-derived cannabinoids may also be limited through the use of preparations with controlled composition and the careful selection of dose and route of administration. The growing number of preclinical studies and clinical trials with compounds that modulate the endocannabinoid system will probably result in novel therapeutic approaches in a number of diseases for which current treatments do not fully address the patients' need. Here, we provide a comprehensive overview on the current state of knowledge of the endocannabinoid system as a target of pharmacotherapy.

Figures

Fig. 1
Fig. 1
The chemical structure and pharmacological activity of selected plant derived (A), synthetic (B), and endogenous cannabinoids (C).
Fig. 2
Fig. 2
Selective agonists (A) and antagonists (B) of CB1 and CB2 receptors.
Fig. 3
Fig. 3
The structure and pharmacological specificity of inhibitors of FAAH and of endocannabinoid membrane transport.
Fig. 4
Fig. 4
Schematic representation of the endocannabinoid system in pre- and postsynaptic neurons. The presynaptic terminal is located in the top, whereas the postsynaptic neuron is located in the bottom. EMT, endocannabinoid membrane transporter; MAGL, monoacylglyceride lipase; DAGL, DAG lipase; AEA, anandamide; NArPE, N-arachidonyl phosphatidylethanolamine; NAT, N-acyltransferase.
Fig. 5
Fig. 5
Effects of anandamide, URB597, SR141716, and AM251 on left ventricular (LV) function in normotensive and spontaneously hypertensive rats. Representative left ventricular pressure-volume (PV) loops from WKY rats (a, d, and g) and SHR (b, c, e, f, h, and i) before (black) and after (red) treatment with indicated agents or their combinations. A leftward shift of PV loops and an increase in amplitude (pressure) indicate increased LV contractility, whereas a rightward shift and decrease in amplitude indicate decreased LV function. Experiments were repeated in three more animals in each treatment group with similar results. AEA, anandamide. Reproduced with permission from Bátkai et al. (2004) Circulation 110:1996–2002; © Lippincott Williams and Wilkins.
Fig. 6
Fig. 6
Cellular source and proposed targets of anti-inflammatory endocannabinoids in inflammatory bowel disease. a, cross-section of inflamed bowel with leukocyte infiltration [polymorphonuclear leukocytes (PNM), lymphocytes (Ly), macrophages, and mast cells]. b, in macrophages, LPS induces the production of TNF-α and chemokines (such as MIP-2macrophage inflammatory protein-2 and CXCL-8) as well as anandamide. Anandamide is released to act as an autocrine mediator to inhibit TNF-α and chemokine production via CB1 or CB2 receptors or both. Activation of CB1 and CB2 receptors may similarly inhibit TNF-α production in mast cells, with these effects resulting in decreased leukocyte infiltration and inflammation. Paracrine activation of CB1 receptors on extrinsic and intrinsic enteric neurons inhibits acetylcholine (ACh) and tachykinin release, respectively, resulting in inhibition of gut motility. These effects are amplified by treatment with a FAAH inhibitor, which prevents the breakdown of anandamide. Reproduced with permission from Kunos and Pacher (2004) Nat Med 10:678–679. © Nature Publishing Group.

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References

    1. Aapro M. Optimising antiemetic therapy: what are the problems and how can they be overcome? Curr Med Res Opin. 2005;21:885–897. - PubMed
    1. Abboud RT, Sanders HD. Effect of oral administration of Δ-tetrahydrocannabinol on airway mechanics in normal and asthmatic subjects. Chest. 1976;70:480–485. - PubMed
    1. Abel EL. Cannabis: effects on hunger and thirst. Behav Biol. 1975;15:255–281. - PubMed
    1. Abood ME, Rizvi G, Sallapudi N, McAllister SD. Activation of the CB1 cannabinoid receptor protects cultured mouse spinal neurons against excitotoxicity. Neurosci Lett. 2001;309:197–201. - PubMed
    1. Abu-Elmagd KM, Zak M, Stamos JM, Bond GJ, Jain A, Youk AO, Ezzelarab M, Costa G, Wu T, Nalesnik MA, et al. De novo malignancies after intestinal and multivisceral transplantation. Transplantation. 2004;77:1719–1725. - PubMed

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