In addition, to validate the pupillography as a medicolegal proof, studies with a larger sample are needed as well as pupillographic analysis in subjects who have taken poli-drugs or drugs and alcohol together. Road traffic injuries are the leading cause of death among people aged between 15 and 29 years and it will rise to become the fifth leading cause of death by 2030. These subjects represent the main prevention target of this method.Neuropathic pain is initiated by a damage to the nervous system which might be attributed to infectious agents such as human immuno deficiency virus , metabolic disease, neurodegenerative disease, multiple sclerosis and physical trauma . Regardless of the cause, damage to the nervous system and subsequent neuropathic pain can be accompanied by dysesthesia or allodynia. As the pathophysiology of neuropathic pain is complex , the current therapeutic modalities are still limited. Hence, it is imperative to find a new therapeutic agent that helps treat or minimize the symptoms associated with neuropathic pain disorder. Cannabis is a promising plant-based medicine that has garnered much attention of late for the treatment of various conditions associated with pain and inflammation. The potential health implications of cannabis are accredited to Δ-9-tetrahydrocannabinol and cannabidiol. In the majority of studies todate, THC and CBD alone or in combination have been examined for the treatment of various disorders, such as pain and inflammation. However, few studies have investigated the biological benefits of full spectrum cannabis plant extract. Given that cannabis is known to produce a large number of cannabinoids along with numerous other biologically relevant products including terpenes and others, it stands to reason that studies involving purified THC and/or CBD may not accurately reflect the potential biological benefits of the full-spectrum cannabis extract especially with regard to their crucial role in the treatment of neuropathic pain and inflammation.
Therefore, the goal of this review is to discuss the current knowledge about the potential beneficial effects of full-spectrum cannabis extract in pre-clinical studies involving rodents with neuropathic pain and inflammation.In 1964, Dr. Raphael Mechoulam discovered THC, which was the first identified cannabinoid. This groundbreaking work paved the way for the discovery of the endogenous cannabinoid system of which anandamide and 2-arachidonoylglycerol are considered the main endogenous cannabinoids in higher order mammals,vertical grow system including humans. Both anadamide and 2-arachidonoylglycerol regulate the sensitivity of serotonin, dopamine, gamma-aminobutyric acid and glutamate in the central nervous system, thus demonstrating how these endogenous cannabinoids regulate many physiological and pathological processes such as pain, immune response, appetite, thermoregulation, energy metabolism, depression, memory and fertility.Anandamide was the first endocannabinoid isolated and it is chemically characterized as N-arachidonoylethanolamine. The name of anandamide originates from Sanskrit term ananda, which refers to “bliss”. Bliss is defined as euphoria that involves physiologic and psychologic harmony. Anandamide is synthesized from the precursor N-arachidonoyl phosphatidylethanolamine by phosphodiesterase phospholipase D enzyme. Once anadamide is synthesized, it is released from the neuronal terminal in a calcium ion-dependent manner and binds to presynaptic cannabinoid receptors. Anandamide is then rapidly up taken by neurons and astrocytes where it is degraded by fatty acid amide hydrolase into ethanolamine and arachidonic acid. The other endogenous cannabinoid is 2- arachidonoylglycerol, which is synthesized by the hydrolysis of an inositol-1,2-diacylglycerol by phospholipase C. Similar to anadamide, 2-arachidonoylglycerol binds to CB receptors and undergoes rapid biological degradation and catalytic hydrolysis, which is mediated by monaoacylglycerol lipase. Of importance, MGL along with FAAH are considered potential therapeutic targets that can regulate endocannabinoid levels.The most well characterized phytocannabinoids are THC, CBD, cannabinol , cannabigerol and cannabichromene . These botanical cannabinoids exist as inactive monocarboxylic acids containing precursors referred to as tetrahydrocannabinoic acid , cannabidiolic acid , cannabigerolic acid , and cannabichromenic acid , respectively. The presence of a carboxylic acid moiety on these chemicals precludes cannabinoids, particularly THC, from being bioavailable and binding to either CB receptors or other biological targets. Thus, the conversion of THCA, CBDA, CBGA, and CBCA to THC, CBD, CBN, CBG, and CBG, respectively, through decarboxylation is necessarily before any biological effect can be observed.
Decarboxylation of these carboxylic acids can be promoted by heating the plant above 105 °C, which can be achieved during the smoking or baking process .THC is the primary psychoactive component of Cannabis sativa and chemically analogous to N-arachidonoylethanolamine. THC is a euphoric agent that has anti-nociceptive, anti-inflflammatory, sedative and muscle relaxant effects. Additionally, THC increases appetite, dilates bronchial muscle and it has anti-emetic, anti-spasmodic, neuroprotective and anti-oxidant properties. Mechanistically, the physiological effect of THC is mediated primarily through the activation of CB1 and CB2 receptors with preferential binding to CB1 receptors.This effect might be attributed to the ability of THC to inhibit N-methylD-aspartate receptor activity in addition to the decrease in the hippocampal acetylcholine release . The decrease in acetylcholine release may be due to the activation of the CB1 receptor on parasympathetic neurons. Intriguingly, it has recently been shown that a low dose of THC reversed the age-related decline in cognitive performance in aged but not young mice. This effect was associated with increased expression of synaptic marker proteins and enhanced hippocampal spine density through glutamatergic CB1 receptors-dependent mechanism . Thus, this study raises the possibility that THC or full-spectrum cannabis extracts may have the potential to reverse cognitive decline in the elderly and suggests an agedependent effect of THC.CBD is the primary non-psychoactive component of Cannabis sativa and possesses sedative, anti-inflammatory, anti-convulsive and anti-psychotic actions, but does not have the typical THC side effects. Of importance, the powerful anti-convulsant effect of CBD appears to be mediated through a CB receptor-independent mechanism. Indeed, CBD mediates neuronal inhibition and anti-epileptic effects through gamma-aminobutyric acid A and adenosine A1 receptors dependent mechanisms. In addition, CBD has anti-psychotic and neuroprotective effects that are mediated via increasing the effect of dopamine and norepinephrine, activating the 5-hydroxytryptamine 1A receptor, inhibiting adenosine transporter, blocking T-type voltage-gated calcium channels and reducing glutamate induced-neurotoxicity. Numerous additional effects of CBD have also been reported. For instance, in the heart, CBD inhibits THC-induced tachycardia through the activation of adenosine A1 receptor.
Moreover, it has been reported that CBD protects against cardiac dysfunction, fibrosis, oxidative stress, and cell death signaling pathways in diabetic cardiomyopathy and doxorubicin-induced cardiotoxicity. In addition to the cardiac effects, CBD has recently been shown to be cytotoxic in estrogen receptor-positive and triple negative breast cancer cells through the induction of apoptosis aswell as it increases the uptake of the chemotherapeutic agent, doxorubicin, to induce apoptosis in these cells through transient receptor potential vanilloid type-2 -dependent mechanism. Thus, the potential benefits of CBD are extensive, even independent from the classical endocannabinoid system involving CB receptors.CBN is an oxidized by-product of THC produced in trace amounts by aged cannabis upon long exposure to air. Studies have shown that while CBN is inactive when administered alone to healthy volunteers, it still can potentiate the sedative effect of THC. Given that CBN is closely related to CBD in terms of the chemical structure, it shares the anti-convulsant and anti-inflammatory effects with CBD. The physiological effect of CBN is attributed to the modulation of the CB2 receptor with lower affinity for the CB1 receptor in comparison to THC .CBC is one of the main phytocannabinoids and appears to have no affinity to CB1 and CB2 receptors. Similar to CBD and THC, CBC possesses anti-inflammatory and anti-nociceptive effects through the inhibition of the cyclooxygenase enzyme and its associated prostaglandins. In contrast to CBD, CBC neither has an anti-convulsant effect nor inhibits the activity of cytochrome P450.CBG is the precursor phytocannabinoid compound of THC, CBD and CBC and is only produced in trace amounts in cannabis. Although CBG has low affinity to CB receptors, it is still capable of reducing pain, erythema and inflammation through the inhibition of peripheral lipooxygenase enzyme and the activation of central α2-adrenergic receptor. Furthermore, CBG has an anti-depressant effect because it is a potent anadamide uptake inhibitor as well as a moderate 5- HT1a antagonist.diate their pharmacological actions by binding to CB1 and CB2 receptors and through the regulation of the production and the degradation of endogenous endocannabinoids. Both CB1 and CB2 receptors are 7-domain Gi/o-protein coupled receptors decreasing the level of cyclic-AMP by suppressing adenylate cyclase. CB1 receptors are abundant and widely expressed throughout the CNS and they are responsible for the psychopharmacological and analgesic effects of THC. Of particular interest, CB1 receptors have high expression level in areas of the brain that are implicated in nociceptive perception, such as the thalamus and amygdala,cannabis grow equipment the midbrain periaqueductal grey matter cells, and the substantia gelatinosa of the spinal cord.
The presynaptic localization of CB1 receptors enables cannabinoids to modulate neurotransmitter release such as dopamine, noradrenaline, glutamate, GABA, serotonin and acetylcholine. The activation of the CB1 receptors in the aforementioned brain areas modulates nociceptive thresholds and produces multiple biological effects by regulating the balance between excitatory and inhibitory neurotransmitters. While the CB2 receptor has limited expression in sensory and CNS cells, it is mainly expressed in peripheral tissues, including keratinocytes and tissues of the immune system such as the lymphatic system. The CB2 receptor was shown to contribute to analgesia through suppressing the release of inflammatory mediators by cells located adjacent to nociceptive nerve terminals. In addition, activation of peripheral CB2 receptors blocks the transduction of pain signals into the CNS. Given that CB2 receptors are expressed in several types of inflammatory cells and immunocompetent cells, it is reasonable to assume that the activation of peripheral CB2 receptors may contribute to analgesic effect in conditions of inflammatory hyperalgesia and neuropathic pain such as MS. Consistent with this notion, increased numbers of microglia/macrophage cells expressing CB2 receptor have been reported in spinal cords derived from MS patients relative to controls, suggesting the involvement of CB2 receptor in the regulation of pain and inflammation in MS patients. Based on these findings, it was proposed that cannabinoid-based pharmacotherapies might be effective therapies for the reduction of pain due to MS.The anti-nociceptive effect of cannabinoids might not necessarily be due entirely to the activation of CB1 and CB2 receptors. Indeed, the analgesic effects may be due to the modulation of the transient receptor potential vanilloid 1 . The evidence supporting this is based on the observation that the anti-nociceptive effect of CBD in neuropathic rats was completely reversed by capsazepine, a known TRPV1 activator. Other receptor sites implicated in the action of CBD include the suppression of putative novel cannabinoid G protein coupled receptor GPR55, NMDAR and α1-adrenoreceptors and the activation of 5HT1A, adenosine A2, and the peroxisome proliferator-activated gamma receptors. In addition, THC and CBD are positive allosteric modulators of the μ- and δ-opioid receptors, suggesting the involvement of these receptors in the anti-nociceptive effect of THC and CBD. Moreover, CBD has been shown to block low-voltage-activated Ca+2 channels, stimulate the glycine-receptor, and modulate the activity of FAAH.
The action of CBD via these pathways may be responsible for the suppression of neuronal excitability and pain perception. In addition, there is evidence that CBD inhibits synaptosomal uptake of dopamine, noradrenaline, GABA, serotonin in addition to cellular uptake of anandamide. The modulation of these neurotransmitters might explain the neuroprotective and the anti-nociceptive effects of CBD. Moreover, CBD and THC have been shown to inhibit the cycloxygenase-2 enzyme and the production of arachidonic acid metabolites, prostaglandins, suggesting anti-inflammatory effects. Of note, the inhibition of cycloxygenase-2 was associated with an increase in the level of endocannabinoids, anandamide and 2-AG. This observation suggests that the suppression of cycloxygenase-2 enzyme by CBD and THC may not only decrease nociceptive and inflammatory prostaglandins but it may produce an indirect increase in the level of endocannabinoids, anandamide and 2-AG .Another important biological system that is affected by cannabinoids, at least when consumed orally, is the gastrointestinal microbiota. The gut microbiota is known to produce various metabolites resulting from the fermentation of molecules of either exogenous source or from endogenous origin. These metabolites can act as signals that can contribute to the maintenance of host immunity and physiology . For example, the gut bacteria Lactobacillus acidophilus, metabolizes tryptophan from dietary sources such as eggs, milk, red meat, and vegetables into diverse metabolites, including indole propionic acid, which can signal through the aryl hydrocarbon receptor.