From “Azalla” to Anandamide: Distilling the Therapeutic Potential of Cannabinoids
The endogenous cannabinoid system—named for the plant that led to its discovery—is Cannabis, derived from a plant and one of the oldest known drugs, has . Sorting these relationships out is an important task, since the. This was called "anandamide". Ananda is Sanskrit for "bliss", and this chemical soon became known as the "blissful" or "bliss" molecule. [and] azalla (cannabis); these seven drugs are a cataplasm for the Hand of a Ghost, with (5) discovered two endogenous ligands that activated CB1R: anandamide It seems that one difference between the two molecules is how they affect.
Getting High on the Endocannabinoid System
In addition to synergistic actions, cannabidiol by itself is anxiolytic, 18 and can reduce inflammation and blood pressure. THC ratio of 1. The anticonvulsant properties of cannabis have been known for centuries. A dramatic account of such action recently received widespread media coverage.
By age 5, she was having up to seizures per day, and experiencing mental and physical developmental stagnation. Her prospects were grim and her parents desperate. With the approval of two doctors, they tried adding an oil extract of cannabis to her food. Amazingly, her seizures immediately dropped to a few per month, an improvement that has persisted for a year, and her normal development resumed. To what extent this positive outcome is attributable to the low THC, the high cannabidiol, or the combination of the two is unknown.
A different nonpsychotropic cannabinoid, cannabidivarin, reduces seizures independently of CB1 in animal models, and this property is not improved by the presence of THC.
- Meet Anandamide - The "Bliss" Molecule
- From “Azalla” to Anandamide: Distilling the Therapeutic Potential of Cannabinoids
Psychotropic side effects of cannabis are caused exclusively by turning on or off brain CB1s. Therefore one strategy is to develop CB1 agonists or antagonists that can be given orally but that do not cross the blood-brain barrier a membranous cellular fence that bars certain chemicals present in the circulation from getting into the brain.
CB1s in fat and other tissues are thought to contribute to obesity, and a peripherally restricted CB1 antagonist could be beneficial in weight control.
Getting High on the Endocannabinoid System
Conversely, cannabinoids are good pain relievers that work in part by stimulating CB1s on peripheral pain sensory neurons. When activated, these CB1s block transmission of the pain signals to the brain—basically what topical anesthetics like novocaine do—and pain signals unable to reach the brain are not felt.
CB1 agonists or antagonists that are restricted from the brain could be quite useful in conditions that do not arise from within the central nervous system. What about manipulating other components of the endocannabinoid system? Rather than stimulating CB1 with drugs, the endocannabinoids can be pressed into service artificially.
Once released, endocannabinoids, like other chemical messengers, are quickly taken back up into cells or otherwise inactivated, which preserves the integrity of the signaling process.
Inhibiting uptake and degradation therapeutically offers the advantage of increasing the endocannabinoid levels, and thereby activating CB1, in those regions in which the messengers are already being mobilized by brain activity itself. Rather than indiscriminate activation of CB1s everywhere for long periods of time, only certain groups of receptors would be activated and only when and where called for naturally.
With a drug that inhibits the enzyme fatty-acid amide hydrolase, FAAH that inactivates the endocannabinoid, anandamide but not 2-AGlevels increase, 22 and an analogous approach inhibits the major degradation enzyme for 2-AG, monoglyceride lipase MGL and 2-AG levels rise.
Iin addition to activating CB1, anandamide turns out to be an excellent activator of a another receptor, TRPV1, 25 a noncannabinoid receptor that actually heightens anxiety, so globally elevating anandamide has complex effects. In this case, pain relief free of psychotropic side effects should be possible with degradative enzyme blockers designed to stay out of the central nervous system.
Finally, a possibility that has gotten little attention is the targeting of conventional neurotransmitter systems that stimulate the production of endocannabinoids. For example, glutamate is the major excitatory neurotransmitter in the brain, and one subtype of glutamate receptors group I mGluRs potently mobilizes endocannabinoids. What Is in Store? The endocannabinoid system is powerful and nearly ubiquitous in the nervous system. The cannabinoid receptors dispersed throughout many brain regions are responsible for regulation of numerous aspects of neuronal activity, and account for the bewildering variety of behavioral and psychological effects caused by THC.
Depending on the nervous system regions and maladies involved, either stimulating or inhibiting the endocannabinoid system could have beneficial effects. A great deal of attention is being given to incorporating nonpsychotropic cannabinoids into medicinal preparations, although in most cases the actual effects of these agents on the nervous system are unknown.
For some purposes, drugs that are restricted to acting on peripheral cannabinoid receptors, and are prevented from entering the central nervous system, could be effective. Finally, therapeutic strategies aimed at developing regionally selective targeting of endocannabinoid system components, perhaps in combination with agents that affect conventional neurotransmitter systems, or nonpsychotropic cannabinoids, offer promise for future advances.
Gaoni Y, Mechoulam R. Isolation, structure and partial synthesis of an active constituent of Hashish. Journal of the American Chemical Society. Determination and characterization of a cannabinoid receptor in rat brain. Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Molecular characterization of a peripheral receptor for cannabinoids. Isolation and structure of a brain constituent that binds to the cannabinoid receptor.
Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochemical and Biophysical Research Communications. Endogenous cannabinoids mediate retrograde signalling at hippocampal synapses.
Endogenous cannabinoids mediate retrograde signals from depolarized postsynaptic neurons to presynaptic terminals. Role of endogenous cannabinoids in synaptic signaling. Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity. Journal of Clinical Investigation.
Anti-obesity effect of SR, a CB1 receptor antagonist, in diet-induced obese mice. American Journal of Physiology.
How does marijuana produce its effects? | National Institute on Drug Abuse (NIDA)
Regulatory, Integrative and Comparative Physiology. The endogenous cannabinoid system controls extinction of aversive memories. Human cannabinoid receptor 1: European Journal of Pharmacology. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: British Journal of Pharmacology.
Endocannabinoid system and mood disorders: Endocannabinoid signaling in microglial cells. Cannabidivarin-rich cannabis extracts are anticonvulsant in mouse and rat via a CB1 receptor-independent mechanism. A psychomotor vigilance task was used to evaluate attention, reaction time, and underlying motoric behavior over time e.
The duration of stimulus presentation was 2 seconds on the first trial of the session, and thereafter both the intermittency of the stimulus presentation after 5-,or second ITI; no blackout during ITI and the stimulus location were randomized across trials. If the subject successfully touched the stimulus within 2 seconds, milk was delivered and the duration of stimulus presentation decreased by 0.
The primary dependent measure under these conditions was mean titrated duration value. A progressive ratio procedure Hodos, was used to measure motivational value in the present study by determining the maximum number of responses that were emitted for milk delivery. Next, a progressive ratio schedule of milk presentation was introduced, and each reinforcer delivery led to an increase in the number of touchscreen responses required for subsequent presentation.
The progressive ratio requirement was programmed with a log 2 step size i. Each milk reinforcer was paired with an millisecond yellow screen flash and followed by a second ITI blackout. Each session was terminated following either 5 minutes without a response or 45 minutes, whichever came first.
Steady-state performance in individual subjects was obtained prior to drug testing and was defined as five consecutive sessions yielding a breakpoint within one of two adjacent step sizes.
Drugs were tested in a quasi-random order. Each dose of each drug was studied on each task individually across sessions with at least three intervening control no drug or saline sessions to minimize the development of tolerance. To assess drug effects on discrimination reversal, subjects first learned a novel discrimination during a trial acquisition session.
Next, subjects were removed from the touchscreen chamber, injected, and placed in a holding chamber for the pretreatment interval, and then returned to the touchscreen chamber with the contingencies reversed. Previous research in our laboratory has indicated that such intervals between acquisition and reversal have no effect on reversal learning see Kangas and Bergman, With the exception of progressive ratio, all experimental sessions were terminated if 15 minutes elapsed without a response.
However, in the present studies, this limit was only contacted in the instances highlighted subsequently when relatively large doses of drugs tested abolished performance. Data Analysis The effects of all drugs on discriminative capability trials, repeated acquisition, and discrimination reversal were expressed as changes in accuracy.
Drug effects on DMTS performance similarly were expressed as changes in accuracy as a function of delay value i. Accuracy was calculated using the following equation: For repeated acquisition, discrimination reversal, and DMTS, if 15 minutes elapsed without a response the session was terminated and accuracy was considered indeterminate.
The effects of drugs on psychomotor vigilance were measured as changes in mean titrated duration. Overall mean titrated duration values were calculated by averaging the titrated duration values recorded in the session. Even after this initial discovery, the mechanism by which these so-called cannabinoids i. It was another 20 years before cannabinoid receptor 1 CB1R was finally identified 4.
The discovery of this receptor prompted the even more intriguing question: Why did the human brain contain a receptor for a compound found in a plant? A joke made at the time was that the receptor existed in the human brain solely so that man may enjoy smoking cannabis. The actual answer emerged a few years later when Mechoulam et al.