Animal Physiology Books Pdf

[Elia Khensamphanh]

Muchhas 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).

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 substantive 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:

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.

Δ9-THC and Δ8-THC are the only compounds in the marijuana plant that produce all the psychoactive effects of marijuana. Because Δ9-THC is much more abundant than Δ8-THC, the psychoactivity of marijuana has been attributed largely to the effects of Δ9-THC. 11-OH-Δ9-THC is the primary product of Δ9-THC metabolism by the liver and is about three times as potent as Δ9-THC.128

There have been considerably fewer experiments with cannabinoids other than Δ9-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 Δ9-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 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

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.

Because drugs injected into animals must be dissolved in a water-based 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 blood-borne 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.

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,27Abood 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 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.

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

The cannabinoid receptor in the brain is a protein referred to as CB1. 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.

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