Disease Definition
MS is a chronic inflammatory disease of the CNS, characterized by the presence of inflammatory infiltrates containing autoreactive T cells, monocytes and macrophages, that lead to demyelination and axonal loss.
Immunomodulatory effects of orally administered cannabinoids in multiple sclerosis, 2003
Pathogenesis
Despite several decades of research on the pathogenesis of MS, the exact cause of the disease is still unknown. MS is a complex T-cell-mediated autoimmune disease with a genetic predisposition which is triggered by a combination of unknown environmental factors, presumably viral infections. MS occurs when T- and B-lymphocytes cross the blood–brain barrier and progress into the central nervous system resulting in destruction of the myelin sheath and axon damage, causing inflammation. This leads to irreversible nerve and tissue damage that manifests as a wide range of symptoms.
Several possibilities exist for the relationship between inflammation and neurodegeneration:
- that inflammation induces neurodegeneration;
- that neurodegeneration causes inflammation;
- other factors contribute to the development of inflammation and/or neurodegeneration;
- inflammation and neurodegeneration participate in a cycle or a cascade in which they augment one another;
- that inflammation can protect against neurodegeneration.
In the context of MS and its animal models these hypotheses are not necessarily mutually exclusive.
The CNS has long been considered to be an immunoprivileged site with few if any lymphocytes present in the absence of active or ongoing infection. However, accumulating evidence has demonstrated that a small number of T cells traffic through the CNS surveying for infection or injury and that T cells activated in the periphery can penetrate the blood–brain barrier (BBB) and enter the CNS.
Autoreactive T and B cells are normal constituents of the immune system. It has been demonstrated that some of these autoreactive cells can be stimulated with myelin components in healthy individuals, but do not appear to be pathogenic unless tolerance is broken and cells activated. Induction of autoimmune responses against myelin components in the CNS is hypothesized to occur through mechanisms such as molecular mimicry, bystander activation and epitope spreading. Once activated, myelin-specific T cells can cross the BBB where they proliferate and secrete pro-inflammatory cytokines which in turn stimulate microglia, macrophages and astrocytes, and recruit B cells, ultimately resulting in damage to myelin, oligodendrocytes and axons.
Inflammation, Demyelination, Neurodegeneration and Neuroprotection in the Pathogenesis of Multiple Sclerosis, 2008
Symptoms
The progress, severity, and specific symptoms of MS are unpredictable and vary from one person to another. Clinical manifestations are varied, and can involve any functional neurological system depending on the affected area of the CNS. The signs and symptoms of Multiple Sclerosis include painful muscle spasms, tremor, ataxia, weakness or paralysis, difficulty in speaking, constipation, and loss of bladder control.
A.D.A.M. Medical Encyclopedia. Multiple sclerosis. MS; Demyelinating disease
National Multiple Sclerosis Society
There is a growing amount of evidence to suggest that cannabis and individual cannabinoids may be effective in suppressing certain symptoms of multiple sclerosis and spinal cord injury, including spasticity and pain.
Although the psychoactive effects of these substances have limited clinical progress to study cannabinoid actions in pain mechanisms, preclinical research is progressing rapidly.
Cannabis sativa extracts, containing known doses of tetrahydrocannabinol and cannabidiol, have granted approval in Canada for the relief of neuropathic pain in multiple sclerosis. Further double-blind placebo-controlled clinical trials are needed to evaluate the potential therapeutic effectiveness of various cannabinoid agonists-based medications for controlling different types of pain.
Cannabinoids and multiple sclerosis, August 2002
Role of the Cannabinoid System in Pain Control and Therapeutic Implications for the Management of Acute and Chronic Pain Episodes,2006 July
Cannabinoids Definition
Cannabinoids are a group of terpenophenolic compounds present in Cannabis (''Cannabis sativa'') and occur naturally in the nervous and immune systems of animals.
The broader definition of cannabinoids refers to a group of substances that are structurally related to tetrahydrocannabinol (THC) or that bind to cannabinoids receptors.
The chemical definition encompasses a variety of distinct chemical classes: the classical cannabinoids structurally related to THC, the nonclassical cannabinoids, the aminoalkylindoles, the eicosanoids related to the endocannabinoids, quinolines and arylsulphonamides, and additional compounds that do not fall into these standard classes but bind to cannabinoid receptors.
The term ''cannabinoids'' also refers to a unique group of secondary metabolites found in the cannabis plant, which are responsible for the plant's peculiar pharmacological effects.
At the present time, there are three general types of cannabinoids: ''phytocannabinoids” occur uniquely in the cannabis plant; endogenous cannabinoids are produced in the bodies of humans and other animals; and ''synthetic cannabinoids'' are similar compounds produced in a laboratory.
Cannabinoids Receptors
Before the 1980s, it was often speculated that cannabinoids produced their physiological and behavioral effects via nonspecific interaction with cell membranes, instead of interacting with specific membrane-bound receptors.
The discovery of the first cannabinoid receptors in the 1980s helped to resolve this debate.
These receptors are common in animals, and have been found in mammals, birds, fish, and reptiles.
At present, there are two known types of cannabinoid receptors, termed CB1 and CB2, with mounting evidence of more.
Cannabinoid receptor type 1
CB1 receptors are found primarily in the brain, to be specific in the basal ganglia and in the limbic system, including the hyppocampus.
CB1 receptors are absent in the medulla oblongata, the part of the brain stem responsible for respiratory and cardiovascular functions. Thus, there is not a risk of respiratory or cardiovascular failure as there is with many other drugs. CB1 receptors appear to be responsible for the euphoric and anticonvulsive effects of cannabis.
Cannabinoid receptor type 2
CB2 receptors are almost exclusively found in the immune system, with the greatest density in the spleen.
While found only in the peripheral nervous system, a report does indicate that CB2 is expressed by a subpopulation of microglia in the human cerebellum.
CB2 receptors appear to be responsible for the anti-inflammatory and possibly other therapeutic effects of cannabis.
Cannabinoids - What are Cannabinoids?
Relaxing and Analgesic Effect
Many in vitro studies unequivocally demonstrated that high doses of cannabinoids suppress immune responses. Physiologically relevant concentrations of cannabinoids, however, resulted in metabolic stimulation of lymphocytes and an increase in pro-inflammatory cytokine production rather than immunosuppression. These dose-dependent actions of cannabinoids, suggesting biphasic mechanisms of THC, need further exploration.
Here are presented the mechanisms of action and the effects that occur after endocannabinoids bind to their specific receptors, while highlighting their role in pain modulation.
Although in the intercellular signaling role they are similar to the well-known monoamine neurotransmitters, such as acetylcholine and dopamine, endocannabinoids differ in numerous ways from them. For instance, they are used in retrograde signaling between neurons. Conventional neurotransmitters are released from a "presynaptic" cell and activate appropriate receptors on a "postsynaptic" cell. Endocannabinoids, on the other hand, are described as retrograde transmitters because they most commonly travel "backward" against the usual synaptic transmitter flow. They are, in effect, released from the postsynaptic cell and act on the presynaptic cell, where the target receptors are densely concentrated on axonal terminals in the zones from which conventional neurotransmitters are released. Activation of cannabinoid receptors temporarily reduces the amount of conventional neurotransmitter released. This endocannabinoid mediated system permits the postsynaptic cell to control its own incoming synaptic traffic. The ultimate effect on the endocannabinoid-releasing cell depends on the nature of the conventional transmitter being controlled. For instance, when the release of the inhibitory transmitter GABA is reduced, the net effect is an increase in the excitability of the endocannabinoid-releasing cell. On the converse, when release of the excitatory neurotransmitter glutamate is reduced, the net effect is a decrease in the excitability of the endocannabinoid-releasing cell. This may be important in the control of neural circuits, such as nociceptive signalling.
Activation of cannabinoid receptors inhibits GABAergic synaptic transmission in a number of central nervous system regions, including areas participating in nociceptive signalling like the amygdala , periaqueductal grey matter , rostral ventromedial medulla (RVM) , and superficial dorsal horn. However, even though cannabinoid receptor-mediated inhibition of glutamatergic transmission occurs in some brain regions including PAG neurons it has not been detected in the medullary dorsal horn.
Activated CB1 receptors couple to Gi/o-protein to inhibit adenylate cyclase, decrease Ca2+ conductance, increase K+ conductance, and increase mitogen-activated protein kinase activity. The presynaptic localisation of CB1 receptors indicates that cannabinoids modulate neurotransmitter release from axon terminals. The effect of cannabinoids on synaptic function consists of inhibition of the release of a variety of neurotransmitters and also the inhibition of electrical activity by a depolarisation phenomenon.
The neurotransmitters whose release is inhibited by activation of cannabinoid receptors include L-glutamate, GABA, noradrenaline, dopamine, serotonin, and acetylcholine. For this reason cannabinoids have a relaxing effect which allows the reduction of muscle contraction limiting muscle spasms and consequently pain.
Conclusions
The knowledge on the therapeutic effects of cannabinoids have yet to be investigated. However, it is important to be aware that cannabinoids do not represent a cure for patients' recovery but an analgesic support that could give them a possibility of a better quality of life.
Bonino Francesca
Branca Ilaria
