Within to date, two cannabinoid receptors have been identified were the CB1 (cloned in 1990), and the CB2 receptor (cloned in 1993), exhibiting 48% amino acid sequence identity. Besides their difference in amino acid sequence, they differ in signaling mechanisms, tissue distribution, and sensitivity to certain agonists and antagonists that show marked selectivity for one or the other receptor type. Activation of cannabinoid receptors causes inhibition of adenylate cyclase, thus, inhibiting the conversion of ATP to cyclic AMP (cAMP).

Other effects have also been observed, e.g. interaction with certain ion channels.

CB1 receptors are mainly found on neurons in the brain, spinal cord and peripheral nervous system, but are also present in certain peripheral organs a tissue, among them endocrine glands, leukocytes, spleen, heart and parts of the reproductive, urinary and gastrointestinal tracts. CB1 receptors are highly expressed in the basal ganglia, cerebellum, hippocampus and dorsal primary afferent spinal cord regions, which reflect the importance of the cannabinoid system in motor control, memory processing and pain modulation, while their expression in the brainstem is low, which may account for the lack of cannabisrelated acute fatalities, e.g. due to depression of respiration.

CB2 receptors are located principally in immune cells, among them leukocytes, spleen and tonsils. Immune cells also express CB1 receptors but there is markedly more mRNA for CB2 than CB1 receptors in the immune system. One of the functions of CB receptors in the immune system is modulation of cytokine release. Activation of the CB1 receptor produces marijuana like effects on psyche and circulation, while activation of the CB2 receptor does not. Hence, selective CB2 receptor agonists have become an increasingly investigated target for therapeutic uses of cannabinoids, among them analgesic, anti-inflammatory and antineoplastic actions. There is increasing evidence for the existence of additional cannabinoid receptor subtypes in the brain and periphery.

Endocannabinoids

The identification of cannabinoid receptors was followed by the detection of endogenous ligands for these receptors, called endocannabinoids, a family of eicosanoids. To date five endocannabinoids have been identified. These are:

• N-arachidonylethanolamide (anandamide)

• 2-arachidonylglycerol (2-AG)

• 2-arachidonylglyceryl ether (noladin ether)

• O-arachidonyl-ethanolamine (virodhamine)

• N-arachidonyl-dopamine (NADA)

Cannabinoid receptors and their endogenous ligands together constitute the cannabinoid system which is teleologically millions of years old and has been found in mammals and many other species.

Endocannabinoids serve as neurotransmitters or neuromodulators. Anandamide and NADA do not only bind to cannabinoid receptors but also stimulate vanilloid receptors (VR1), non-selective ion channels associated with hyperalgesia.

The first two discovered endocannabinoids, anandamide and 2-AG, are best studied. They are produced “on demand” by cleavage of membrane lipid precursors and released from cells in a stimulus-dependent manner. After release, they are rapidly deactivated by uptake into cells and metabolized. Metabolism of anandamide and 2-AG occurs by enzymatic hydrolysis by fatty acid amide hydrolase (FAAH) and other metabolic processes, including hydrolysis of 2-AG by monoglyceride lipase.

Tonic Activity of the Endocannabinoid System

When administered by themselves antagonists at the cannabinoid receptor may behave as inverse agonists in several bioassay systems. This means that they do not only block the effects of endocannabinoids but produce effects that are opposite in direction from those produced by cannabinoid receptor agonists, e.g. cause hyperalgesia, suggesting that the cannabinoid system is tonically active. This tonic activity may be due to a constant release of endocannabinoids or from the result of a portion of cannabinoid receptors which exist in a constitutively active state.

Tonic activity of the cannabinoid system has been demonstrated in several conditions. Elevated levels of endocannabinoid have been demonstrated in a pain circuit of the brain (periaqueductal gray) following painful stimuli. Tonic control of spasticity by the endocannabinoid system has been observed in chronic relapsing experimental autoimmune encephalomyelitis (CREAE) in mice, an animal model of multiple sclerosis.

An increase of cannabinoid receptors following nerve damage was demonstrated in a rat model of chronic neuropathic pain and in a mice model of intestinal inflammation. This may increase the potency of cannabinoid agonists used for the treatment of these conditions. Tonic activity has also been demonstrated with regard to appetite control and with regard to vomiting in emetic circuits of the brain.