Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.
Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.
OCR for page 33
Page 33 2 CANNABINOIDS AND ANIMAL PHYSIOLOGY Introduction Much has been learned since the publication of the 1982 Institute of Medicine (IOM) report Marijuana and Health.* Although it was clear then that most of the effects of marijuana were due to its actions on the brain, there was little information about how THC acted on brain cells (neurons), which cells were affected by THC, or even what general areas of the brain were most affected by THC. Too little was known about cannabinoid physiology to offer any scientific insights into the harmful or therapeutic effects of marijuana. That is no longer true. During the past 16 years, there have been major advances in what basic science discloses about the potential medical benefits of cannabinoids, the group of compounds related to THC. Many variants are found in the marijuana plant, and other cannabinoids not found in the plant have been chemically synthesized. Sixteen years ago it was still a matter of debate as to whether THC acted nonspecifically by affecting the fluidity of cell membranes or whether a specific pathway of action was mediated by a receptor that responded selectively to THC (Table 2.1). *The field of neuroscience has grown substantially since the publication of the 1982 IOM report. The number of members in the Society for Neuroscience provides a rough measure of the growth in research and knowledge about the brain: as of the middle of 1998, there were over 27,000 members, more than triple the number in 1982.
OCR for page 34
Page 34 TABLE 2.1 Landmark Discoveries Since the 1982 IOM Report Year Discovery Primary Investigators 1986 Potent cannabinoid agonists are developed; they are the key to discovering the receptor. M. R. Johnson and L. S. Melvin75 1988 First conclusive evidence of specific cannabinoid receptors. A. Howlett and W. Devaneh36 1990 The cannabinoid brain receptor (CB,) is cloned, its DNA sequence is identified, and its location in the brain is determined. L. Matsuda107 and M. Herkenham et al60 1992 Anandamide is discovereda naturally occurring substance in the brain that acts on cannabinoid receptors. R. Mechoulam and W. Devane37 1993 A cannabinoid receptor is discovered outside the brain; this receptor (CB2) is related to the brain receptor but is distinct. S. Munro112 1994 The first specific cannabinoid antagonist, SR 141716A, is developed. M. Rinaldi-Carmonal32 1998 The first cannabinoid antagonist, SR144528, that can distinguish between CB1 and CB2 receptors discovered. M. Rinaldi-Carmona133 Basic science is the wellspring for developing new medications and is particularly important for understanding a drug that has as many effects as marijuana. Even committed advocates of the medical use of marijuana do not claim that all the effects of marijuana are desirable for every medical use. But they do claim that the combination of specific effects of marijuana enhances its medical value. An understanding of those specific effects is what basic science can provide. The multiple effects of marijuana can be singled out and studied with the goals of evaluating the medical value of marijuana and cannabinoids in specific medical conditions, as well as minimizing unwanted side effects. An understanding of the basic mechanisms through which cannabinoids affect physiology permits more strategic development of new drugs and designs for clinical trials that are most likely to yield conclusive results. Research on cannabinoid biology offers new insights into clinical use, especially given the scarcity of clinical studies that adequately evaluate the medical value of marijuana. For example, despite the scarcity of sub-
OCR for page 35
Page 35 stantive clinical data, basic science has made it clear that cannabinoids can affect pain transmission and, specifically, that cannabinoids interact with the brain's endogenous opioid system, an important system for the medical treatment of pain (see chapter 4). The cellular machinery that underlies the response of the body and brain to cannabinoids involves an intricate interplay of different systems. This chapter reviews the components of that machinery with enough detail to permit the reader to compare what is known about basic biology with the medical uses proposed for marijuana. For some readers that will be too much detail. Those readers who do not wish to read the entire chapter should, nonetheless, be mindful of the following key points in this chapter: · The most far reaching of the recent advances in cannabinoid biology are the identification of two types of cannabinoid receptors (CB1 and CB2) and of anandamide, a substance naturally produced by the body that acts at the cannabinoid receptor and has effects similar to those of THC. The CB1 receptor is found primarily in the brain and mediates the psychological effects of THC. The CB2 receptor is associated with the immune system; its role remains unclear. · The physiological roles of the brain cannabinoid system in humans are the subject of much active research and are not fully known; however, cannabinoids likely have a natural role in pain modulation, control of movement, and memory. · Animal research has shown that the potential for cannabinoid dependence exists, and cannabinoid withdrawal symptoms can be observed. However, both appear to be mild compared to dependence and withdrawal seen with other drugs. · Basic research in cannabinoid biology has revealed a variety of cellular pathways through which potentially therapeutic drugs could act on the cannabinoid system. In addition to the known cannabinoids, such drugs might include chemical derivatives of plantderived cannabinoids or of endogenous cannabinoids such as anandamide but would also include noncannabinoid drugs that act on the cannabinoid system. This chapter summarizes the basics of cannabinoid biologyas known today. It thus provides a scientific basis for interpreting claims founded on anecdotes and for evaluating the clinical studies of marijuana presented in chapter 4.
OCR for page 36
Page 36 The Value of Animal Studies Much of the research into the effects of cannabinoids on the brain is based on animal studies. Many speakers at the public workshops associated with this study argued that animal studies of marijuana are not relevant to humans. Animal studies are not a substitute for clinical trials, but they are a necessary complement. Ultimately, every biologically active substance exerts its effects at the cellular and molecular levels, and the evidence has shown that this is remarkably consistent among mammals, even those as different in body and mind as rats and humans. Animal studies typically provide information about how drugs work that would not be obtainable in clinical studies. At the same time, animal studies can never inform us completely about the full range of psychological and physiological effects of marijuana or cannabinoids on humans. The Active Constituents of Marijuana D9-THC and D8-THC are the only compounds in the marijuana plant that produce all the psychoactive effects of marijuana. Because D9-THC is much more abundant than D8-THC, the psychoactivity of marijuana has been attributed largely to the effects of D9-THC. 11-OH-D9-THC is the primary product of D9-THC metabolism by the liver and is about three times as potent as D9-THC.128 There have been considerably fewer experiments with cannabinoids other than A9-THC, although a few studies have been done to examine whether other cannabinoids modulate the effects of THC or mediate the nonpsychological effects of marijuana. Cannabidiol (CBD) does not have the same psychoactivity as THC, but it was initially reported to attenuate the psychological response to THC in humans;81,177 however, later studies reported that CBD did not attenuate the psychological effects of THC.11,69 One double-blind study of eight volunteers reported that CBD can block the anxiety induced by high doses of THC (0.5 mg/kg).177 There are numerous anecdotal reports claiming that marijuana with relatively higher ratios of THC:CBD is less likely to induce anxiety in the user than marijuana with low THC:CBD ratios; but, taken together, the results published thus far are inconclusive. The most important effect of CBD seems to be its interference with drug metabolism, including D9-THC metabolism in the liver.14, 114 It exerts that effect by inactivating cytochrome P450s, which are the most important class of enzymes that metabolize drugs. Like many P450 inactivators, CBD can also induce P450s after repeated doses.13 Experiments in which mice were treated with CBD followed by THC showed that CBD treatment was associated with a substantial increase in brain concentrations of
OCR for page 37
Page 37 THC and its major metabolites, most likely because it decreased the rate of clearance of THC from the body.15 In mice, THC inhibits the release of luteinizing hormone, the pituitary hormone that triggers the release of testosterone from the testes; this effect is increased when THC is given with cannabinol or CBD.113 Cannabinol also lowers body temperature and increases sleep duration in mice.175 It is considerably less active than THC in the brain, but studies of immune cells have shown that it can modulate immune function (see ''Cannabinoids and the Immune System'' later in this chapter). The Pharmacological Toolbox A researcher needs certain key tools in order to understand how a drug acts on the brain. To appreciate the importance of these tools, one must first understand some basic principles of drug action. All recent studies have indicated that the behavioral effects of THC are receptor mediated.27 Neurons in the brain are activated when a compound binds to its receptor, which is a protein typically located on the cell surface. Thus, THC will exert its effects only after binding to its receptor. In general, a given receptor will accept only particular classes of compounds and will be unaffected by other compounds. Compounds that activate receptors are called agonists. Binding to a receptor triggers an event or a series of events in the cell that results in a change in the cell's activity, its gene regulation, or the signals that it sends to neighboring cells (Figure 2.1). This agonist-induced process is called signal transduction. Another set of tools for drug research, which became available only recently for cannabinoid research, are the receptor antagonists, so-called because they selectively bind to a receptor that would have otherwise been available for binding to some other compound or drug. Antagonists block the effects of agonists and are tools to identify the functions of a receptor by showing what happens when its normal functions are blocked. Agonists and antagonists are both ligands; that is, they bind to receptors. Hormones, neurotransmitters, and drugs can all act as ligands. Morphine and naloxone provide a good example of how agonists and antagonists interact. A large dose of morphine acts as an agonist at opioid receptors in the brain and interferes with, or even arrests, breathing. Naloxone, a powerful opioid antagonist, blocks morphine's effects on opiate receptors, thereby allowing an overdose victim to resume breathing normally. Naloxone itself has no effect on breathing. Another key tool involves identifying the receptor protein and determining how it works. That makes it possible to locate where a drug activates its receptor in the brainboth the general region of the brain and
OCR for page 38
Page 38 Figure 2.1 Diagram of neuron with synapse. Individual nerve cells, or neurons, both send and receive cellular signals to and from neighboring neurons, but for the purposes of this diagram only one activity is indicated for each cell. Neurotransmitter molecules are released from the neuron terminal and move across the gap between the "sending" and "receiving" neurons. A signal is transmitted to the receiving neuron when the neurotransmitters have bound to the receptor on its surface. The effects of a transmitted signal include: · Changing the cell's permeability to ions, such as calcium and potassium. · Turning a particular gene on or off. · Sending a signal to another neuron. · Increasing or decreasing the responsiveness of the cell to other cellular signals. Those effects can lead to cognitive, behavioral, or physiological changes, depending on which neuronal system is activated. Continued on bottom of p. 39
OCR for page 39
Page 39 the cell type where the receptor is located. The way to find a receptor for a drug in the brain is to make the receptor "visible" by attaching a radioactive or fluorescent marker to the drug. Such markers show where in the brain a drug binds to the receptor, although this is not necessarily the part of the brain where the drug ultimately has its greatest effects. Because drugs injected into animals must be dissolved in a waterbased solution, it is easier to deliver water-soluble molecules than to deliver fat-soluble (lipophilic) molecules such as THC. THC is so lipophilic that it can stick to glass and plastic syringes used for injection. Because it is lipophilic, it readily enters cell membranes and thus can cross the blood brain barrier easily. (This barrier insulates the brain from many bloodborne substances.) Early cannabinoid research was hindered by the lack of potent cannabinoid ligands (THC binds to its cannabinoid receptors rather weakly) and because they were not readily water soluble. The synthetic agonist CP 55,940, which is more water soluble than THC, was the first useful research tool for studying cannabinoid receptors because of its high potency and ability to be labeled with a radioactive molecule, which enabled researchers to trace its activity. Cannabinoid Receptors The cannabinoid receptor is a typical member of the largest known family of receptors: the G protein-coupled receptors with their distinctive pattern in which the receptor molecule spans the cell membrane seven times (Figure 2.2). For excellent recent reviews of cannabinoid receptor biology, see Childers and Breivogel,27 Abood and Martin,1 Felder and Glass,43 and Pertwee.124 Cannabinoid receptor ligands bind reversibly (they bind to the receptor briefly and then dissociate) and stereoselectively (when there are molecules that are mirror images of each other, only one The expanded view of the synapse illustrates a variety of ligands, that is, molecules that bind to receptors. Anandamide is a substance produced by the body that binds to and activates cannabinoid receptors; it is an endogenous agonist. THC can also bind to and activate cannabinoid receptors but is not naturally found in the body; it is an exogenous agonist. SR 141716A binds to but does not activate cannabinoid receptors. In this way it prevents agonists, such as anandamide and THC, from activating cannabinoid receptors by binding to the receptors without activating them; SR 141716A is an antagonist, but it is not normally produced in the body. Endogenous antagonists, that is, those normally produced in the body, might also exist, but none has been identified.
OCR for page 40
Page 40 Figure 2.2 Cannabinoid receptors. Receptors are proteins, and proteins are made up of strings of amino acids. Each circle in the diagram represents one amino acid. The shaded bar represents the cell membrane, which like all cell membranes in animals is composed largely of phospholipids. Like many receptors, the cannabinoid receptors span the cell membrane; some sections of the receptor protein are outside the cell membrane (extracellular); some are inside (intracellular). THC, anandamide, and other known cannabinoid receptor agonists bind to the extracellular portion of the receptor, thereby activating the signal pathway inside the cell. The CB1 molecule is larger than CB2. The receptor molecules are most similar in four of the seven regions where they are embedded in the cell membrane (known as the transmembrane regions). The intracellular loops of the two receptor subtypes are quite different, which might affect the cellular response to the ligand because these loops are known to mediate G protein signaling, the next step in the cell signaling pathway after the receptor. Receptor homology between the two receptor subtypes is 44% for the full-length protein and 68% within the seven transmembrane regions. The ligand binding sites are typically defined by the extracellular loops and the transmembrane regions. version activates the receptor). Thus far, two cannabinoid receptor subtypes (CB1 and CB2) have been identified, of which only CB1 is found in the brain. The cell responds in a variety of ways when a ligand binds to the cannabinoid receptor (Figure 2.3). The first step is activation of G proteins, the first components of the signal transduction pathway. That leads to changes in several intracellular components-such as cyclic AMP and calcium and potassium ionswhich ultimately produce the changes in cell functions. The final result of cannabinoid receptor stimulation de-
OCR for page 41
Page 41 Figure 2.3 Cannabinoid agonists trigger a series of reactions within cells. Cannabinoid receptors are embedded in the cell membrane, where they are coupled to G proteins (G) and the enzyme adenylyl cyclase (AC). Receptors are activated when they bind to ligands, such as anandamide or THC in this case. This triggers a variety of reactions, including inhibition (-) of AC, which decreases the production of cAMP and cellular activities dependent on cAMP; opening of potassium (K+) channels, which decreases cell firing; and closing of calcium (Ca2+) channels, which decreases the release of neurotransmitters. Each of those changes can influence cellular communication. pends on the particular type of cell, the particular ligand, and the other molecules that might be competing for receptor binding sites. Different agonists vary in binding potency, which determines the effective dose of the drug, and efficacy, which determines the maximal strength of the signal that they transmit to the cell. The potency and efficacy of THC are both relatively lower than those of some synthetic cannabinoids; in fact, synthetic compounds are generally more potent and efficacious than endogenous agonists. CB1 receptors are extraordinarily abundant in the brain. They are more abundant than most other G protein-coupled receptors and 10 times more abundant than mu opioid receptors, the receptors responsible for the effects of morphine.148
OCR for page 42
Page 42 The cannabinoid receptor in the brain is a protein referred to as CB,. The peripheral receptor (outside the nervous system), CB2, is most abundant on cells of the immune system and is not generally found in the brain.43,124 Although no other receptor subtypes have been identified, there is a genetic variant known as CB1A (such variants are somewhat different proteins that have been produced by the same genes via alternative processing). In some cases, proteins produced via alternative splicing have different effects on cells. It is not yet known whether there are any functional differences between the two, but the structural differences raise the possibility. CB1 and CB2 are similar, but not as similar as members of many other receptor families are to each other. On the basis of a comparison of the sequence of amino acids that make up the receptor protein, the similarity of the CB1 and CB2 receptors is 44% (Figure 2.2). The differences between the two receptors indicate that it should be possible to design therapeutic drugs that would act only on one or the other receptor and thus would activate or attenuate (block) the appropriate cannabinoid receptors. This offers a powerful method for producing biologically selective effects. In spite of the difference between the receptor subtypes, most cannabinoid compounds bind with similar affinity* to both CB1 and CB2 receptors. One exception is the plant-derived compound CBD, which appears to have greater binding affinity for CB2 than for CB1,112 although another research group has failed to substantiate that observation.129 Other exceptions include the synthetic compound WIN 55,212-2, which shows greater affinity for CB2 than CB,, and the endogenous ligands, anandamide and 2-AG, which show greater affinity for CB1, than CB2.43 The search for compounds that bind to only one or the other of the cannabinoid receptor types has been under way for several years and has yielded a number of compounds that are useful research tools and have potential for medical use. Cannabinoid receptors have been studied most in vertebrates, such as rats and mice. However, they are also found in invertebrates, such as leeches and mollusks.156 The evolutionary history of vertebrates and invertebrates diverged more than 500 million years ago, so cannabinoid receptors appear to have been conserved throughout evolution at least this long. This suggests that they serve an important and basic function in animal physiology. In general, cannabinoid receptor molecules are similar among different species.124 Thus, cannabinoid receptors likely fill many similar functions in a broad range of animals, including humans. *Affinity is a measure of how avidly a compound binds to a receptor. The higher the affinity of a compound, the higher its potency; that is, lower doses are needed to produce its effects.
OCR for page 43
Page 43 The Endogenous Cannabinoid System For any drug for which there is a receptor, the logical question is, "Why does this receptor exist?" The short answer is that there is probably an endogenous agonist (that is, a compound that is naturally produced in the brain) that acts on that receptor. The long answer begins with a search for such compounds in the area of the body that produces the receptors and ends with a determination of the natural function of those compounds. So far, the search has yielded several endogenous compounds that bind selectively to cannabinoid receptors. The best studied of them are anandamide37 and arachidonyl glycerol (2-AG).108 However, their physiological roles are not yet known. Initially, the search for an endogenous cannabinoid was based on the premise that its chemical structure would be similar to that of THC; that was reasonable, in that it was really a search for another "key" that would fit into the cannabinoid receptor "keyhole," thereby activating the cellular message system. One of the intriguing discoveries in cannabinoid biology was how chemically different THC and anandamide are. A similar search for endogenous opioids (endorphins) also revealed that their chemical structure is very different from the plant-derived opioids, opium and morphine. Further research has uncovered a variety of compounds with quite different chemical structures that can activate cannabinoid receptors (Table 2.2 and Figure 2.4). It is not yet known exactly how anandamide and THC bind to cannabinoid receptors. Knowing this should permit more precise design of drugs that selectively activate the endogenous cannabinoid systems. Anandamide The first endogenous cannabinoid to be discovered was arachidonyl-ethanolamine, named anandamide from the Sanskrit word ananda, meaning "bliss."37 Compared with THC, anandamide has only moderate affinity for CB1 receptor and is rapidly metabolized by amidases (enzymes that remove amide groups). Despite its short duration of action, anand-amide shares most of the pharmacological effects of THC.37,152 Rapid degradation of active molecules is a feature of neurotransmitter systems that allows them control of signal timing by regulating the abundance of signaling molecules. It creates problems for interpreting the results of many experiments and might explain why in vivo studies with anandamide injected into the brain have yielded conflicting results. Anandamide appears to have both central (in the brain) and peripheral (in the rest of the body) effects. The precise neuroanatomical localiza-
OCR for page 72
Page 72 12. Bloom AS, Dewey WL, Harris LS, Brosius KK. 1977. 9-nor-9b-hydroxyhexahydrocannabinol, a cannabinoid with potent antinociceptive activity: Comparisons with morphine. Journal of Pharmacology and Experimental Therapeutics 200:263-270. 13. Bornheim LM, Everhart ET, Li J, Correia MA. 1994. Induction and genetic regulation of mouse hepatic cytochrome P450 by cannabidiol. Biochemical Pharmacology (England) 48:161-171. 14. Bomheim LM, Kim KY, Chen B, Correia MA. 1993. The effect of cannabidiol on mouse hepatic microsomal cytochrome P450-dependent anandamide metabolism. Biochenmical and Biophysical Research Communications (United States) 197:740-746. 15. Bornheim LM, Kim KY, Li J, Perotti BY, Benet LZ. 1995. Effect of cannabidiol pretreatment on the kinetics of tetrahydrocannabinol metabolites in mouse brain. Drug Metabolism and Disposition (United States) 23:825-831. 16. Breivogel CS, Sim LJ, Childers SR. 1997. Regional differences in cannabinoid receptor/G-protein coupling in rat brain. Journal of Pharmacology and Experimental Therapeutics 282:1632-1642. 17. British Medical Association. 1997. Therapeutic Uses of Cannabis. Amsterdam, The Netherlands: Harwood Academic Publishers. 18. Burkey TH, Quock RM, Consroe P, Roeske WR, Yamamura HI. 1997. Delta-9-tetrahydrocannabinol is a partial agonist of cannabinoid receptors in mouse brain. European Journal of Pharmacology 323:R3-R4. 19. Buxbaum DM. 1972. Analgesic activity of A9-tetrahydrocannabinol in the rat and mouse. Psychopharmacology 25:275-280. 20. Cabral GA, Dove Pettit DA. 1998. Drugs and immunity: Cannabinoids and their role in decreased resistance to infectious disease. Journal of Neu roimmu n ology 83:116-123. 21. Cabral GA, Lockmuller JC, Mishkin EM. 1986. Delta-9-tetrahydrocannabinol decreases alpha/beta interferon response to herpes simplex virus type 2 in the B6C3F1 mouse. Proceedings of the Societyfor Experimental Biology and Medicine 181:305-311. 22. Calignano A, La Rana G, Giuffrida A, Piomelli D. 1998. Control of pain initiation by endogenous cannabinoids. Nature 394:277-281. 23. Campbell KA, Foster TC, Hampson RE, Deadwyler SA. 1986a. Delta-9-tetrahydrocannabinol differentially affects sensory-evoked potentials in the rat dentate gyrus. Journal of Pharmacology and Experimental Therapeutics 239:936-940. 24. Campbell KA, Foster TC, Hapson RE, Deadwyler SA. 1986b. Effects of delta-9-tetrahydrocannabinol on sensory-evoked discharges of granule cells in the dentate gyrus of behaving rats. Journal of Pharmacology and Experimental Therapeutics 239:941945. 25. Chen J, Marmur R, Pulles A, Paredes W, Gardner EL. 1993. Ventral tegmental microinjection of delta-9-tetrahydrocannabinol enhances ventral tegmental somatodendritic dopamine levels but not forebrain dopamine levels: Evidence for local neural action by marijuana's psychoactive ingredient. Brain Research 621:65-70. 26. Childers SR. 1997. Opioid receptors: Pinning down the opiate targets. Current Biology 7:R695-R697. 27. Childers SR, Breivogel CS. 1998. Cannabis and endogenous cannabinoid systems. Drug and Alcohol Dependence 51:173-187. 28. Coffey RG, Yamamoto Y, Shella E, Pross S. 1996. Tetrahydrocannabinol inhibition of macrophage nitric oxide production. Biochemical Pharmacology 52:743-751. 29. Collins DR, Pertwee RG, Davies SN. 1994. The action of synthetic cannabinoids on the induction of long-term potentiation in the rat hippocampal slice. European Journal of Pharmacology 259:R7-R8.
OCR for page 73
Page 73 30. Collins DR, Pertwee RG, Davies SN. 1995. Prevention by the cannabinoid antagonist, SR141716A, of cannabinoid-mediated blockade of long-term potentiation in the rat hippocampal slice. British Journal of Pharmacology 115:869-870. 31. Costa B, Parolaro D, Colleoni M. 1996. Chronic cannabinoid, CP-55,940, administration alters biotransformation in the rat. European Journal of Pharmacology 313:17-24. 32. Daaka Y, Friedman H, Klein T. 1996. Cannabinoid receptor proteins are increased in Jurkat, human T-cell line after mitogen activation. Journal of Pharmacology and Experimental Therapeutics 276:776-783. 33. Daaka Y, Zhu W, Friedman H, Klein T. 1997. Induction of interleukin-2 receptor o gene by A9-tetrahydrocannabinol is mediated by nuclear factor KB and CBi cannabinoid receptor. DNA and Cell Biology 16:301-309. 34. Deadwyler SA, Heyser CJ, Hampson RE. 1995. Complete adaptation to the memory disruptive effects of delta-9-THC following 35 days of exposure. Neuroscience Research Communications 17:9-18. 35. Derocq JM, Segui M, Marchand J, Le Fur G, Casellas P. 1995. Cannabinoids enhance human B-cell growth at low nanomolar concentrations. FEBS Letters 369:177-182. 36. Devane WA, Dysarc FA, Johnson MR, Melvin LS, Howlett AC. 1988. Determination and characterization of a cannabinoid receptor in rat brain. Molecular Pharmlacology 34:605-613. 37. Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Griffing F, Gibson D, Mandelbaum A, Etinger A, Mechoulam R. 1992. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258:1946-1949. 38. Dewey WL. 1986. Cannabinoid pharamacology. Pharmacology Review 38:151-178. 39. Di Chiara G, Imperato A. 1988. Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proceedings of the National Academy of Sciences, USA 85:5274-5278. 40. Dill JA, Howlett AC. 1988. Regulation of adenylate cyclase by chronic exposure to cannabimimetic drugs. Journal of Pharmacology and Experimental Therapeutics 244:11571163. 41. Evans DJ, Keith DEJ, Morrison H, Magendzo K, Edwards RH. 1992. Cloning of a delta opioid receptor by functional expression. Science 258:1952-1955. 42. Fan F, Tao Q, Abood ME, Martin BR. 1996. Cannabinoid receptor down-regulation without alteration of the inhibitory effect of CP 55,940 on adenylyl cyclase in the cerebellum of CP 55,940-tolerant mice. Brain Research 706:13-20. 43. Felder CC, Glass M. 1998. Cannabinoid receptors and their endogenous agonists. Ann ual Reviews of Pharmacology and Toxicology 38:179-200. 44. Felder CC, Nielsen A, Briley EM, Palkovits M, Priller J, Axelrod J, Nguyen DN, Richardson JM, Riggin RM, Koppel GA, Paul SM, Becker GW. 1996. Isolation and measurement of the endogenous cannabinoid receptor agonist, anandamide, in brain and peripheral tissues of human and rat. FEBS Letters 393:231-235. 45. Fields HL. 1987. Pain. New York: McGraw-Hill. 46. Formukong EA, Evans AT, Evans FJ. 1988. Analgesic and antiinflammatory activity of constituents of Cannabis sativa L. Inflammation 12:361-371. 47. French ED. 1997. Delta-9-tetrahydrocannabinol excites rat VTA dopamine neurons through activation of cannabinoid CB1 but not opioid receptors. Neuroscience Letters 226:159-162. 48. Galiegue S, Mary S, Marchand J, Dussossoy D, Carriere D, Carayon P, Bouaboula M, Shire D, Le Fur G, Casellas P. 1995. Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations. European Journal of Biochemistry 232:54-61.
OCR for page 74
Page 74 49. Gessa GL, Mascia MS, Casu MA, Carta G. 1997. Inhibition of hippocampal acetylcholine release by cannabinoids: Reversal by SR 141716A. European Journal of Pharmacology 327:R1-R2. 50. Gifford AN, Ashby Jr CR. 1996. Electrically evoked acetylcholine release from hippocampal slices is inhibited by the cannabinoid receptor agonist, WIN 55212-2, and is potentiated by the cannabinoid antagonist, SR 141716A. Journal of Pharmacology and Experimental Therapeutics 277:1431-1436. 51. Gifford AN, Gardner EL, Ashby CRJ. 1997. The effect of intravenous administration of delta-9-tetrahydrocannabinol on the activity of A10 dopamine neurons recorded in vivo in anesthetized rats. Neuropsychobiology 36:96-99. 52. Glass M, Dragunow M, Faull RLM. 1997. Cannabinoid receptors in the human brain: A detailed anatomical and quantitative autoradiographic study in the fetal, neonatal and adult human brain. Neuroscience 77:299-318. 53. Hadden JW, Hadden EM, Haddox MK, Goldberg ND. 1972. Guanosine 3':5'-cyclic monophosphates: A possible intracellular mediator of mitogenic influences in lymphocytes. Proceedings of the National Academy of Sciences, USA 69:3024-3027. 54. Hampson AJ, Grimaldi M, Axelrod J, Wink D. 1998. Cannabidiol and (-)delta-9-tetrahydrocannabinol are neuroprotective antioxidants. Proceedings of the National Academy of Sciences, USA 95:8268-8273. 55. Haney M, Ward AS, Comer SD, Foltin RW, Fischman MW. 1999. Abstinence symptoms following oral THC administration to humans. Psychopharmacology 141:385-394. 56. Haney M, Ward AS, Comer SD, Foltin RW, Fischman MW. 1999. Abstinence symptoms following smoked marijuana in humans. Psychopharmacology 141:395-404. 57. Herkenham M. 1995. Localization of cannabinoid receptors in brain and periphery. In: Pertwee RG, Editor, Cannabinoid Receptors. New York: Academic Press. Pp. 145166. 58. Herkenham M, Lynn AB, de Costa BR, Richfield EK. 1991a. Neuronal localization of cannabinoid receptors in the basal ganglia of the rat. Brain Research 547:267-274. 59. Herkenham M, Lynn AB, Johnson MR, Melvin LS, de Costa BR, Rice KC. 1991b. Characterization and localization of cannabinoid receptors in rat brain: A quantative in vitro autoradiographic study. Journal of Neuroscience 11:563-583. 60. Herkenham M, Lynn AB, Little MD, Johnson MR, Melvin LS, de Costa BR, Rice KC. 1990. Cannabinoid receptor localization in the brain. Proceedings of the National Academy of Sciences, USA 87:1932-1936. 61. Herring AC, Koh WS, Kaminski NE. 1998. Inhibition of the cyclic AMP signaling cascade and nuclear factor binding to CRE and kappa B elements by cannabinol, a minimally CNS-active cannabinoid. Biochemical Pharmacology 55:1013-1023. 62. Herzberg U, Eliav E, Bennett GJ, Kopin IJ. 1997. The analgesic effects of R(+)-WIN 55,212-2 mesylate, a high affinity cannabinoid agonist, in a rat model of neuropathic pain. Neuroscience Letters 221:157-160. 63. Heyser CJ, Hampson RE, Deadwyler SA. 1993. Effects of delta-9-tetrahydrocannabinol on delayed match to sample performance in rats: Alterations in short-term memory associated with changes in task-specific firing of hippocampal cells. Journal of Pharmacology and Experimental Therapeutics 264:294-307. 64. Hohmann AG, Briley EM, Herkenham M. 1999. Pre- and postsynaptic distribution of cannabinoid and mu opioid receptors in rat spinal cord. Brain Research 822:17-25. 65. Hohmann AG, Herkenham M. 1998. Regulation of cannabinoid and mu opioid receptor binding sites following neonatal capsaicin treatment. Neuroscience Letters 252:1316.
OCR for page 75
Page 75 66. Hohmann AG, Herkenham M. 1999. Localization of central cannabinoid CBI receptor mRNA in neuronal subpopulations of rat dorsal root ganglia: A double-label in situ hybridization study. Neuroscience 90:923-931. 67. Hohmann AG, Martin WJ, Tsou K, Walker JM. 1995. Inhibition of noxious stimulus-evoked activity of spinal cord dorsal horn neurons by the cannabinoid WIN 55,212-2. Life Sciences 56:2111-2119. 68. Hollister LE. 1986. Health aspects of cannabis. Pharmacological Reviews 38:1-20. 69. Hollister LE, Gillespie BA. 1975. Interactions in man of delta-9-THC. II. Cannabinol and cannabidiol. Clinical Pharmacology and Therapeutics 18:80-83. 70. Hughes J, Smith TW, Kosterlitz HW, Fothergill LA, Morgan BA, Morris HR. 1975. Identification of two related pentapeptides from the brain with potent opiate agonists activity. Nature 258:577-580. 71. Jackson AL, Murphy LL. 1997. Role of the hypothalamic-pituitary-adrenal axis in the suppression of luteinizing hormone release by delta-9-tetrahydrocannabinol. Neuroendocrinology 65:446-452. 72. Jacob J, Ramabadran K, Campos-Medeiros M. 1981. A pharmacological analysis of levonantradol antinociception in mice. Journal of Clinical Pharmacology 21:327S-333S. 73. Jaggar SI, Hasnie FS, Sellaturay S, Rice AS. 1998. The anti-hyperalgesic actions of the cannabinoid anandamide and the putative CB2 receptor agonist palmitoylethanolamide in visceral and somatic inflammatory pain. Pain 76:189-199. 74. Jeon YJ, Yang K-H, Pulaski JT, Kaminski NE. 1996. Attenuation of inducible nitric oxide synthase gene expression by delta-9-tetrahydrocannabinol is mediated through the inhibition of nuclear factor-kB/Rel activation. Molecular Pharmacology 50:334-341. 75. Johnson MR, Melvin LS. 1986. The discovery of non-classical cannabinoid analgesics. In: Mechoulam R, Editor, Cannabinoids as Therapeutic Agents. Boca Raton, FL: CRC Press, Inc. Pp. 121-145. 76. Jones RT, Benowitz NL, Herning RI. 1981. Clinical relevance of cannabis tolerance and dependence. Journal of Clinical Pharmacology 21:143S-152S. 77. Kaminski NE. 1996. Immune regulation by cannabinoid compounds through the inhibition of the cyclic AMP signaling cascade and altered gene expression. Biochemical Pharmacology 52:1133-1140. 78. Kaminski NE, Abood ME, Kessler FK, Martin BR, Schatz AR. 1992. Identification of a functionally relevant cannabinoid receptor on mouse spleen cells that is involved in cannabinoid-mediated immune modulation. Molecular Pharmacology 42:736-742. 79. Kaminski NE, Koh WS, Yang KH, Lee M, Kessler FK. 1994. Suppression of the humoral immune response by cannabinoids is partially mediated through inhibition of adenylate cyclase by a pertussis toxin-sensitive G-protein coupled mechanism. Biochemical Pharmacology 48:1899-1908. 80. Kaminski NE. 1998. Regulation of cAMP cascade, gene expression and immune function by cannabinoid receptors. Journal of Neuroimmunology 83:124-132. 81. Karniol IG, Shirakawa I, Kasinski N, Pfeferman A, Carlini EA. 1975. Cannabidiol interferes with the effects of delta-9-tetrahydrocannbinol in man. European Journal of Pharmacology 28:172-177. 82. Kieffer BL, Befort K, Gaveriaux-Ruff C, Hirth CG. 1992. The delta-opioid receptor: Isolation of a cDNA by expression cloning and pharmacological characterization. Proceedings of the National Academy of Sciences, USA 89:12048-12052. 83. Kirby MT, Hampson RE, Deadwyler SA. 1995. Cannabinoids selectively decrease paired-pulse perforant path synaptic potentials in the dentate gyrus in vitro. Brain Research 688:114-120.
OCR for page 76
Page 76 84. Klein TW, Friedman H. 1990. Modulation of murine immune cell function by marijuana components. In: Watson R, Editor, Drugs of Abuse and Immune Function. Boca Raton, FL: CRC Press. 85. Klein TW, Friedman H, Specter SC. 1998. Marijuana, immunity and infection. Journal of Neuroimmunology 83:102-115. 86. Klein TW, Newton C, Friedman H. 1987. Inhibition of natural killer cell function by marijuana components. Journal of Toxicology and Environmental Health 20:321-332. 87. Klein TW, Newton C, Friedman H. 1994. Resistance to Legionella pneumophila suppressed by the marijuana component, tetrahydrocannabinol. Journal of Infectious Diseases 169:1177-1179. 88. Klein TW, Newton C, Friedman H. 1998. Cannabinoid receptors and immunity. Immunology Today 19:373-381. 89. Klein TW, Newton C, Widen R, Friedman H. 1985. The effect of delta-9-tetrahydrocannabinol and 11-hydroxy-delta-9-tetrahydrocannabinol on T-lymphocyte and Blymphocyte mitogen responses. Journal of Immunopharmacology 7:451-466. 90. Klein TW, Newton C, Widen R, Friedman H. 1993. Delta-9-tetrahydrocannabinol injection induces cytokine-mediated mortality of mice infected with Legionella pneumophila. Journal of Pharmacology and Experimental Therapeutics 267:635-640. 91. Koh WS, Yang KH, Kaminski NE. 1995. Cyclic AMP is an essential factor in immune responses. Biochemical and Biophysical Research Communications 206:703-709. 92. Ledent C, Valverde 0, Cossu G, Petitet F, Aubert JF, Beslot F, Bohme GA, Imperato A, Pedrazzini T, Roques BP, Vassart G, Fratta W, Parmentier M. 1999. Unresponsiveness to cannabinoids and reduced addictive effects of opiates in CB1 receptor knockout mice. Science 283:401404. 93. Lee M, Yang KH, Kaminski NE. 1995. Effects of putative cannabinoid receptor ligands, anandamide and 2-arachidonyl-glycerol, on immune function in B6C3F1 mouse splenocytes. Journal of Pharmacology and Experimental Therapeutics 275:529-536. 94. Lepore M, Liu X, Savage V, Matalon D, Gardner EL. 1996. Genetic differences in delta 9-tetrahydrocannabinol-induced facilitation of brain stimulation reward as measured by a rate-frequency curve-shift electrical brain stimulation paradigm in three different rat strains. Life Sciences 58:365-372. 95. Lepore M, Vorel SR, Lowinson J, Gardner EL. 1995. Conditioned place preference induced by delta 9-tetrahydrocannabinol: Comparison with cocaine, morphine, and food reward. Life Sciences 56:2073-2080. 96. Lichtman AH, Martin BR. 1991a. Spinal and supraspinal components of cannabinoidinduced antinociception. Journal of Pharmacology and Experimental Therapeutics 258:517523. 97. Little PJ, Compton DR, Mechoulam R, Martin BR. 1989. Stereochemical effects of 11OH-delta-8-THC-dimethylheptyl in mice and dogs. Pharmacology, Biochemistry Behavior 32:661-666. 98. Lu F, Ou DW. 1989. Cocaine or delta-9-tetrahydrocannabinol does not affect cellular cytotoxicity in vitro. International Journal of Pharmacology 11:849-852. 99. Luo YD, Patel MK, Wiederhold MD, Ou DW. 1992. Effects of cannabinoids and cocaine on the mitogen-induced transformations of lymphocytes of human and mouse origins. International Journal of Immunopharmacology 14:49-56. 100. Lyman WD, Sonett JR, Brosnan CFER, Bornstein MB. 1989. Delta 9-tetrahydrocannabinol: A novel treatment for experimental autoimmune encephalomyelitis. Journal of Neuroimmunology 23:73-81. 101. Mailleux P, Vanderhaeghen JJ. 1992. Distribution of neuronal cannabinoid receptor in the adult rat brain: A comparative receptor binding radioautography and in situ hybridization histochemistry. Neuroscience 48:655-668.
OCR for page 77
Page 77 102. Martin WJ, Hohmann AG, Walker JM. 1996. Suppression of noxious stimulus-evoked activity in the ventral posterolateral nucleus of the thalamus by a cannabinoid agonist: Correlation between electrophysiological and antinociceptive effects. The Journal of Neuroscience 16:6601-6611. 103. Martin WJ, Patrick SL, Coffin PO, Tsou K, Walker JM. 1995. An examination of the central sites of action of cannabinoid-induced antinociception in the rat. Life Sciences 56:2103-2109. 104. Martin WJ, Patrick SL, Coffin PO, Tsou K, Walker JM. 1995. An examination of the central sites of action of cannabinoid-induced antinociception in the rat. Life Sciences 56:2103-2109. 105. Martin WJ, Tsou K, Walker JM. 1998. Cannabinoid receptor-mediated inhibition of the rat tail-flick reflex after microinjections into the rostral ventromedial medulla. Neuroscience Letters 242:33-36. 106. Martoletta MC, Cossu G, Fattore L, Gessa GL, Fratta W. 1998. Self-administration of the cannabinoid receptor agonist WIN 55,212-2 in drug-naive mice. Neuroscience 85:327-330. 107. Matsuda L, Lolait SJ, Brownstein MJ, Young AC, Bonner TI. 1990. Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 346:561-564. 108. Mechoulam R, Ben-Shabat S, Hanus L, Ligumsky M, Kaminski NSA, Gopher A, Almog S, Martin BR, Compton D, Pertwee RG, Griffin G, Bayewitch M, Barg J, Vogel Z. 1995. Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochemical Pharmacology 50:83-90. 109. Mechoulam R, Hanus L, Fride E. 1998. Towards cannabinoid drugsrevisited. In: Ellis GP, Luscombe DK, Oxford AW, Editors, Progress in Medicinal Chemistry. v. 35. Amsterdam: Elsevier Science. Pp. 199-243. 110. Meng ID, Manning BH, Martin WJ, Fields HL. 1998. An analgesia circuit activated by cannabinoids. Nature 395:381-383. 111. Miller AS, Walker JM. 1996. Electrophysiological effects of a cannabinoid on neural activity in the globus pallidus. European Journal of Pharmacology 304:29-35. 112. Munro S, Thomas KL, Abu-Shaar M. 1993. Molecular characterization of a peripheral receptor for cannabinoids. Nature 365:61-65. 113. Murphy LL, Steger RW, Smith MS, Bartke A. 1990. Effects of delta-9-tetrahydrocannabinol, cannabinol and cannabidiol, alone and in combinations, on luteinizing hormone and prolactin release and on hypothalamic neurotransmitters in the male rat. Neuroendocrinology 52:316-321. 114. Narimatsu S, Watanabe K, Matsunaga T, Yamamoto I, Imaoka S, Funae Y, Yoshimura H. 1993. Suppression of liver microsomal drug-metabolizing enzyme activities in adult female rats pretreated with cannabidiol. Biological and Pharmaceutical Bulletin (Japan) 16:428-430. 115. Newton CA, Klein T, Friedman H. 1994. Secondary immunity to Legionella pneumophilia and Thl activity are suppressed by delta-9-tetrahydrocannabinol injection. Infection and Immunity 62:4015-4020. 116. Norwicky AV, Teyler TJ, Vardaris RM. 1987. The modulation of long-term potentiation by delta-9-tetrahydrocannabinol in the rat hippocampus, in vitro. Brain Researcl Bulletin 19:663. 117. O'Leary D, Block RI, Flaum M, Boles Ponto LL, Watkins GL, Hichwa RD. 1998. Acute marijuana effects on rCBF and cognition: A PET study. Abstracts-Society for Neuroscience: 28th Annual Meeting. Los Angeles, November 7-12, 1998. Washington, DC: Society for Neuroscience.
OCR for page 78
Page 78 118. Ohlsson A, Lindgren J-E, Wahlen A, Agurell S, Hollister LE, Gillespie HK. 1980. Plasma delta-9-tetrahydrocannabinol concentrations and clinical effects after oral and intravenous administration and smoking. Clinical Pharmacology and Therapeutics 28:409-416. 119. Oviedo A, Glowa J, Herkenham M. 1993. Chronic cannabinoid administration alters cannabinoid receptor binding in rat brain: A quantitative autoradiographic study. Brain Research 616:293-302. 120. Pacheco MA, Ward SJ, Childers SR. 1993. Identification of cannabinoid receptors in cultures of rat cerebellar granule cells. Brain Research 603:102-110. 121. Patel V, Borysenko M, Kumar MSA, Millard WJ. 1985. Effects of acute and subchronic delta-9-tetrahydrocannabinol administration on the plasma catecholamine, beta-endorphin, and corticosterone levels and splenic natural killer cell activity in rats. Proceedings of the Society for Experimental Biology and Medicine 180:400-404. 122. Pepe S, Ruggiero A, Tortora G, Ciaardiello F, Garbi C, Yokozaki H, Cho-Chung YS, Clair T, Skalhegg BS, Bianco AR. 1994. Flow cytometric detection of the RI alpha subunit of type-I cAMP-dependent protein kinase in human cells. Cytometry 15:7379. 123. Pert CB, Snyder SH. 1973. Opiate receptor: Demonstration in nervous tissue. Science 179:1011-1014. 124. Pertwee RG. 1997b. Pharmacology of cannabinoid CB1 and CB2 receptors. Pharmacology and Therapeutics 74:129-180. 125. Pertwee RG, Stevenson LA, Griffin G. 1993. Cross-tolerance between delta-9-tetrahydrocannabinol and the cannabimimetic agents, CP 55,940, WIN 55,212-2 and anandamide [published erratum appears in British Journal of Pharmacology, 1994, 111(3):968]. British Journal of Pharmacology 110:1483-1490. 126. Pertwee RG, Wickens AP. 1991. Enhancement by chlordiazepoxide of catalepsy induced in rats by intravenous or intrapallidal injections of enantiomeric cannabinoids. Neuropharmacology 30:237-244. 127. Pross SH, Nakano Y, Widen R, McHugh S, Newton C, Klein TW, Friedman H. 1992. Differing effects of delta-9-tetrahydrocannabinol (THC) on murine spleen cell populations dependent upon stimulators. International Journal of Immunopharmacology 14:1019-1027. 128. Razdan RK. 1986. Structure-activity relationships in cannabinoids. Pharmacology Review 38:75-149. 129. Rhee MH, Vogel Z, Barg J, Bayewitch M, Levy R, Hanus L, Breuer A, Mechoulam R. 1997. Cannabinol derivatives: Binding to cannabinoid receptors and inhibition of adenyl-cyclase. Journal of Medicinal Chemistry 40:3228-3233. 130. Richardson JD, Aanonsen L, Hargreaves KM. 1998. Hypoactivity of the spinal cannabinoid system results in NMDA-dependent hyperalgesia. Journal of Neuroscience 18:451-457. 131. Richardson JD, Kilo S, Hargreaves KM. 1998. Cannabinoids reduce hyperalgesia and inflammation via interaction with peripheral CBI receptors. Pain 75:111-119. 132. Rinaldi-Carmona M, Barth F, Heaulme M, Shire D, Calandra B, Congy C, Martinez S, Maruani J, Neliat G, Caput D, Ferrara P, Soubrie P, Breliere JC, Le Fur G. 1994. SR141716A, a potent and selective antagonist of the brain cannabinoid receptor. FEBS Letters 350:240-244. 133. Rinaldi-Carmona M, Barth F, Millan J, Defrocq J, Casellas P, Congy C, Oustric D, Sarran M, Bouaboula M, Calandra B, Portier M, Shire D, Breliere J, Le Fur G. 1998. SR144528, the first potent and selective antagonist of the CB2 cannabinoid receptor. Journal of Pharmacology and Experimental Therapeutics 284:644-650.
OCR for page 79
Page 79 134. Rodriguez de Fonseca F, Fernandez-Ruiz JJ, Murphy LL, Eldridge JC, Steger RW, Bartke A. 1991. Effects of delta-9-tetrahydrocannabinol exposure on adrenal medullary function: Evidence of an acute effect and development of tolerance in chronic treatments. Pharmacology, Biochemistry and Behavior 40:593-598. 135 Rodriguez de Fonseca F, Carrera MRA, Navarro M, Koob G, Weiss F. 1997. Activation of corticotropin-releasing factor in the limbic system during cannabinoid withdrawal [see comments Science 1997, 276:1967-1968]. Science 276:2050-2054. 136. Rodriguez de Fonseca F, Gorriti MA, Fernandez-Ruiz JJ, Palomo T, Ramos JA. 1994. Down-regulation of rat brain cannabinoid binding sites after chronic delta-9-tetrahydrocannabinol treatment. Pharmacology, Biochemistry and Behavior 47:33-40. 137. Romero J, Garcia L, Fernndez-Ruiz JJ, Cebeira M, Ramos JA. 1995. Changes in rat brain cannabinoid binding sites after acute or chronic exposure to their endogenous agonist, anandamide, or to delta-9-tetrahydrocannabinol. Pharmacology, Biochemistry and Behavior 51:731-737. 138. Romero J, Garcia-Palomero E, Castro JG, Garcia-Gil L, Ramos JA, Ferandez-Ruiz JJ. 1997. Effects of chronic exposure to delta-9-tetrahydrocannabinol on cannabinoid receptor binding and mRNA levels in several rat brain regions. Molecular Brain Research 46:100-108. 139. Russell DH. 1978. Type I cyclic AMP-dependent protein kinase as a positive effector of growth. Advances in Cyclic Nucleotide Research 9:493-506. 140. Sanudo-Pena MC, Tsou K, Delay ER, Hohmann AG, Force M, Walker JM. 1997. Endogenous cannabinoids as an aversive or counter-rewarding system in the rat. Neuroscience Letters 223:125-128. 141. Sanudo-Pena MC, Walker JM. 1997. Role of the subthalamic nucleus in cannabinoid actions in the substantia nigra of the rat. Journal of Neurophysiology 77:1635-1638. 142. Schatz AR, Koh WS, Kaminski NE. 1993. Delta-9-tetrahydrocannabinol selectively inhibits T-cell dependent humoral immune responses through direct inhibition of accessory T-cell function. Immunopharmacology 26:129-137. 143. Schlicker E, Timm J, Zenter J, Goethert M. 1997. Cannabinoid CB1 receptor-mediated inhibition of noradrenaline release in the human and guinea-pig hippocampus. Naunyn-Schmiedeberg's Archives of Pharmacology 356:583-589. 144. Shen M, Piser TM, Seybold VS, Thayer SA. 1996. Cannabinoid receptor agonists inhibit glutamatergic synaptic transmission in rat hippocampal cultures. Journal of Neuroscience 16:4322-4334. 145. Shivers SC, Newton C, Friedman H, Klein TW. 1994. Delta 9-tetrahydrocannabinol (THC) modulates IL-1 bioactivity in human monocyte/macrophage cell lines. Life Sciences 54:1281-1289. 146. Shohami E, Gallily R, Mechoulam R, Bass R, Ben-Hur T. 1997. Cytokine production in the brain following closed head injury: Dexanabinol (HU-211) is a novel TNF-alpha inhibitor and an effective neuroprotectant. Journal of Neuroimmunology 72:169-177. 147. Sim LJ, Hampson RE, Deadwyler SA, Childers SR. 1996. Effects of chronic treatment with delta-9-tetrahydrocannabinol on cannabinoid-stimulated [35S]GTPyS autoradiography in rat brain. Journal of Neuroscience 16:8057-8066. 148. Sim LJ, Xiao R, Selley DE, Childers SR. 1996. Differences in G-protein activation by mu- and delta-opioid, and cannabinoid, receptors in rat striatum. European Journal of Pharmacology 307:97-105. 149. Simon EJ. 1973. In search of the opiate receptor. American Journal of Medical Sciences 266:160-168.
OCR for page 80
Page 80 150. Skaper SD, Buriani A, Dal Toso R, Petrelli L, Romanello S, Facci L, Leon A. 1996. The ALIAmide palmitoylethanolamide and cannabinoids, but not anandamide, are protective in a delayed postglutamate paradigm of excitotoxic death in cerebellar granule neurons. Proceedings of the National Academy of Sciences, USA 93:3984-3989. 151. Smith JW, Steiner AL, Newberry WM, Parker CW. 1971. Cyclic adenosine 3',5'-monophosphate in human lymphocytes: Alteration after phytohemagglutinin. Journal of Clinical Investigation 50:432-441. 152. Smith PB, Compton DR, Welch SP, Razdan RK, Mechoulam R, Martin BR. 1994. The pharmacological activity of anandamide, a putative endogenous cannabinoid, in mice. Journal of Pharmacology and Experimental Therapeutics 270:219-227. 153. Smith PB, Welch SP, Martin BR. 1994. Interactions between delta 9-tetrahydrocannabinol and kappa opioids in mice. Journal of Pharmacology and Experimental Therapeutics 268: 1381-1387. 154. Sofia RD, Nalepa SD, Harakal JJ, Vassar HB. 1973. Anti-edema and analgesic properties of delta-9-tetrahydrocannabinol (THC). Journal of Pharmacology and Experimental Therapeutics 186:646-655. 155. Specter S, Lancz G, Hazelden J. 1990. Marijuana and immunity: Tetrahydrocannabinol mediated inhibition of lymphocyte blastogenesis. International Journal of Immunophar-macology 12:261-267. 156. Stefano G, Salzet B, Salzet M. 1997. Identification and characterization of the leech CNS cannabinoid receptor: Coupling to nitric oxide release. Brain Research 753:219224. 157. Stella N, Schweitzer P, Piomelli D. 1997. A second endogenous cannabinoid that modulates long term potentiation. Nature 388:773-778. 158. Strangman NM, Patrick SL, Hohmann AG, Tsou K, Walker JM. 1998. Evidence for a role of endogenous cannabinoids in the modulation of acute and tonic pain sensitivity. Brain Research 813:323-328. 159. Sulcova E, Mechoulam R, Fride E. 1998. Biphasic effects of anandamide. Pharmacology, Biochemistry and Behavior 59:347-352. 160. Szabo B, Dorner L, Pfreundtner C, Norenberg W, Starke K. 1998. Inhibition of GABAergic inhibitory postsynaptic currents by cannabinoids in rat corpus striatum. Neuroscience 85:395-403. 161. Tanda G, Pontieri FE, Di Chiara G. 1997. Cannabinoid and heroin activation of mesolimbic dopamine transmission by a common 1l opioid receptor mechanism. Science 276:2048-2049. 162. Terenius L. 1973. Characteristics of the ''receptor'' for narcotic analgesics in synaptic plasma membrane fraction from rat brain. Acta Pharmacologica Et Toxicologica 33:377384. 163. Terranova JP, Michaud JC, Le Fur G, Soubrie P. 1995. Inhibition of long-term potentiation in rat hippocampal slice by anandamide and WIN55212-2: Reversal by SR141716 A, a selective antagonist of CB] cannabinoid receptors. NaunynSchmiedeberg's Archives of Pharmacology 352:576-579. 164. Titishov N, Mechoulam R, Zimmerman AM. 1989. Stereospecific effects of (-) and (+)-7-hydroxy-delta-6-tetrahydrocannabinol-dimethylheptyl on the immune system of mice. Pharmacology 39:337-349. 165. Tsou K, Brown S, Sanudo-Pena MC, Mackie K, Walker JM. 1998. Immunohistochemical distribution of cannabinoid CB1 receptors in the rat central nervous system. Neuroscience 83:393-411. 166. Tsou K, Patrick SL, Walker JM. 1995. Physical withdrawal in rats tolerant to delta-9-tetrahydrocannabinol precipitated by a cannabinoid receptor antagonist. European Journal of Pharmacology 280:R13-R15.
OCR for page 81
Page 81 167. Watson PF, Krupinski J, Kempinski A, Frankenfield C. 1994. Molecular cloning and characterization of the type VII isoform of mammalian adenylyl cyclase expressed widely in mouse tissues and in S49 mouse lymphoma cells. Journal of Biological Chemistry 269:28893-28898. 168. Watzl B, Scuder P, Watson RR. 1991. Marijuana components stimulate human peripheral blood mononuclear cell secretion of interferon-gamma and suppress interleukin-1 alpha in vitro. International Journal of Inmmnopharimology 13:1091-1097. 169. Weidenfeld J, Feldman S, Mechoulam R. 1994. Effect of the brain constituent anandamide, a cannabinoid receptor agonist, on the hypothalamo-pituitary-adrenal axis in the rat. Neuroendocrinology 59:110-112. 170. Welch SP. 1993. Blockade of cannabinoid-induced antinociception by norbinaltorphimine, but not N,N-diallyl-tyrosine-Aib-phenylalanine-leucine, ICI 174,864 or naloxone in mice. Journal of Pharmacology and Experimental Therapeutics 265:633-640. 171. Welch SP, Thomas C, Patrick GS. 1995. Modulation of cannabinoid-induced antinociception after intracerebroventricular versus intrathecal administration to mice: Possible mechanisms for interaction with morphine. Journal of Clinical and Experimental Therapeutics 272:310-321. 172. Wirguin I, Mechoulam R, Breuer A, Schezen E, Weidenfeld J, Brenner T. 1994. Suppression of experimental autoimmune encephalomyelitis by cannabinoids. lmmunopharma-cology 28:209-214. 173. Wirth PW, Watson ES, ElSohly M, Turner CE, Murphy JC. 1980. Anti-inflammatory properties of cannabichromene. Life Sciences 26:1991-1995. 174. Yaksh TL. 1981. The antinociceptive effects of intrathecally administered levonantradol and desacetyl-levonantradol in the rat. Journal of Clinical Pharmacology 21:334S-340S. 175. Yoshida H, Usami N, Ohishi Y, Watanabe K, Yamamoto I, Yoshimura H. 1995. Synthesis and pharmacological effects in mice of halogenated cannabinol derivatives. Chemical and Pharmlaceutical Bulletin 42:335-337. 176. Zhu W, Newton C, Daaka Y, Friedman H, Klein TW. 1994. Delta 9-tetrahydrocannabinol enhances the secretion of interleukin 1 from endotoxin-stimulated macrophages. Journal of Pharmacology and Experimental Therapeutics 270:1334-1339. 177. Zuardi AW, Shirakawa I, Finkelfarb E, Kariol IG. 1982. Action of cannabidiol on the anxiety and other effects produced by delta 9-THC in normal subjects. Psychoplarlnacology (Berl) 76:245-250. 178. Zurier RB, Rossetti RG, Lane JH, Goldberg JM, Hunter SA, Burstein SH. 1998. Dimethylheptyl-THC-11 oic acid: A non-psychoactive antiinflammatory agent with a cannabinoid template structure. Arthritis and Rheumatism 41:163-170.
OCR for page 82
Tab/e 2.8 Historical comparisons between cannabinoicis and opiates Comparisons between cannabinoids and opiates Cannabinoids Pharmacological Discoveries Discovery of receptor existence identification of receptor anfagonisf Discovery of tsf enclogenous ligand Ask Receptor cloned Natural functions of cannabinoic] / opiate systems 1988 (Howlett and Devane)36, 40 1994 SR141716A (Rinaldi Carmona)l32 1992 Anandamide (Devane and Mechoulam)37 1990 (Matsuda)l07 Unknown Opiates 1973 (Pert and Snyder, Terenius, and Simon)123, 149, 162 pre-1973 Naloxone 1975 Met- and Leu-enkephalin (Hughes et al)70 1992 (Evans et al. and Kieffer et al.)41, 82 Pain, reproduction, mood, movement, and others There are several research tools that will greatly aid such investigations in particular, a greater selection of agonists and antagonists that permit discrimination between the activation of CB~ versus CB2 receptors; hydrophilic agonists (that can be delivered to animals or cells more effectively than hydrophobic compounds). In the area of drug development, fixture progress should continue to provide more specific agonists and antagonists for CB~ and CB2 receptors, with varying potential for therapeutic uses. There are certain areas that wall provide keys to a better understanding of the potential therapeutic value of cannabinoids. For example, basic biology indicates a role for cannabinoids in pain and control of movement, which is consistent with a possible therapeutic role in these areas. The evidence is relatively strong for the treatment of pain, and intriguingly, although less well-established, for movement disorders. The neuroprotective properties of cannabinoids might prove therapeutically useful, although it should be noted that this is a new area and other, better studied, neuroprotective drugs have not yet been shown to be therapeutically useful. Cannabinoid research is clearly relevant not only to drug abuse, but also to 2.44
Representative terms from entire chapter: