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Cannabinoid Receptors and Endocannabinoids The AAPS Journal 2006; 8 (2) Article 34 (http://www.aapsj.org). Themed Issue: Lipid Mediator Lipidomics: New Pathways in Mapping Resolution Guest Editors - Charles N. Serhan, Song Hong and Yan Lu Cannabinoid Receptors and Endocannabinoids: Evidence for New Players Submitted: December 29 , 2005 ; Accepted: February 28 , 2006; Published: April 28, 2006 Ken Mackie1 and Nephi Stella2 1 Departments of Anesthesiology and Physiology and Biophysics, University of Washington, Seattle WA 2 Departments of Pharmacology, Psychiatry, and Behavioral Sciences, University of Washington, Seattle, WA A BSTRACT nabinoids, and are getting much closer to overcoming It is now well established that the psychoactive effects of these 2 challenges. Cannabis sativa are primarily mediated through neuronal C sativa contains ~60 phytocannabinoids, a handful of which CB1 receptors, while its therapeutic immune properties are bioactive as defi ned by their ability to specifi cally inter- are primarily mediated through CB2 receptors. Two endo- act with membrane-associated receptors, the cannabinoid cannabinoids, arachidonoylethanolamide and 2-arachi- receptors. The best-known phytocannabinoid is Δ 9 -tetrahy- donoylglycerol, have been identifi ed, their action on CB1 drocannabinol (THC),3 which is thought to mediate most — if and CB2 thoroughly characterized, and their production not all — of the psychotropic and addictive properties of C and inactivation elucidated. However, many signifi cant sativa . 4 Recent evidence suggest that some of the antiinfl am- exceptions to these rules exist. Here we review the evi- matory properties of C sativa may be accounted for by can- dence suggesting that cannabinoids can modulate synaptic nabinol (CBN) and cannabidiol (CBD), 2 nonpsychotropic transmission, the cardiovascular system, and the immune phytocannabinoids that constitute promising lead com- system through receptors distinct from CB1 and CB2, and pounds to develop cannabinoid-based antiinfl ammatory that an additional “ independent ” endocannabinoid sig- medicines.5 , 6 Thus, while some might focus on THC to study naling system that involves palmitoylethanolamide may the psychotropic and addictive properties of C sativa , others exist. might focus on CBN and CBD as a means to develop cannabinoid-based antiinfl ammatory therapeutics devoid of adverse effects. Here we will review our current understand- K EYWORDS: drug of abuse , cannabinoids , marijuana , ing of the cannabinoid receptors that mediate the effects of receptor cannabinoids and provide examples of the biological func- tions regulated by them, with a special emphasis on those receptors that have been pharmacologically characterized I NTRODUCTION and yet still remain to be cloned. We will also review our Cannabis sativa , also known as marijuana or hashish current understanding of the endogenous cannabinoids, the depending on the particular preparation, is both a wide- endocannabinoids, with a special emphasis on palmitoyleth- spread illegal drug of abuse and a well-recognized medici- anolamide (PEA), whose production and inactivation can nal plant.1 , 2 A current challenge in pharmacology is to occur independently of other endocannabinoids, and whose increase our understanding of the molecular mechanisms biological effects are mediated by interactions with one of underlying the abuse property of C sativa in order to the novel cannabinoid receptors. develop means to prevent it. Another challenge is to iso- late the bioactive components that impart the medicinal properties ascribed to this plant with the goal of develop- Cannabinoids Activate at Least 5 Distinct ing novel, cannabinoid-based therapeutics devoid of Cannabinoid Receptors adverse effects. After approximately 40 years of research, Two cannabinoid receptors, CB1 and CB2, have been iden- we have a much clearer understanding of the pharmacol- tifi ed by molecular cloning and are unambiguously estab- ogy and molecular mechanisms mediating the bioactivity lished as mediators of the biological effects induced by of plant-derived cannabinoid compounds, the phytocan- cannabinoids, either plant derived, synthetic, or endoge- nously produced. CB1 and CB2 are 7 transmembrane Gi/ o-coupled receptors that share 44% protein identity and Corresponding Author: Nephi Stella, Department of display different pharmacological profi les and patterns of Pharmacology, 357280, University of Washington, 1959 expression, 7 , 8 a dichotomy that provides a unique opportu- Pacifi c Ave N, Seattle, WA 98195-7280 . Tel: (206) nity to develop pharmaceutical approaches. Studies per- 221-5520 ; Fax: (206) 543-9520 ; E-mail: nstella@ formed with CB1 − / − and/or CB2 − / − mice identifi ed additional u.washington.edu cannabinoid receptors, 3 of which will be discussed below. E298 The AAPS Journal 2006; 8 (2) Article 34 (http://www.aapsj.org). CB1 Receptors experiments performed with CB2 − /− mice show that canna- The vast majority of CB1 receptors are expressed in the binoids engaging these receptors lead to changes in immune central nervous system (CNS), and their distribution in this responses, particularly at the level of macrophage-induced 8,22,26 tissue has been documented in detail using highly specifi c helper T-cell activation. CBN is more effi cacious at 27 antibodies and CB1 − / − tissue controls. The current picture CB2 receptors than THC, making this phytocannabinoid depicts abundant presynaptic expression in the adult more likely to account for the antiinfl ammatory properties mammalian brain.9 In some cases, these receptors are also of C sativa . For example, activation of CB2 receptors inhib- present on the dendrites and soma of neurons,10 although at its the ability of macrophages to process antigens and prime 26,28-31 lower levels and frequency than their presynaptic counter- helper T cells and at high concentrations may induce 32 parts. CB1 receptors are also expressed at low levels by immune cell apoptosis. various astrocytes, oligodendrocytes, and neural stem While many laboratories have reported the absence of CB2 cells. 11-13 To the best of our knowledge, expression of CB1 receptor expression in healthy brain,8 , 22 , 33-36 a new study receptors in situ by ependymal cells and/or microglia has has found that neurons located in specifi c brain structures, not been reported. such as the brain stem, express detectable levels of CB2 CB1 receptors couple to Gi/o proteins and, under specifi c mRNA and functional receptors, the activation of which is 37 conditions, also to Gs proteins (only when other Gi/o thought to regulate emesis. Furthermore, while resting protein-coupled receptors are concomitantly activated).14 , 15 microglia present in healthy CNS tissue express few — if By coupling to Gi/o proteins, CB1 receptors regulate the any — CB2 receptors, activated microglial cells, such as activity of many plasma membrane proteins and signal those found in mouse models of multiple sclerosis and transduction pathways, including ion channels, enzymes Alzheimer ’ s disease, express signifi cant levels of CB2 38,39 producing cyclic nucleotide second messengers, and vari- receptors. This result is not surprising since pathologi- ous kinases. Thus, depending on the coupling and cell type cal conditions are known to induce CB2 receptor expression 36 expressing CB1 receptors, cannabinoids may regulate dis- in leukocytes. Microglial cells in culture, which by default tinct cell functions. For example, activation of presynaptic are considered chronically activated, also express CB2 CB1 receptors inhibits N-type calcium channels, thus reduc- receptors, particularly at the leading edges of lamellipodia, 40 ing synaptic transmission.9 It is likely that THC induces protrusions involved in cell migration. Accordingly, appli- most — if not all — of its acute cognitive and intoxicating cation of CB2 agonists induces cell migration, a response 41-43 effects through this molecular mechanism.16 Whether THC that can be extended to other CB2-expressing cells. produces its effect by partially activating CB1 receptors Furthermore, several laboratories have shown that CB2 or antagonizing the action of endocannabinoids on this agonists reduce the release of cytotoxins by immune cells 44-47 receptor remains an open question.17 , 18 Activation of CB1 and increase their proliferation rate. Taken together, receptors expressed on the somata of neurons increases Erk these studies suggest that the ability of CB2-selective com- activity and induces brain-derived neurotrophic factor pounds to reduce infl ammation might be caused by an (BDNF) expression. 10 It is likely that the neuroprotective increase in proliferation and recruitment of immune cells, in properties of cannabinoids are in part mediated through particular a population of immune cells that do not release this mechanism. Recent evidence shows that CB1 receptor detrimental mediators and thus could be involved in the may also control the fate of neural stem cells, the outgrowth immune-mediated repair of damaged tissue. Again, blood- of neurites and the formation of functional synapses, empha- derived leukocytes expressing CB2 receptors and invading sizing the importance of this receptor in the remodeling the CNS via a disrupted blood brain barrier are likely to be of neuronal networks.13 , 19-21 Note that blood-derived leuko- activated by cannabinoids accumulating in the CNS and to cytes also express CB1 receptors, 22 suggesting that under modulate the development of neuroinfl ammation. Whether neuropathological conditions, whereby the blood brain
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