Marijuana and Medicine Assessing the Science Base (1999) / Chapter Skim
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2 Cannabinoids and Animal Physiology
2 Cannabinoids and Animal Physiology
Pages 33-82
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From page 33... ...
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~.
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From page 34... ...
Anandamide is discovered a naturally occurring substance in the brain that acts on cannabinoid receptors. 1993 A cannabinoid receptor is discovered S
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From page 35... ...
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 (CB~ 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.
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From page 36... ...
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.
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From page 37... ...
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.
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From page 38... ...
38 MARIJUANA AND MEDICINE / \ Endogenous Anonists (e.g., anandamide) Exogenous Agonists (e.g., THC)
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From page 39... ...
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.
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From page 40... ...
. THC, anandamide, and other known cannabinoid receptor agonists bind to the extracellular portion of the receptor, thereby activating the signal pathway inside the cell.
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From page 41... ...
Cannabinoid receptors are embedded in the cell membrane, where they are coupled to G proteins (G) and the enzyme adenylyl cyclase (AC)
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From page 42... ...
In spite of the difference between the receptor subtypes, most cannabinoid compounds bind with similar affinity to both CB~ and CB2 receptors. One exception is the plant-derived compound CBD, which appears to have greater binding affinity for CB2 than for CAB, although another research group has failed to substantiate that observation.~29 Other exceptions include the synthetic compound WIN 55,212-2, which shows greater affinity for CB2 than CUB, and the endogenous ligands, anandamide and 2-AG, which show greater affinity for CB~ 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.
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From page 43... ...
.~°8 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.
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From page 44... ...
THC analogue, 100- to 800-fold greater potency than THC97. Chemical structure unlike THC or anandamide WIN-55,212-2 Chemical structure different from known cannabinoids, but binds to both cannabinoid receptors; chemically related to cyclo-oxygenase inhibitors, which include antiinflammatory drugs.
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From page 45... ...
The importance of knowing specific brain circuits that involve anandamide (and other endogenous cannabinoid ligands) is that such circuits are the pivotal elements for regulating specific brain functions, such as mood, memory, and cognition.
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From page 46... ...
But substantial concentrations of anandamide are also found in the thalamus, an area of the brain that has relatively few CB~ receptors.~24 Anandamide has also been found outside the brain. It has been found in spleen tissue, which also has high concentrations of CB2 receptors, and small amounts have been detected in heart tissue.44 In general, the affinity of anandamide for cannabinoid receptors is only one-fourth to one-half that of THC (see Table 2.3~.
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From page 47... ...
At the time of this writing, all known endogenous cannabinoid receptor agonists (including anandamide) were eicosanoids, which are arachidonic acid metabolites.
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From page 48... ...
inhibitors are used in hypertensive patients to interfere with the conversion of angiotensin I, which is inactive, to the active hormone, angiotensin II. SITES OF ACTION Cannabinoid receptors are particularly abundant in some areas of the brain.
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From page 49... ...
These cells include the substantia nigra pars reticulate, entopeduncular nucleus, and globus pallidus, regions that are generally involved in coordinating body movements. Patients with Parkinson's or Huntington's disease tend to have impaired functions in these regions.
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From page 50... ...
and on the same cell as GABA receptors, they will probably mimic the effects of GABA; in that case, the net effect would be inhibition. ~44 ~60 CB~ is the predominant brain cannabinoid receptor.
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From page 51... ...
Cannabinoids clearly affect movement in rodents, but the effects depend on the dose: low doses stimulate and higher doses inhibit locomotion.~ ~59 Cannabinoids mainly inhibit the transmission of neural signals, and they inhibit movement through their actions on the basal ganglia and cerebellum, where cannabinoid receptors are particularly abundant (Figure 2.6~. Cannabinoid receptors are also found in the neurons that project from the striatum and subthalamic nucleus, which inhibit and stimulate movement, respectively.58 ~0~ Cannabinoids decrease both the inhibitory and stimulatory inputs to the substantia nigra and therefore might provide dual regulation of move
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From page 52... ...
The major output pathways of the basal ganglia arise from the globus pallidus and pars reticulate of the substantia nigra. Their main target is the thalamus.
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From page 53... ...
(Catalepsy is a condition of diminished responsiveness usually characterized by trancelike states and waxy rigidity of the muscles.) Several other brain regions the cortex, the cerebellum, and the neural pathway from cortex to striatum are also involved in the control of movement and contain abundant cannabinoid receptors.5259 ~0~ They are therefore possible additional sites that might underlie the effects of cannabinoids on movement.
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From page 54... ...
Thus, the different cannabinoid receptor subtypes might act synergistically. Experiments in which pain is induced by injecting dilute formalin into a mouse's paw have shown that anandamide and palmitylethanolamide (PEA)
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From page 55... ...
Cannabinoids decrease the response of immediate-early genes (genes that are activated in the early or immediate stage of response to a broad range of cellular stimuli) to noxious stimuli in the spinal cord, decrease response of pain neurons in the spinal cord, and decrease the responsiveness of pain neurons in the ventral posterolateral nucleus of the thalamus.67 ~02 Those changes are mediated by cannabinoid receptors, are selective for pain neurons, and are unrelated to changes in skin temperature or depth of anesthesia, and they follow the time course of the changes in behavioral responses to painful stimuli but not the time course of motor changes.67 On-cells and off-cells in the rostral ventral medulla control pain transmission at the level of the spinal cord, and cannabinoids also modulate their responses in a manner that is very similar to that of morphine.~° Endogenous Cannabinoids Modulate Pain Endogenous cannabinoids can modulate pain sensitivity through both central and peripheral mechanisms.
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From page 56... ...
Chronic cannabinoid treatment also produces changes in brain cannabinoid receptors and cannabinoid receptor mRNA concentrations an indication that pharmacodynamic effects are important as well. Most studies have found that brain cannabinoid receptor concentra
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From page 57... ...
It produces substantial desensitization of cannabinoid-activated G proteins in a number of rat brain regions.~47 The time course of this desensitization varies across brain regions. It is difficult to extend the findings of short-term animal studies to human marijuana use.
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From page 58... ...
Antagonism of cannabinoid receptors is also rewarding in rats; in conditioned place preference tests, animals show a preference for the place they receive the cannabinoid antagonist SR 141716A at both low and high doses.~40 Cannabinoids increase dopamine concentrations in the mesolimbic dopamine system of rats, a pathway associated with reinforcement.2539~6~ However, the mechanism by which THC increases dopamine concentrations appears to be different from that of other abused drugs (see chapter 3 for further discussion of reinforcement)
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From page 59... ...
In spleen and tonsils the CB2 mRNA~ content is equivalent to that of CB~ mRNA in the brain.48 The rank order, from high to low, of CB2 mRNA levels in immune cells is B-cells > natural killer cells >> monocytes > polymorphonuclear neutrophil cells > T8 cells > T4 cells. In tonsils the CB2 receptors appear to be restricted to B-lymphocyteenriched areas.
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From page 60... ...
THC Drug injected into mice >5 mg/kg HU-210 Drug injected into mice >0.05 mg/kg THC, 11-OH-THC, Splenocytes in vitro 1-30 ,uM CBD, CP 55,940, CON THC Drug injected into rodents 3 mg/kg per day for 25 days, 40 mg/kg per day for 2 days THC, 11-OH-THC Natural killer cells in vitro 0.1-32 ,uM THC Peritonealmacrophages and 3-30 ,uM monocytes THC, CBD Drug injected into mice; in one case, >5 mg/kg per day for in vitro tests done on spleens 4 days or 50 mg/kg every 5 days for up to 8 weeks THC, CBD Peripheral blood mononuclear cells <0.1 ,uM in vitro 30 ,uM THC, CBD THC THC THC Splenocytes and T cells in vitro 10 ,uM Phorbol myristate acetate- 10-20 ,uM differentiated macrophage in vitro Endotoxin-activated macrophages 10-30 ,uM in vitro Peritoneal macrophages in vitro 10-30 ,uM
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From page 61... ...
· . in vitro Little or no effect on T cell proliferation Decreased B cell proliferation Increased B cell proliferation Antibody production suppressed Antibody production suppressed Antibody production suppressed Luo, 1992; Pross, 1992;b Klein, 1985;C Specter, 1990;d Lee, 1995;a Herring, 1998 Luo, 1992; Lee, 1995;a Pross, 1992b Lee, 1995;a Devane, 1992 Klein, 1985;C Lee, 1995a Derocq, 1995 Baczynsky, 1983; Schatz, 1993 Titishov, 1989 Klein, 1990; Baczynsky, 1983; Kaminski 1992, 1994; Herring, 1998 Repeated low doses or a high dose of THC Patel, 1985; Klein, 1987 suppressed the activity of natural killer cells Doses of 210 ,uM suppressed natural killer cell cytolytic activity; doses <10 ,uM produced no effect Variable doses of THC suppressed macophage functions in vitro THC suppressed normal immune response; interferons failed to increase when exposed to cytokine inducer; COD had no suppressive effect Increased interferon production Decreased interferon production Klein, 1987; Luo, 1989 Lopez-Cepero, 1986; Specter, 1991; Tang, 1992 Cabral, 1986; Blanchard, 1986 Watzl, 1991 Both THC and COD suppressed Condie, 1996 interleukin-2 secretion and number of interleukin-2 transcripts Increased tumor necrosis factor production Shivers, 1994 and interleukin-1 supernatant bioactivity Increased processing and release of interleukin-1 rather than cellular production of interleukin-1 Zhu, 1994 Increased interleukin-1 bioactivity Klein, 1990 Continued
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From page 62... ...
* Drug concentrations are given in the standard format of molarity (M)
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From page 63... ...
CANNABINOIDS AND ANIMAL PHYSIOLOGY 63 Result Reference Cytokine-mediated septic shock and death Klein, 1993,1994; Newton, 1994 occurred with exposure to sublethal dose of bacteria Survival occurred, but with greater susceptiblity to infection when challenged with bacteria and death when challenged with a lethal dose of bacteria Two high doses of THC potentiated the effects of herpes simplex and enhanced the progression of death Single dose did not promote death Specter, 1991 weight of THC is 314, so a 1-M solution would be 314 g of THC in 1 L of solution, and a 10-,uM solution would be 3.14 mg THC/L. A 1- to 10-,uM concentration will generally elicit a physiologically relevant response in immune cell cultures.
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From page 64... ...
are exposed to antigens and mitogens~ can be inhibited by THC, 11-OH-THC, cannabinol, and 2-AG, as well as synthetic cannabinoid agonists such as CP 55,940; WIN 55,212-2; and HU210.6~ 89 93 99 ~27 ~55 In contrast, one study testing anandamide revealed little or no effect on T cell proliferation.93 However, these drug effects are variable and depend on experimental conditions, such as the experimental drug dose used, the mitogen used, the percentage of serum in the culture, and the timing of cannabinoid drug exposure. In general, lower doses of cannabinoids increase proliferation and higher doses suppress proliferation.
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From page 65... ...
Natural Killer Cells Repeated injections of relatively low doses of THC (3 mg/kg/day~2~) or two injections of a high dose (40 mg/kg86)
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From page 66... ...
When injected into mice, THC suppresses the production of those cytokines that modulate the host response to infection (see below) .~5 Cannabinoids also modulate interferons induced by viral infection, as well as other interferon inducers.85 Furthermore, in human cell cultures, interferon production can be increased by low concentrations but decreased by high concentrations of either THC or CBD.~68 In addition to Thl cytokines, cannabinoids modulate the production of cytokines such as interleukin-1 (IL-1)
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From page 67... ...
Likewise, the cannabinoid, HU-211, was shown to suppress brain inflammation that resulted from closed-head injury or infectious meningitis7 in studies on rats. HU-211 is a synthetic cannabinoid that does not bind to cannabinoid receptors and is not psychoactive;7 thus, without direct evidence, the effects of marijuana cannot be assumed to include those of HU211.
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From page 68... ...
It is interesting to note that two reports of cannabinoid-induced analgesia are based on the ability of the endogenous cannabinoids, anandamide and PEA, to reduce pain associated with local inflammation that was experimentally induced by subcutaneous injections of dilute formalin.22 73 Both THC and anandamide can increase serum levels of ACTH and corticosterone in animals.~69 Those hormones are involved in regulating many responses in the body, including those to inflammation. The possible link between experimental cannabinoid-induced analgesia and reported antiinflammatory effects of cannabinoids is important for potential therapeutic uses of cannabinoid drugs but has not yet been established.
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From page 69... ...
A key focus for future study is the neurobiology of endogenous cannabinoids; establishing the precise brain localization (in which cells and where) of cannabinoids, cellular storage and release mechanisms, and uptake mechanisms will be crucial in determining the biological role of this system.
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From page 70... ...
. CONCLUSION: The different cannabinoid receptor types found in the body appear to play different roles in normal physiology.
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From page 71... ...
1993. Development of behavioral tolerance to delta 9-THC without alteration of cannabinoid receptor binding or mRNA levels in whole brain.
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From page 72... ...
1997. Regional differences in cannabinoid receptor/G-protein coupling in rat brain.
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From page 73... ...
1996. Isolation and measurement of the endogenous cannabinoid receptor agonist, anandamide, in brain and peripheral tissues of human and rat.
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From page 74... ...
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.
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From page 75... ...
1992. Identification of a functionally relevant cannabinoid receptor on mouse spleen cells that is involved in cannabinoid-mediated immune modulation.
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From page 76... ...
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.
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From page 77... ...
1998. Self-administration of the cannabinoid receptor agonist WIN 55,212-2 in drug-naive mice.
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From page 78... ...
1993. Chronic cannabinoid administration alters cannabinoid receptor binding in rat brain: A quantitative autoradiographic study.
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From page 79... ...
1997. Effects of chronic exposure to delta-9-tetrahydrocannabinol on cannabinoid receptor binding and mRNA levels in several rat brain regions.
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From page 80... ...
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.
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From page 81... ...
1994. Effect of the brain constituent anandamide, a cannabinoid receptor agonist, on the hypothalamo-pituitary-adrenal axis in the rat.
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From page 82... ...
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)
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