Cannabis and endocannabinoid modulators: Therapeutic promises and challenges

The discovery that botanical cannabinoids such as THC exert some of their effect through binding specific cannabinoid receptor sites,has led to the discovery of the Endocannabinoid Signaling System, which in turn has spurred research into the mechanisms of action and addiction potential of cannabis.

This paper reviews current understanding of CB1, CB2, and other possible cannabinoid receptors, their arachidonic acid derived ligands (e.g. anandamide 2 arachidonoyl glycerol), and their possible physiological roles. CB1 is heavily represented in the central nervous system, but is found in other tissues as well CB2 tends to be localized to immune cells. Activation of the endocannabinoid system can result in enhanced or dampened activity in various neural circuits depending on their own state of activation.

This suggests that one function of the endocannabinoid system may be to maintain steady state. The therapeutic action of botanical cannabis or of synthetic molecules that are agonists, antagonists, or which may otherwise modify endocannabinoid metabolism and activity indicates they may have promise as neuroprotectants, and may be of value in the treatment of certain types of pain, epilepsy, spasticity, eating disorders, inflammation, and possibly blood pressure control.

Throughout much of the twentieth century discourse on marijuana was framed principally in sociopolitical terms throughout much of the world, and most especially in the US. The official, governmental point of view in the US, Canada, and Western Europe was that marijuana was an addicting drug devoid of therapeutic benefits. Hence, it was classified as a ‘Schedule 1’ agent, i.e. a dangerous drug of no medical value.

An opposing view, which gradually gained currency from the 1960 s onward, was that marijuana was a relatively harmless naturally occurring substance. Most users experienced marijuana as having calming, perhaps soporific effects, causing transient memory and other cognitive impairment, and stimulating appetite. While occasional untoward effects were acknowledged (e.g. anxiety reactions,psychotic phenomena), the general view was that any alterations in mood and cognition were transient and that marijuana had little or no addiction potential, at least as evidenced by apparent lack of physiological withdrawal symptoms on its discontinuation.

Gaoni and Mechoulam’s  characterization of some of marijuana’s cannabinoid constituents, and in particular, the identification of THC as the prime psychoactive drug, stimulated laboratory, animal model, and human research however, whereas, some of the animal studies probed various physiological properties of the cannabinoids, including some that might have therapeutic values, human studies generally concentrated on the addictive and adverse affects of THC and marijuana. As a result, by the last decade of the twentieth century it remained an open question whether the cannabinoids could have any therapeutic value whatever.

1. Discovery of the endocannabinoid system

A major paradigmatic shift occurred with the discovery  and cloning  of delta-9 THC binding sites. The first discovered cannabinoid receptor was termed CB1. Subsequently, a second receptor, termed CB2 was characterized. Thereafter, anandamide and 2-arachidonoyl-glycerol (2-AG), derivatives of arachidonic acid, were identified as endogenous ligands to CB1 and CB2.

The CB1 receptor is heavily concentrated in the central nervous system, but is found in other tissues as well, including liver, gut, uterus, prostate, adrenals, and the cardiovascular system. CB2 tends to be localized to cells of immune origin. In the brain the CB1 receptors tend to be concentrated in sub cortical structures including cerebellum, basal ganglia, and other limbic lobe circuitries, as well as in the hippocampus. Though less concentrated, CB1 receptors are also found in other parts of the cortex. As noted above, other tissues are also populated by CB1, and in particular, these include the pituitary, adrenal, GI tract, urinary bladder, and heart and blood vessels. 

Of the botanically derived cannabinoids, delta-9 THC, which is the most potent psychoactively, binds to both CB1 and CB2 receptors. Delta-8 THC also binds to both, though somewhat less strongly. Cannabidiol binds to none of the receptors, is devoid of psychoactive effect, yet may have some anti-inflammatory and smooth muscle contraction inhibitory actions mediated either by a yet uncharacterized CB receptor or another mechanism entirely.

2. Structure and function of CB receptors

The CB receptors are part of the super family of G-protein coupled receptors. Common features of such receptors are that they consist of a protein with seven transmembrane regions that can couple to stimulatory or inhibitory intracellular G-proteins. Such G-proteins can then up or down regulate enzymes such as adenyl cyclase which can then increase or decrease cyclic AMP (c-AMP) production. c-AMP in turn can activate protein kinase to phosphorylate transcription factors such as cyclic AMP response element binding protein (CREB), which can in turn activate gene expression through production of various messenger RNAs. In the case of activation of the CB1 cannabinoid receptor, the typical action is actually inhibitory, that is reduction of c-AMP formation 

Such down regulation of c-AMP is one possible explanation for the putative neuroprotective actions of CB1 agonists. Neurons can be injured by activation of NMDA receptors that permit entry of calcium, which in turn can activate calcium channel receptors (ryanodine receptors) intracellularly on the endoplasmic reticulum. Ryanodine receptors, when activated by calcium can cause further release of calcium into the cytoplasm producing a toxic cascade. CB1 agonists may act through two mechanisms to ‘protect’ the neuron; first, through a G-protein coupled mechanism they may reduce NMDA-controlled calcium influx; second, since protein kinase A (PKA) can stimulate the ryanodine receptor, CB1 agonists, by reducing PKA may effectively reduce efflux of calcium from the endoplasmic reticulum.

Cannabinoid CB1 receptors are located at many of the sites associated with peripheral and central processing of nociceptive messages including medium and large-sized cells of rat dorsal root ganglia (DRG)  and spinal interneurons. Immunostaining studies report strong coexpression of CB1 receptors and vanilloid VR1 receptors in adult rat DRG neurons, which is of particular interest given that anandamide is an agonist both at inhibitory cannabinoid receptors and at pronociceptive VR1 receptors. The antinociceptive activity of cannabinoids is mediated through both central and peripheral mechanisms, as antinociceptive effects of cannabinoids have been widely reported following peripheral, spinal and intracerebroventricular administration of different classes of cannabinoid receptor agonists. While the CB1 receptor has been most commonly thought of as the important receptor in antinociceptive actions of cannabinoids, recent evidence also suggests the peripheral CB2 receptor agonism can elicit anti-nociceptive effects, and there may be other, as yet unidentified CB receptor or non-receptor based mechanisms.

The CB1 receptor has also been implicated as essential in the development of the feeding response in mice pup neonates—in the absence of CB1 receptor signaling, mediated either by CB1 antagonism or genetic CB1 deletion, mice pups do not draw milk from the mother and die. These data suggest that endocannabinoids play a critical role in survival of the newborn mouse by controlling milk ingestion. Combined with the finding that the level of 2-AG in rodent pup brains peaks immediately after birth , it has been suggested that the clinical application of cannabinoids in treating infant failure to thrive deserves investigation as well.

CB1 receptors are expressed at high levels in brain regions such as the amygdala, which are implicated in the control of anxiety and fear. Pharmacological or genetic disruption of CB1 receptor activity elicits anxiety-like behaviors in rodents, suggestive of the existence of an intrinsic anxiolytic tone mediated by endogenous cannabinoids. Further, mice lacking CB1 receptors show strongly impaired extinction but unaffected acquisition and consolidation of aversive memories. These effects are associated with elevated levels of endocannabinoids in the basolateral amygdala, and suggest that endocannabinoids are crucial for the extinction of aversive memories.

CB1 receptors have been detected on enteric nerves, and pharmacological effects of their activation include gastro-protection, reduction of gastric and intestinal motility and reduction of intestinal secretion. The digestive tract also contains endogenous cannabinoids (i.e. the endocannabinoids anandamide and 2-aracidonylglycerol) and mechanisms for endocannabinoid inactivation (i.e. endocannabinoid uptake and enzymatic degradation by fatty acid amide hydrolase—FAAH).

The CB1 receptor is present in cholinergic nerve terminals of the myenteric and submucosal plexus of the stomach, duodenum and colon, and it is probable that cannabinoid-induced inhibition of digestive tract motility is caused by blockade of acetylcholine release in these areas. There is also evidence that cannabinoids act on CB1 receptors that are localized in the dorsal–vagal complex of the brainstem(the region of the brain that controls the vomiting reflex, explaining anti-emetic effects)

Endocannabinoids and their inactivating enzymes are present in the gastrointestinal tract and may also play a physiological role in the control of emesis, although evidence suggests that the central effects may be activated at lower doses of cannabinoids than the peripheral effects.

(Supported by the University of California Center for Medicinal Cannabis Research and in part by the NIGMS Medical Scientist Training Grant #T32 GM07198.)

Source : https://www.ncbi.nlm.nih.gov