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Biosynthesis of the AAContaimng Endocannabinoids AEA and 2AG

Endogenous compound shown to mimic various behavioral, physiological, and psychological effects of the Cannabis sativa-derived cannabinoid D9-tetrahydrocannabinol (THC) (Di Marzo, 1998 Mechoulam et al., 1998). The second endocannabinoid discovered was 2-AG and exhibits higher selectivity and efficacy for both cannabinoid CB1 and CB2 receptors than AEA, and is considered to be a full agonist for these receptors, whereas AEA is a partial agonist (Di Marzo and Petrosino, 2007).

CB Receptor Dependent and Independent Effects of Endocannabinoids

Recent research interest has turned to the role of endocannabinoids as retrograde neurotransmitters in synaptic modulations. Among five identified endocannabinoids, AEA, the amide between arachidonic acid (AA) and ethanolamine, was the first endocannabinoid named as an endogenous ligand for cannabinoid (CB) receptors. Unlike classical neurotransmitters, the endo-cannabinoids can travel backward to presynaptic neurons after released from the postsynaptic neurons upon depolarization. The endocannabinoids bind to and activate the presynaptic CB1 receptors (Pacher et al., 2006 Wilson and Nicoll, 2001). Activation of the CB1 receptors in turn inhibits neurotransmitter release by inducing hyperpolarization and or shutting voltage sensitive calcium channels. This retrograde endocannabinoid signaling plays an essential role in synaptic plasticity. On the other hand, accumulating evidence has emerged to show that some pharmacological effects produced by endogenous and exogenous CB receptor...

Cannabinoids Modulate Cell Migration

Research to fully elucidate the exact functions of CB1 and CB2, as well as putative novel cannabinoid receptors, and their endogenous ligands with regard to the regulation of cellular motility is ongoing. It is already becoming increasingly clear that the effects cannabinoids have on cell migration are complex, as both stimulation and inhibition of chemotaxis have been reported (Franklin and Stella, 2003 Franklin et al., 2003 Joseph et al., 2004 Kishimoto et al., 2003, 2005 McHugh et al., 2008 Millar and Stella, 2008 Mo et al., 2004 Sacerdote et al., 2000 Song and Zhong, 2000 Oka et al., 2004 Vaccani et al., 2005 Walter et al., 2003). This bidirectionality is not particularly surprising given that both families of the structurally distinct chemokines and neurotransmitters have members that not only induce migration but exert inhibitory functions as well. With the above backdrop in mind, it is only relatively recently that studies have begun to characterize the role cannabinoids and...

Endocannabinoids

Two subtypes of G protein-coupled receptors for cannabis's psychotropic component, A9-tetrahydrocannabinol (THC), have been cloned to date, the cannabinoid CBi and CB2 receptors (Howlett et al. 2004). Yet, five different types of endogenous agonists for these cannabinoid receptors have been identified so far (Fig. 1). These compounds, named endocannabinoids by analogy with THC (Di Marzo and Fontana 1995), are all derived from long-chain polyunsaturated fatty acids. In particular (1) the anandamides are amides of ethanolamine with polyunsaturated fatty acids with at least 20 carbon atoms and three 1,4-diene double bonds. The C20 4 homologue in this series, N-arachidonoylethanolamine (AEA) (Devane et al. 1992), also known simply as anandamide, has been most studied.

Marijuana

Marijuana is the most commonly used illicit substance in the United States. Also known as pot, grass, weed, hash, or tetrahydrocannabinol (THC), it is a hallucinogenic agent prepared from the dried leaves of Cannabis sativa. Its primary psychoactive constituent is THC. The medical use of cannabis in the treatment of pain and other symptomatology has long been practiced. The first recorded use of medical cannabis dates back to 2700 BC in the United States, medical marijuana was routinely used until 1942. However, because of growing concerns over its addictive potential, the medical and psychosocial side effects of its chronic use, US physicians had been prohibited by the federal government to prescribe these drugs. Other countries such as the Netherlands and Canada still routinely use medical marijuana in the treatment of pain and other disorders such as anorexia (Cohen 2008). Marijuana is most commonly inhaled, i.e., smoked via cigarette, a water pipe, or a blunt (a hollow cigar...

Peptidergic Neurotransmission

Neuropeptides have garnered increasing attention as critical modulators of CNS function. In general, peptide transmitters are released from neurons when they are stimulated at higher frequencies from those required to facilitate release of traditional neurotransmitters, but they can also be colocalized and coreleased together with other neurotransmitters (Cooper et al. 2001 Nestler et al. 2001). Modulation of the firing rate pattern of neurons and subsequent release of neurotransmitters and peptides in a circumscribed fashion are likely important in the basal functioning of the brain as well as response to specific stimuli. For instance, cannabinoids, an example of a neuropeptide neurotransmitter, do not alter the firing rates of hippocampal neurons but instead change the temporal coordination of those neurons, an effect that correlates with memory deficits in individuals (Soltesz and Staley 2006). Virtually every known mammalian bioactive peptide is synthesized first as a precursor...

Nuclear signaling pathways

Astrocytes are intimately involved in regulating energy metabolism in the CNS (Magistretti and Pellerin, 1999) and it has been suggested that the endogenous cannabinoid system plays a role in regulating astrocyte metabolic activity (reviewed by Guzman and Sanchez, 1999). Cannabinoid stimulation has certainly been linked to changes in metabolic activity in astrocytes but the majority of work to date has utilized plant-derived and synthetic cannabinoids which may not be indicative of the actions of the endocannabinoids in m two systems. In various astrocyte-related cell lines activation ofthe MAPK pathway has been described upon stimulation with anandamide and other cannabinoids (Bouaboula et al., 1995 Wartmann et al., 1995). This pathway of activation was investigated in more depth in primary rat astrocytes where it was found that both D9THC and the potent synthetic cannabinoid, HU210, induced p42 44 MAPK induction via Raf-1 to increase glucose metabolism and glycogen synthesis through...

Evidence fOR Additional Receptors

Cannabinoids are generally of a highly lipophilic nature this raises complications in their mechanisms of action as cannabinoid interactions with integral membrane proteins are not limited to their exposed surface. Anandamide may be able to pass through the plasma membrane by passive diffusion or active transport to access both the intracellular and extracellular domains of proteins as well as gaining access to their membrane spanning regions. Many of the effects of anandamide, which cannot be attributed to the cannabinoid receptors or TRPV1, appear to be mediated through direct interactions with a variety of proteins and modulation of their activity. The apparent promiscuity of anandamide may be attributed, at least in part, to its incorporation into and subtle alteration of the lipid bilayer. This would also impact the proteins within the modified region of bilayer, potentially modifying their activity state (Morris and Juranka, 2007 Oz, 2006).

Pharmacological Properties

The unique pharmacological properties of the preparations of Cannabis sativa plant have been recognized for thousands of years. There is evidence that Cannabis was cultivated in China as early as 4,000 B.C. for multiple purposes, including its use as a food and medicinal agent. In India, the use of Cannabis for medicinal purposes began approximately 1,000 BC. Cannabis extracts were used by these cultures to reduce pain, seizures, anxiety, mania and muscle spasms, and to stimulate appetite. The introduction of Cannabis to Western medicine occurred in the mid-19th century through the writings of William B. O'Shaughnessy, an Irish physician, who became aware of indigenous use of Cannabis plant during his service under the British in India. O'Shaughnessy reported the beneficial therapeutic effects of Cannabis for convulsions and muscular spasms caused by rabies and tetanus. Jacques-Joseph Moreau, a French psychiatrist, also discovered Cannabis during his travel in the Far East and studied...

Role of Pharmacotherapy

Controversy Over Cannabis Dependence Controversy regarding the addictive potential of cannabis has propagated since the early 1900s. Advances in the clinical, neurobiological, and behavioral sciences over the last 20 years have provided an empirical base to resolve the major aspects of this enduring controversy. Epidemiologi-cal, laboratory, and clinical studies have demonstrated that cannabis dependence occurs, is relatively common, is clinically significant, causes harm, and is difficult to treat. As with other drugs, the majority of people who have tried cannabis do not develop a problem with addiction. However, in the USA, approximately 4 of those older than 12 years, at some time in their lives, have met criteria for cannabis dependence disorder, as defined in the Diagnostic and Statistical Manual of Mental Disorders ( DSM). This prevalence rate is more than double the lifetime dependence rate for any other illicit drug, reflecting the widespread use of cannabis. Conditional...

A9Tet RahYdRocannabinoL CB1 and CB2 Receptors

The hemp plant, Cannabis sativa, has been exploited by humankind for over 5000 years. According to the archeological record, the first use was apparently for its fibers and later it was found to be a highly nutritious foodstuff. Its medicinal properties were being exploited in Chinese culture about 4000 years ago and it was prescribed for treatment of malarial fever, constipation, and arthritic pains. Much later, Indo-Aryan cultures exploited its psychoactive properties as well as its benefits in fevers and gastrointestinal conditions. Despite this long history, it is less than 50 years since the groundbreaking demonstration by Gaoni and Mechoulam (1964) that A9-tetrahydrocannabinol was the primary active ingredient of cannabis. For some years after this discovery there was a debate as to whether or not the drug acted on specific receptors. One hypothesis was that its primary interaction with cells took the form of a disturbance of the function of the cell membrane arising from its...

Lysophosphatidylinositol

These contradictory findings with cannabinoid ligands may become easier to reconcile following recently published data describing the likely endogenous ligand for GPR55 as being LPI. Oka et al. (2007) described experiments in which activation ofERK1 ERK2 in GPR55-transfected HEK293 cells was used as the assay. GPR55-specific phosphorylation of the kinases occurred in response to LPI, whereas anandamide, 2-arachidonoylglycerol, virodhamine, oleoylethanolamide, and palmitoylethanolamide were ineffective as were the synthetic cannabinoids CP55,940 and WIN55,212-2. Lauckner et al. (2008) also found that LPI was an agonist in the large dorsal root ganglion neurons supporting the concept that the lipid might be an endogenous ligand for GPR55 when the receptor is naturally expressed. In corroboration ofthe suggestion that LPI is the natural ligand, the study of Henstridge et al. (2009) also showed it evoked oscillatory Ca2+ signals in GPR55-HEK293 cells. Furthermore, the identification of...

Receptor dimerization in GPCRs

The correlation between ligand specificity in yeast, where GPR55 is isolated from other mammalian proteins, with that described by Henstridge et al. (2009) in GPR55-HEK293 cells suggests interaction with AM251, LPI, and CP55,940 (Modality 1) is an intrinsic property of GPR55. By inference, interaction with the wider array of cannabinoids (Modality 2) could result from the interaction of GPR55 with a secondary modifying factor. The defining property of this factor would be that it confers on GPR55 affinity for diverse cannabinoid ligands. Given the propensity of GPCRs to heterodimerize we should consider the possibility that cannabi-noid receptors combine with GPR55 to yield the specificity observed by Ryberg et al. (2007). This is attractive because several of the ligands differing between modalities 1 and 2 are ofcourse validated ligands at CB1 receptors, for example, anandamide. Moreover, this hypothesis is testable by combinatorial expression of CB1 with GPR55. Signaling of CB1 in...

Allosteric effects and biased agonism

Alternatively, the apparent agonist effects in GTPgS-binding may be due to allosteric modulation. If, for example, low concentrations of LPI were present in the membrane preparations used by Ryberg et al. (2007) and Johns et al. (2007) cannabinoids such as anandamide might act at as modulators, potentiating effects at an orthosteric LPI-binding site but without having being pure agonists in their own right. This seems unlikely, because CP55,940 would be predicted to behave as an antagonist, but in fact it activates GTPgS binding. Furthermore, 0-1602 and abnormal cannabidiol have not been observed to potentiate GPR55 agonists in the yeast assay (A. J. Brown, unpublished observations). A third property of GPCRs that can underlie differing patterns ofligand specificity is biased agonism. This is not fully satisfactory for GPR55, however, primarily because most examples of biased agonism involve changes in orders of efficacy among panels of ligands when comparing different signaling...

B CB1 receptors and preterm birth Corticosterone and prenatal stress

Cannabinoid CBa receptor blockade with rimonabant (SR141716) administered during late pregnancy in mice resulted in a modest (less than 1 day in mice) but highly significant shortening of pregnancy. Similarly, CB1 receptor knockout mice displayed a shorter gestational period than wildtype mice. Analogous silencing of the CB2 receptor did not affect gestational length (Wang et al., 2008). Interestingly, a slight but significant reduction on gestational length was reported in a population of heavy (> 6 times a week) marijuana smoking women (Fried et al., 1984). The study by Dey and colleagues (Wang et al., 2008) also reported a shift in peak levels of corticosterone (CCS) to an earlier gestational age in CB1 receptor knockout mice (from day 17-18 in wild type to day 15-16 CB1 in knockouts). Strikingly, a similar shift of the maternal CCS peak values was observed in prenatally stressed rats (day 17 compared to day 18 of gestation in controls) (Fride and Weinstock, 1985 Weinstock et...

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There was some association of hallucinogenic effects with catnip in humans, particularly through administration by smoking. This was reported in a 1969 paper, but apparently resulted from confusion with cannabis (Tyler 1994). Any reports of hallucinogenic or sedative effects of catnip in humans, at this point, are purely anecdotal. Hops

Central Nervous System Stimulants

This chapter discusses a broad range of agents that stimulate the central nervous system (CNS). The analeptics classically are a group of agents with a limited range of use because of the general nature of their effects. The methyl-xanthines have potent stimulatory properties, mainly cortical at low doses but with more general effects as the dose is increased. The central sympathomimetic agents amphetamine and close relatives have alerting and antidepressant properties but are medically used more often as anorexi-ants. The antidepressant drugs are used most frequently in depressive disorders and can be broadly grouped into the monoamine oxidase inhibitors (MAOIs), the monoamine reuptake inhibitors, and agents acting on autoreceptors. A small group of miscellaneously acting drugs, which includes several hallucinogens, cocaine, and cannabinoids, concludes the chapter.

Current Concepts and State of Knowledge

Inhalant use is a very prevalent behavior, especially among youth aged 12-25 years. For example, in the US, lifetime prevalence in 18-25 year olds is about 15 and past year use is about 2 of the population (Wu and Ringwalt 2006), placing inhalant use as just below alcohol, tobacco, and cannabis use in this age group and making the use far more prevalent than the use of more widely studied drugs such as cocaine and heroin. Among 12-13 year olds, inhalant use is even more prevalent than cannabis use In addition, among all past year inhalant users, the prevalence of dependence was 8 . The association of early inhalant abuse with increased risk of many substance use disorders has also been described (Neumark et al. 1998), and there is also a very high rate of comorbidity of inhalant use and other psychiatric disorders. For example, Wu and Howard (2007) recently reported a very high rate of psychiatric disorders among inhalant abusers in the general US population. For example, 70 of...

Should Parts of the Past Be Extinguished

Memory becomes a reality, there may be emerging, as yet unconsidered, ethical considerations. However, we should also bear in mind that reports of the use of compounds producing anterograde amnesia like alcohol and cannabis date back thousands of years. Indeed, this seems to be one of the appealing properties of drugs of abuse. When asked in surveys, drug and alcohol users often cite the memory-impairing capacities of drugs as a pleasurable effect. Given it seems accepted that individuals erase memories of the present by using drugs and alcohol, will it in future be acceptable for them to erase memories of the past

Overview of the Endocannabinoid System

Endocannabinoids are endogenous ligands of cannabinoid receptors that mimic several actions of the natural Cannabis sativa component D9-tetrahydrocannabinol (THC) this substance accounts for the majority of the reproductive hazards in marijuana users (Piomelli, 2004). The best characterized endocannabinoids are N-arachidonoylethanolamine (anandamide, AEA) and 2-arachidonoylglycerol (2-AG), which bind to and activate type-1 and type-2 cannabinoid receptors (CB1R and CB2R). The latter proteins belong to the rhodopsin family of G protein-coupled seven-transmembrane spanning receptors (Howlett et al., 2002). CB1R has been found mainly in the central nervous system, but it is also present in ovary, uterine endome-trium, testis, vas deferens, urinary bladder, and other peripheral endocrine and neurological tissues. CB2R has been identified mainly in immune cells, but is expressed also in brainstem (Van Sickle et al., 2005). Signal transduc-tion pathways regulated by CBR-coupled Gi o...

Key Learning Points

Pain is common with multiple sclerosis (40-70 percent any pain type 30 percent central neuropathic pain). Central poststroke pain is most common after lateral medullary and thalamic infarctions and occurs in 2-8 percent of those with strokes in other locations. The literature most strongly supports the following medications for the treatment of at least one central neuropathic pain subtype gabapentin, pregabalin, lamotrigine, amitriptyline, and cannabinoids.

Polyunsaturated Fatty Acids Neurotransmission

Determination of brain fatty acid profile in cerebral cortex of (MPTP) model of monkeys indicates that levodopa increases ARA content, but reduces DHA concentration and total n-3 n-6 fatty acids ratio compared to drug-naive MPTP treated animals 106 . Similarly, PD patients who experienced motor complications to levodopa have higher ARA concentrations in the cortex compared to controls and to levodopa-treated PD patients devoid of motor complications. Collective evidence suggests that levodopa treatment produces changes in brain fatty acid concentrations not only in a non-human primate model of Parkinsonism, but also in PD patients 106 . Polyunsaturated fatty acids are precursors for endogenous cannabinoids that are associated with the control of movement through the modulation of dopaminergic activity in basal ganglia 107 , supporting the view that the intake of polyunsaturated fatty acids influences the risk of PD.

Alterations in Polyunsaturated Fatty Acids

In addition, there is evidence for the involvement of cannabinoids in depression. Cannabinoids block long-term potentiation in the hippocampus, a process that underlies memory formation at the cellular level. Studies on comparison of hippocampal synapses in CB1 knockout mice and wild-type controls indicate that CB1 knockout mice exhibit a half-larger long-term potentiation than the controls indicating capacity for stronger synaptic connections related to memory formation. During two-trial recognition tests, CB1 knockout mice retained memory for at least 48 h, whereas spatial learning in rats can be impaired by agonizing cannabinoid receptors 111 . A significant decrease in 2-AG levels and CBj receptor protein is observed in hippocampus of rats subjected to 3 weeks of chronic unpredictable stress 112 . These rats also display an impairment of reversal learning in Morris water maze test, which can be corrected by treating animals with cannabinoid agonist HU210 supporting the view that...

Pharmacologic management

Table 28.1 lists the grade II evidence (randomized, double-blind, placebo-controlled) for the pharmacologic treatment of central neuropathic pain. Included is a randomized, controlled, blinded, dose-response, but no placebo-controlled study on opioids for central pain.97 A couple of newer studies of cannabinoids for MS-related pain are included giving the level of the study structure and or notable sample size, despite pain measurements being a secondary outcome.98,99 Unfortunately, most of these high quality studies stand alone (either as a positive or negative study) without further confirmatory or doseranging studies. Hence there is no grade I evidence (i.e. strong evidence from a systemic review of multiple grade II studies) for any of the pharmacologic treatments of central neuropathic pain.

Abstain from using interventions that do not have worthwhile efficacy

To these interventions belong propofol for induction,6 metoclopramide,12 and ginger root.27 Cannabinoids have shown some efficacy for the control of chemotherapy-related sickness however, their adverse-effect profile (psychosis, depression, hallucination) precludes widespread clinical use and data from the PONV setting are sparse and do not suggest any usfulness.55

Activation of Endocannabinoid Biosynthesis

For more than a century, paracetamol has been among the most popular medicines, being widely used as analgesic, antipyretic, and nonsteroidal antiinflammatory drug. Its mode of action, however, remained a mystery until 2005, when it was demonstrated that it indirectly causes the activation of cannabinoid receptors (Hogestatt et al., 2005). In the brain and spinal cord, paracetamol, following deacetylation to its primary amine (p-aminophenol), is conjugated with AA to form N-arachidonoylphenolamine, also known as AM404, which is a blocker for the endocannabinoid transporter. Therefore, paracetamol causes CB1 and CB2 receptors activation by preventing endo-cannabinoids reuptake and subsequent metabolization. Interestingly, AM404 is also an inhibitor of COX enzymes in the brain (Bertolini which is likely to further contribute to endocannabinoid built-up, since COX is implicated in the nonhydrolytic, metabolization of endocannabi-noids in the CNS and peripheral tissues. For instance, the...

CrosstaLk Between GCs and COX2 in the Control of Neuroinammation and Neuroprotection

Effects were not mediated by the same prostanoid receptors known to bind the corresponding AA-derived prostanoids. Furthermore, inhibition of COX2 activity reduced spontaneous inhibitory synaptic activity and augmented the depolarization-induced suppression of inhibition (DSI, the CB1-mediated inhibition of presynaptic GABAergic neurons by depolarization-induced release of endocannabinoids from the postsynaptic neurons), indicating that tonic COX2 activity may control endocannabi-noid levels both during basal conditions and after depolarization-induced endocannabinoid biosynthesis. In agreement with this assumption, enhancement of COX2 activity not only stimulated GABAergic synaptic transmission but also abolished DSI (Sang et al., 2006). PGE2-G was also shown to directly stimulate excitatory (glutamatergic) synaptic activity in the hippocampus, as revealed by CB1-independent increase in the frequency of miniature excitatory postsynaptic currents (Sang et al., 2006). Hence, PGE2-G is...

CrosstaLk Between GCs and COX2 in the Control of Synaptic Plasticity and Learning Processes

Conditions in which the cannabinoid CB1 receptor-mediated effect is induced by the release of endogenous cannabinoids. On the other hand, other reports show that exogenous application of endocannabinoids may actually suppress the formation of LTP (Paton et al., 1998 Terranova et al., 1995), leading to the assumption that endocannabinoid-mediated suppression ofLTP in the hippocampus is mediated by a mechanism other than the suppression of inhibition (Paton et al., 1998). The exact mechanisms underlying endocannabinoid-mediated synaptic plasticity in the hippocampus, and its implications for the cognitive process are still far from being completely understood however, there are enough evidences to support their protagonist role in selective memory extinction and or consolidation. Therefore, GC inhibitory effect on COX2 activity, and perhaps its stimulatory effect on endocannabinoids synthesis, may contribute to deficits on reversal learning caused by chronic stress (Bondi et al., 2008...

Miscellaneous treatments

Smaller studies, or other neuropathic pain conditions but for which neither category 1 or 2 evidence exists. Intra-thecal administration of lidocaine and methyl pred-nisolone combined appears to be associated with remarkable benefit in PHN patients.71 II However, the therapy has potentially dangerous short- and long-term side effects and the trial has not yet been replicated.72 Therefore, further high-quality controlled trials of this therapy are required before definite recommendations can be made.50 Based on pathophysiological pain mechanisms and animal studies, N-methyl-D-aspartic acid (NMDA) receptor antagonists are pain-relieving candidates. However, data from three controlled studies did not demonstrate a superior efficacy over placebo in humans.50'73'74' 75,76 The anticonvulsant valproate was effective in one controlled study on 48 PHN patients.77 Anticonvulsants such as lamotrigine, the selective serotonin and nora-drenaline reuptake inhibitors venlafaxine and duloxetine, and...

Electrophysiological Evidence

The next endeavor was to examine if Tat-3L4F interfering peptide could suppress the rewarding effects of abused drugs that lead to addiction. Marijuana is one of many abused drugs that induce gratifying effects by enhancing dopamine levels in the NAc after stimulating VTA dopamine neurons (Zangen et al. 2006). With the in vivo recording of the activity of VTA dopamine neurons again, we observed that when D9-tetrahydrocannabinol (THC), the major psychoactive ingredient of marijuana, was systemically injected alone, dopamine neuronal activity significantly increased as expected (Ji et al. 2006). However, when THC and Tat-3L4F were systemically administered together, the firing rate of VTA dopamine neurons was significantly suppressed, resembling injection by the 5-HT2C agonist R0600175, and reversed by the 5-HT2C antagonist SB 242084 (Ji et al2.C2006). These results imply that Tat-3L4f interfering peptide may be able to block the rewarding effects of marijuana.

Anesthetic and Sedative Agents

The combination of droperidol, a dopa-mine D2 antagonist, with an opioid analgesic induced plasma cortisol elevations. In contrast, a mixture of pro-pofol (acting at GABAA and maybe glycine and endo-cannabinoids) and remifentanyl (mu opiate receptor agonist) did not activate the HPA axis, and even blocked HPA axis responses during surgery. However, still under anesthesia with propofol, synthetic ACTH was still capable of inducing a profound cortisol plasma level elevation. Thiopental, a barbiturate acting on GABA receptors, also decreased plasma levels of cortisol during anesthesia and surgery. Other analgesic drugs such as aspirin did not affect basal or stress-induced HPA axis responses. Cannabinoids. Smoking of marijuana or acute administration of tetrahydrocannabinol (THC) induces release of ACTH and cortisol. However, endocannabinoids limit activation of the HPA axis. This difference in action probably results from context-dependent effects of endo-cannabinoids...

Signal transduction and receptor modulation

Given that arachidonic acid derivatives are putative endogenous ligands of the cannabinoid receptors, it is of note that cannabinoid receptor activation has been reported to couple to an increase in arachidonic acid release (Burstein et al. 1994) and eicosanoid biosynthesis, as well as synthesis of the endocannabinoid anandamide (Hunter and Burstein 1997). Furthermore, it is apparent that activation of cannabinoid receptors by either anandamide or THC in WI-38 fibroblasts leads to stimulation of the ERK MAP kinase signal transduction pathway which, in turn, leads to increased phosphorylation and activation of the arachidonate-specific cytoplasmic phospholipase A2 (Wartmann et al. 1995). ERK MAP kinase activation has also been reported to couple cannabinoid receptor activation to other effectors, including the NHE-1 isoform of the Na+ H+ exchanger (Bouaboula etal. 1999) and glucose metabolism in primary astrocytes (Sanchez et al. 1998). Other studies suggest, however, that cannabinoids...

Physiology and disease relevance

CBi receptors are thought to mediate the psychoactive responses to administration of extracts from the cannabis plant, whereas CB2 receptors mediate the non-psychoactive immune responses . It has been appreciated for decades that application of cannabis extracts and synthetic cannabinoids in vivo elicits a classical 'tetrad' of symptoms in experimental animals catalepsy, hypothermia, antinociception, and hypokinesia. In vivo, these responses depend upon CB1 receptor activation because they are reversed by the CB1 -selective antagonist, SR141716 and are absent in CB1 knockout mice (Ledent etal. 1999 Mascia etal. 1999). Many of the behavioural effects of cannabinoids are consistent with effects on hormone transmitter release observed in vivo (Table 13.5). Anandamide, however, exhibits several properties at variance with other agonists. In particular, hypothermia, antinociception, and catalepsy induced by the endocannabinoid are not reversed by SR141716. Cannabinoid-related processes...

Conceding Discussion

It is clear from the data presented in this chapter that fatty acids and cannabinoids critically regulate the functions of the Cys-loop LGICs through CB1 2 receptor-independent mechanisms. The receptor-independent effects of cannabinoids should be given enough attention since most of the EC50 values of cannabinoid action on the Cys-loop LGICs are either clinically relevant or close to the EC50 values of these ligands to bind to CB receptors. For instance, the EC50 values of AEA to modulate the function of nACh a7, 5-HT3, and Glya1 receptors are within a range of 38-319 nM (Barann et al., 2002 Hejazi et al., 2006 Oz et al., 2003 Yang et al., 2008). This is close to the range of the Kd values of AEA to binding to CB1 receptors (Howlett et al., 2002). Similarly, THC has been found to inhibit and potentiate 5-HT3A and Glya1 receptor-mediated responses by 110 and 73 nM (Barann et al., 2002 Hejazi etal., 2006). These values are even lower than plasma THC concentration (162 nM) detected 1 h...

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Woodcut of cannabis (Cannabis sativa). Reprinted with permission from Schultes RE, Hofman A. (1992). Plants of the Gods Their Sacred, Healing, and Hallucinogenic Powers. Rochester, VT Healing Arts Press. not certain. Galen wrote that cakes made with hemp were intoxicating. Women of Thebes were said to use cannabis to dispel sorrow and bad humor (Bibra 1995). In medieval Europe, herbalists used cannabis for medicinal, but not psychoactive purposes. Cannabis was widely cultivated in Europe, and later in the American colonies (figure 10.2). Hemp fiber was a valuable commodity at the time, used to make rope and canvas. Although it is true that many farmers at the time grew hemp, including George Washington, there is nothing to indicate that they were aware of its psychoactive effects.

Peripheral indications

CB2 receptors are thought to mediate the non-psychoactive, immune responses to administration of extracts from the cannabis plant a suggestion supported by studies on mice carrying a targeted deletion of the cnr2 gene (like cnr1 on chromosome 4, Buckley et al. 2000). Specifically, CB2 receptor stimulation appears to cause immunosuppresssion, although, as yet, there are no reports of additional physiological pathophysiological roles for CB2 receptors. Cannabinoids have anti-tumoral actions. THC induces apoptosis of transformed neural cells in culture and WIN 55212-2 is reported to cause regression of malignant gliomas in rats via an action involving sustained ceramide accumulation and both CB1 and CB2 receptors (Galve-Roperh etal. 2000).

Regulation Of Faok Flux In Brain And Cultured Astrocytes

From the foregoing discussion, it appears that the presence and activation of PPARa HMGCS2 in brain indicates the capacity of brain to conduct ketogenesis. This has been corroborated by studies examining FAOK in whole-brain and astrocyte cultures. Thus, in vivo, brain homogenates derived from ciprofibrate-treated rats exhibit potently increased capacities to oxidize radiolabeled fatty acids (28). Moreover, regarding the calorie-restriction aspect of the KD, brain preparations derived from suckling rat pups fed a normal diet that is 50 calorie restricted compared with controls exhibit a threefold increase in fatty acid oxidation (29). In vitro, several studies have shown that primary cultures of neonatal cortical astrocytes are capable of tightly regulated ketoge-nesis from the long-chain fatty acid palmitate. Thus, Auestad et al. (30) were the first to demonstrate that cultured astrocytes convert palmitate to the ketone bodies acetoacetate and 3-hydroxybutyrate. Furthermore,...

Endocannabinoid Effects on BasaL Locomotion of Neutrophils

In 2004, Joseph et al. and Oka et al. reported, respectively, that the endogenous cannabinoids, AEA (40 nM) and 2-AG (10 nM 10 mM), have no stimulatory effect on the basal locomotion of human neutrophils. Kurihara et al. (2006) similarly found that 2-AG (300 nM) had no effect. McHugh et al. (2008) confirmed these findings for AEA and 2-AG over a concentration range of 0.01 nM 1 mM and also demonstrated that PEA does not stimulate migration above basal levels of spontaneous activity. In contrast, McHugh et al. found that virodhamine (O-arachidonoylethanola-mine, that is, arachidonic acid linked to ethanolamine via an ester bond) acted as a weak chemoattractant at 100 nM, inducing a small but significant stimulation of human neutrophil migration.

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In response to THC has also been related to an increase of slow-wave activity on EEG (Domino 1981). In vitro THC (1-100 nM) inhibited muscarinic receptor binding, which also ocurred with two nonpsychoactive cannabinoids (cannabidiol and cannabinol) (Ali et al. 1991). However, these effects were not observed in vivo. Monoamines Cannabinoid agonists produce dose-related activation of meso-prefrontal dopaminergic transmission, which depends upon the CB1 receptor (Diana et al. 1998a). Conversely, withdrawal from chronic cannabinoid administration produces a reduction in mesolimbic dopaminergic transmission. Although THC stimulates the presynaptic activity of mesolimbic dopaminergic neurons, there is a decrease in postsynaptic sensitivity (Bonnin et al. 1993). Further, this effect is modulated by estrogen, but not estradiol. THC increases the firing rate and burst-pattern firing in the ventral tegmental area and substantia nigra, although the ventral tegmental area is more sensitive in...

Inhibitory Signal Transduction Mechanisms Receptor Crosstalk

The apparent bidirectional co-operativity exhibited between these two receptors is a difference in underlying signal transduction depending on cell type. CB2 and or the novel non-CB1, SR141716A-sensitive target may also cross-modulate with fMLP receptors in a similar manner to inhibit induced neutrophil migration. Consistent with this, Rahaman et al. (2006) reported that the IL-8 receptor, CXCR1 formed constitutive heterodimers with S1P4 receptors in human neutrophils. Exogenously applied S1P (sphingosine-1-phosphate) was found to reduce IL-8 induced neutrophil chemotaxis together with transcription of the IL-8 receptor a complete understanding of the molecular basis of this inhibition has not yet been fully elucidated. Such reports in the literature of established chemotactic receptors undergoing heterologous desensitization or dimerization, support ''receptor crosstalk'' as another potential mechanism through which the cannabinoids may be acting.

CB1 Activity in MaLe Reproduction Mammauan And Nonmammauan Animal Models

The importance of the endocannabinoid system (ECBS) and its involvement in several physiological processes is still increasing. Since the isolation of the main active compound of Cannabis sativa, A9-THC, several lines of research have evidenced the basic roles of this signaling system mainly considering its high conservation during evolution.

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Cannabis accessible to patients under certain circumstances (Voth and Schwartz 1997). Antiemetic THC was first used to control nausea and vomiting during chemotherapy in the 1970s (Vincent et al. 1983). Until the development of 5-HT3 antagonists, dronabinol and cannabis were frequently used by cancer patients receiving chemotherapy (Taylor 1998). THC and synthetic cannabinoids have been effective in controlled clinical trials. THC is superior to placebo and as effective or superior to prochlorperazine. Although there are more drug-related effects associated with THC than prochlorperazine, they did not reduce the patients' preference for the drug (Ungerleider et al. 1982). The antiemetic effectiveness of THC correlates with the subjective high reported (Vincent et al. 1983). THC is effective in several chemotherapy regimens, including methotrexate and the combination. Cisplatin treatment, however, is more resistant. Side effects of THC are generally well tolerated, and use may be...

Receptor Properties

Studies carried out on CB1_ , CB2_ , and CB1 CB2 double knockout (KO) mice reveal the existence of no CB1 CB2 mediated response to cannabinoids. In this respect, besides CB1 and CB2, the orphan G-coupled receptor GPR55 is currently accounted as the third CB (Lauckner et al.,

Hivassociated Sensory Neuropathy

Although the condition responds to most usual drug therapies, a unique approach was trialed in a group of 50 patients with HIV-SN. The average daily pain score for the patients was at least three on the Numeric Rating Scale. Patients who had previously indicated that they had use cannabis at least six times in their lives were assigned to smoke cannabis cigarettes. The first cannabis cigarette reduced daily pain scores by a median of 72 versus 15 for the placebo group. Overall, the study participants who smoked cannabis reduced daily pain by 34 (Abrams et al., 2007). Although this study had the patients actually smoke a cannabis cigarette, there are drugs currently in the development stage that have the active ingredients of cannabis but do not produce euphoria. Because neuropathic pain is so difficult to treat, researchers are continually looking for options that are worth developing for treating this type of pain. Although this cannabis study proves the effect of the drug, using a...

Managing Pain in the Addicted Patient

Approximately 20 million Americans have some form of substance abuse disorder, and about one-third of the US population has used illicit drugs (Substance Abuse and Mental Health Services Administration office of Applied Studies 2007). Substance abuse is known to occur in 10-16 of outpatients in general medical practice, 25-40 of hospital admissions, and 40-60 of major trauma patients (Manchikanti et al. 2003, Rosenblatt and Mekhail 2005). In chronic pain management settings, illicit drug use has been reported in 14-34 of patients (Manchikanti et al. 2006). Among the illicit drugs, use of marijuana is reported most common, followed by that of cocaine, hallucinogens, and methamphetamines. Such high prevalence of illicit use, along with concerns of drug abuse and addiction, and its association with life-threatening pathophysiological effects, often has a negative influence on pain treatment. Pain patients who have current or remote histories of drug abuse present a multitude of medical...

Substance Dependent and Substance Abusing Patients

Detoxification is required for the patient who is alcohol dependent. In some cases, the substances abused might have appeal as a means of controlling one's psychological distress (e.g., cannabis and benzodiazepine abuse to address underlying anxiety or ineffective coping). Hence, psychological interventions, along with prudent psychopharmacologic interventions for underlying psychiatric disorders, might also be required to effect optimal pain control.

How to Probe the Sites of Action of Drug Molecules

This chapter will briefly review this multifaceted approach for studying drug-active site interactions by focusing on the cannabinoids, a research area with which we have considerable familiarity. Examples will be used to illustrate each of these methods and to demonstrate how the results from the different experiments can be integrated in order to provide a more unified picture of the mechanism of action of these drug molecules. Cannabinoids produce a complex pattern of pharmacological actions, some of which are believed to be related to their effects on cellular membranes,1-3 whereas others are thought to be produced through an interaction with one or more cannabinoid receptors.4-7 Existing evidence indicates that the membrane effects involve canna-binoid interactions with noncatalytic amphipathic sites, resulting in perturbation of the membrane and a modification of the functions of membrane-associated proteins. There is also an evidence that the cannabinoid-membrane interactions...

Cannabinoid topography in the membrane

Our experiments with (-)-A9-THC, (-)-A8-THC, and their inactive O-methyl analog provided us with data that complemented the 2H-NMR results. Such experiments required the synthesis of these cannabinoids as well as analogues having a halogen (I) substituent in the 5'-position of the cannabinoid side chain (Figure 21.5). A biophysical method that can be used in an analogous manner with the x-ray method described earlier is neutron diffraction. In this method, the high electron density halogen marker used in the x-ray experiment is now replaced with deuterium atoms. The two membrane preparations in this method contain, respectively, unlabeled and specifically 2H-labeled cannabinoids. The location of the 2H-label is then revealed by the difference between the data from the two preparations. One advantage of this method is that the two membrane samples being compared are almost identical. This avoids the potential pitfall encountered in the x-ray experiment where the samples being compared...

Social Interaction Test Definition

Two animals, typically rats or mice, are placed into an arena and their interactions, for example, investigation, following, and grooming, are recorded for a period of time, usually 5 to 10 min. Social behaviors such as following, adjacent lying, and anogenital sniffing are recorded by an observer or via automated image analysis. Many drugs modulate behavior on the social interaction test benzodiazepines, MDMA, and oxytocin tend to increase social interaction while amphetamines, cannabinoids, NMDA antagonists, and withdrawal from various

Central pain in multiple sclerosis

In a recent randomized placebo-controlled study concerning the effect of cannabinoids on CP in MS 46 , seven of the included patients had PTS and the authors stated that treatment response for this subgroup was as good as treatment response for patients with dysesthetic limb pain (see next section). ami, amitriptyline carb, carbamazepine CBM, cannabis-based medicine CI, confidence interval CP, central pain D, double-blinded The efficacy of cannabinoids in the treatment of central pain in MS has recently been evaluated in two RCT. Svendsen et al. 49 conducted a randomized cross-over trial including 24 MS patients with CP. Three weeks' treatment with orally administered synthetic S-9-tet-rahydrocannabinol (THC) (dronabinol) in a maximal dose of 10 mg reduced the intensity of ongoing and paroxysmal pain. In a randomized placebo-controlled parallel trial by Rog et al. 46 a whole-plant cannabis-based oromucusal spray (CBM) was administered to MS In the same line a large randomized...

Psychoactive substances and the law

Some of the medical and legal issues in the United States have been considered by Bloodworth.3 There are three international conventions under which most countries (within their own legislative framework) agree to restrict nonmedical use of and trade in certain classes of drugs, including opioids, cannabis, cocaine, hallucinogens, and various hypnotics and sedatives.4 Individual countries may prohibit other substances, such as alcohol.

Epidemiology of substance misuse

Dependence on psychoactive substances is a common global problem. The British Crime Survey 2005 6 showed that a third of 15-59-year-olds have used illegal drugs at some stage with the figure rising to 45.1 percent in the 16-24 age group with cannabis being the most frequently used drug, cocaine powder or crack cocaine being used by 2.4 percent of individuals, and heroin or methadone being used by 0.1 percent of this age group.5 Other surveys of developed countries paint a similar picture. Data from Canada, the USA, and European countries suggest that more than 2 percent of young people report heroin use and almost 5 percent reported smoking cocaine at some stage. More than 20 percent of those surveyed in the USA report using at least one illicit drug other than cannabis.6 More recent data give a substance dependence or abuse prevalence in the US population over the age of 12 years of 9.4 percent, with the vast majority of these not receiving treatment for addiction.7 The United...

An Agent Possessing Both An Indolethylamine And A Phenylethylamine Moiety

Tetrahydrocannabinoid is a depressant with apparent stimulant sensations arising from depression of higher centers. Many effects, reputedly subjectively construed as pleasant, are evident at low doses. The interested reader may consult a pharmacology text for a detailed account. At higher doses, psychotomimetic actions, including dysphoria, hallucinations, and paranoia, can be marked. Structural features associated with activity among cannabis-derived compounds have been reviewed.42 Notably, the phenolic OH is required for activity. Certain SARs (especially separation of potency between enantiomers) for cannabinoids suggested action at receptors.43 Two receptors for THC have been discovered. The relevant receptor for CNS actions is CB1.44 CB2 occurs in immune tissues. The first natural ligand found for the receptor is the amide derivative of arachidonic acid, anandamide.45 Other natural cannabinoids are arachidonic acid 2-glycerol ester and 2-arachidonyl glycerol ether.46 The...

Nucleus Accumbens Receptors

Nucleus Accumbens Receptors

From an evolutionary perspective, reinforcement of natural stimulation that enhances survival or the perpetuation of genes (such as food and sex) would be beneficial to the continuation of the species. The system of conditioning through reward and gratification remains one of the most fundamental examples of such reinforcement. However, there is a small fraction of pharmacological substances that possess the ability to abnormally intensify this reward function in the brain, known as drugs of abuse, which include the psychostimulants (cocaine and amphetamine), the opiates (heroin and opioids), nicotine, ethanol, and marijuana (i.e., cannabis or cannabi-noids) (Hyman et al. 2006). These abused drugs act on specific receptors in the brain to mediate their actions, each resulting in distinct behavioral and physiological responses. While reasons for individual self-administration may differ, a major motivational factor may be to experience the euphoric sensations resulting from stimulation...

Therapeutic Potential of 5HT2C Receptor Drugs for Reward Related Behavioral Problems

Because 5-HT2C receptors modulate reward-related behaviors, a logical question about the therapeutic potential of drugs like lorcaserin is whether this can be extended to the treatment of drug abuse. Several neurochemical systems, including DA, endogenous opioids, and cannabinoids, that are involved in drug abuse and dependence are also involved in the control of different aspects of feeding behavior (Kirkham 2009 Barbano and Cador 2007 Barbano et al. 2009). Similarly, the neuropeptides leptin and orexin that are involved in mediating aspects of feeding behavior also modulate reward-related behaviors (Borgland et al. 2006 Fulton et al. 2000). Thus, there is convergence and overlap of brain mechanisms and systems involved in reward-related behaviors relevant to obesity and substance abuse (Trinko et al. 2007 Volkow and Wise 2005). It is feasible then that a serotonergic drug that is effective in treating obesity may have potential in treating addiction.

O General Pathways Of Drug Metabolism

To illustrate, consider the principal psychoactive constituent of marijuana, A9-tetrahydrocannabinol (A9-THC, also known as A1-THC, depending on the numbering system being used). This lipophilic molecule (octanol water partition coefficient 6,000)9 undergoes allylic hydroxylation to give 11-hydroxy-A9-THC in humans.10,11 More polar than its parent compound, the 11-hydroxy metabolite is further oxidized to the corresponding carboxylic acid derivative A9-THC-11-oic acid, which is ionized (pKa COOH 5) at physiological pH. Subsequent conjugation of this metabolite (either at the COOH or phenolic OH) with glucuronic acid leads to water-soluble products that are readily eliminated in the urine.12

Coordination of GCMediated Control of the Neuroimmune Response and Energy Homeostasis Control

Both GCs (Tempel et al., 1993) and the cannabis-derived cannabinoid THC (Verty et al., 2005) cause increased appetite and weight gain when injected directly into the PVN. In fact, the PVN is the only hypothalamic center in which local GC application leads to hyperphagia (Tempel et al., 1993). The fact that endocannabinoids mediate the inhibitory effects of GCs in the PVN, along with several indirect evidences, indicates that the orexigenic effect of GCs are mediated, at least in part, by endocannabinoids via cannabinoid CB1 receptor activation in the PVN, which also contributes to explain the orexigenic effect of marijuana (Di et al., 2003

Interactions of sorbent and Analyte in sPE and selective Extractions Based on sorbent Chemistry

By a recent report demonstrating the retention of a hydrophobic molecule like THC carboxylic acid (a metabolite of THC, the major constituent of marijuana see Figure 1.1) on a strong cation exchanger like strata-X-C even when subjected to a 30 to 40 acetonitrile wash without breakthrough.97

Cannabinoid Receptor Expression in Neutrophils

Receptors, that is, AEA acts as a CB1 partial agonist (Mackie et al., 1993 Sugiura et al., 2000), virodhamine as a CB1 antagonist (Porter et al., 2002) 2-AG, which is a full agonist at CB1 receptors (Pertwee and Ross, 2002), in the hands of McHugh et al., had no effect on neutrophil migration, while Kurihara et al. report an inhibitory effect for 2-AG that remains unaffected by the presence of 1 mM AM251 and although the inhibition of fMLP-induced migration observed by McHugh et al. was significantly attenuated by SR141716A, the apparent KB value was inconsistent with a CB1-mediated effect (MacLennan et al., 1998). Taken together, these results are indicative of a role for a non-CB1, SR141716A-sensitive receptor mediating the effect of these cannabinoids. account for the array of ligands exerting modulatory activity on spontaneous or induced neutrophil migration observed by Kurihara ei a . and McHugh ei a . The exception being the non-CBj, non-CB2 pharamcological target named the...

Aea Cb1 Cb2 Angiogenesis Invasion Migration

In order for a migrating cancer cell to then invade another organ, the existing extracellular matrix components (e.g., collagens and proteoglycans) must be broken down and hence the rigid architecture of the target organ must be compromised. Matrix metalloproteinases (MMPs) are emerging as a family of enzymes that exerts important functions during tumor invasion (Curran and Murray, 2000 Stamenkovic, 2000). Tissue inhibitors of MMPs (TIMPs), and in particular TIMP-1, have also been shown to inhibit the proteolytic activity of MMPs and suppress vascular tumor growth and angiogenesis in xenograft animal models (Zacchigna ei a ., 2004). Furthermore, there appears to be a correlation between high cancer invasiveness and decreased TIMP-1 expression (Chan ei a ., 2005 Khokha ei a ., 1989). Recently, the effects of AEA on MMP and TIMP expression were evaluated in various cancer cell types. Using a cervical cancer cell line, Met-AEA as well as D9-THC, inhibited the invasive properties of these...

Half Life of Detection and Cut Offs in Urine Drug Screening

The cut-offs presented in the next table are those used for immunoassays in federally mandated urine drug testing programs 59 . The detection time of a drug in urine indicates how long after administration a person excretes the drug and or its metabolite(s) at a concentration above a specific test cut-off concentration 69, 71 . Although it is governed by several factors, including dose, route of administration, metabolism, urine volume, and pH, the detection time of most drugs in urine is less than 5 days, typically 1-3 days 21, 69, 70 . Long-term use of lipid-soluble drugs, such as marijuana, diazepam, or phencyclidine, may extend the window of detection to as long as a month 59, 21, 69 . At the cut-off value of 1000ng mL, urine samples can be positive for amphetamine for up to 5 days after intake 69 . On average, after smoking one marijuana cigarette, tetrahydrocannabinol (THC) may be detectable for 2-4 days in urine more frequent users can be positive for a month 69 . Street doses...

Mechanism of Action of Opioids and Clinical Effects

The opium poppy probably reached China about the seventh century A.D. through the efforts of Arab traders who advocated its use for medicinal purposes. In Chinese literature, however, there are earlier references to its use. The noted Chinese surgeon Hua To of the Three Kingdoms (220-264 A.D.) used opium preparations and Cannabis indica for his patients to swallow before undergoing major surgery.

C CB1 Receptormediated regulation of ion channels 1 Calcium channels

In addition to neuronal cells, anandamide may also produce responses in glial cells in the brain. In a glial cell model application of anandamide or elevation of endogenous levels by inhibiting FAAH activity reduced intracellular Ca2+ and S100B protein levels as well as limiting cell proliferation through the CB1 receptor (Iuvone et al., 2007). In this model anandamide was also shown to act as a pro-survival factor to cocultured neuronal cells. Confirmation of glial responses to anandamide was published by Navarrete and Araque (2008) who showed CB1 receptor stimulation with cannabinoids caused increased intracellular Ca2+ levels in primary cultured rodent astrocytes. This was probably mediated through coupling to Gq 11 G proteins in hippocampal mouse slices as the effect was PLC dependent. However, coupling of the CB1 receptor to Gq 11 G proteins may be a cell and agonist specific phenomenon and requires further investigation. In HEK 293 cells transfected with the rat CB1 receptor...

Pharmacology of GPR55

The two patents clearly showed that GPR55 binds to, and is activated by, a variety of cannabinoid ligands but aspects of its pharmacology are not consistent with it being the receptor which mediates all, if any, of the functional effects ascribed to actions of anandamide and other cannabinoids at receptors other than the classical CB1 and CB2 types. in HEK293 cells stably expressing recombinant GPR55 several of their observations are not consistent with those of Lauckner et al. (2008). They observed characteristic oscillatory increases in cytoplasmic Ca2+ concentration evoked by receptor activation (primarily using lysophosphatidylinositol (LPI) as the agonist see below). Crucially, of the cannabinoid ligands described, neither 2-arachidonoylglycerol nor, and more importantly, anandamide (30 mM) activated Ca2+ oscillations in GPR55-expressing cells, whereas AM251 behaved as a weak agonist with an EC50 of 612 nM. CP55940 (3 mM) had no agonist activity but acted as an antagonist,...

Histo RicaL View of Lipid Signaung Discoveries

The use of natural products for a variety of ailments in folklore medicine attracted scientists to explore their mechanisms of bioactivity (Caterina et al., 1997 Mechoulam and Gaoni, 1965 Naef et al., 2003 Urca et al., 1977). The finding that plant-derived active ingredients such as the opium-derived morphine and cannabis-derived D9-hydrotetracannabinol (D9-THC cannabinoids) that had a wide range of biological activity promoted the identification ofnovel endogenous cannabinoid-like signaling molecules and pathways in the mammalian nervous system that would likewise drive these actions. The discovery of these signaling molecules has opened new avenues into research that continue to expand our knowledge of basic biochemical functioning.

Hypothalamic PituitaryAdrenal Axis Dysfunction in Schizophrenia

Dynamic challenges of the HPA axis have also provided conflicting results probably for the same reasons quoted above. That aside, the dexamethasone suppression test (dexamethasone normally inhibits the secretion of ACTH and cortisol) is abnormal in nearly 50 of subjects with schizophrenia 12 though this is not a very sensitive test as such findings have also been shown in post-traumatic stress disorder 13 and Alzheimer's disease 14 . Delta-9-tetrahydro-cannbinol, an active cannabis ingredient, when given to subjects with schizophrenia results in high cortisol levels and can cause a heightening of positive, negative and cognitive symptoms 15 . ACTH increases are greater in patients than matched controls when metabolic stress is induced centrally by 2-deoxy-D-glucose (2-DG) 5 while some investigators have shown that CRH-stimulated ACTH and cortisol are normal however, pretreatment with dexamethasone leads to increased cortisol secretion in patients with established schizophrenia 16 .

Conclusion evidencebased treatment of central pain

Cannabinoids were shown to be effective in reducing MS-related central pain and were well tolerated in low-dose regimens 46, 49 . However, possible long-term effects including psychiatric symptoms have not been ruled out and cannabi-noids are therefore not recommended as first-line treatment in CP. The same is true of opioids and tramadol, in which long-term side effects and drug addiction are concerns. Small studies in CP have failed to document an effect of opioids in stroke patients 16 and MS patients 48 . However, opi-oids as well as tramadol are effective in reducing peripheral neuropathic pain and may also be considered in refractory CP.

Modulation of Neurotransmission

P Q-type Ca2+ channels, Na+ channels and inwardly rectifying K+ channels, and ligand-gated ion channels such as 5-HT3, and nicotinic ACh receptors 62 . Furthermore, functional modulations of ion-transporting membrane proteins such as transient potential receptor-class channels, gap junctions, and neurotransmitter transporters by endocannabinoids have also been demonstrated. Although the molecular mechanisms associated with these effects are unclear, but it is likely that these direct actions of endocannabinoids may be due to their lipophilic structures. It is proposed that additional molecular targets for endocannabinoids may also exist and that these targets represent important sites for cannabinoids to alter either the excitability of the neurons or the response of the neuronal systems 62 . Anandamide mediated signal is deactivated through a two step process, whereby the lipid mediator is transported into cells by a presently uncharacterized entity, and then degraded by the...

Regulation Of Aqueous Humor Formation

The aqueous humor secretion is subjected to modulation by a number of different cascades including catecholamines, antinatriuretic peptide, endothelin, purines, muscarinic receptors, cannabinoids, tumor necrosis factor-alpha, glucocorticoids, prostanoids, cAMP, cyclic guanosine 3',5'-monophosphate (cGMP), nitric oxide, Ca2+, pH, PKC, PKA, tyrosine kinase, and MAP kinase (137, 138, 143, 169-179). Among these potential cascades, the mechanisms of three common regulatory pathways involving cAMP, A3 adenosine receptor, and nitric oxide on aqueous inflow will be discussed below.

Drug Addiction And Drug Abuse Drug Dependence

Reinforcing properties of drugs are associated with their capacity to increase neuronal activity in critical brain areas (see Chapter 12). Cocaine, amphetamine, ethanol, opioids, cannabinoids, and nicotine all reliably increase extracellular fluid dopamine (DA) levels in the ventral striatum, specifically the nucleus accumbens region.

Endocannabinoid System

The endocannabinoid system is an endogenous signaling system composed of endocannabinoids, their receptors, and the proteins involved in their synthesis and degradation (Pazos et al. 2005). Anandamide and 2-arachidonoylglycerol, the two principal endocannabinoids in the brain, bind to and activate the G protein-coupled cannabinoid receptors, CB1 and CB2. The CB1 receptor, the predominant endocannabinoid receptor in the brain, mediates most of the behavioral effects of endogenous and exogenous cannabinoids (Zimmer et al. 1999). The CB2 receptor is principally expressed in non-neural tissues, such as immune system organs (e.g., spleen). CB1 receptors are located primarily on presynaptic axon terminals and mediate the retrograde signaling of endocannabinoids in synaptic plasticity processes, such as depolarization-induced suppression of inhibition (Alger 2002). In the neocortex, the CB1 receptor is highly expressed in the subpopulation of GABA-containing inhibitory interneurons...

Cannabinoid system

The endogenous cannabinoid system has received much interest within the field of neuropathic pain due to the fact that unlike the opioid system, spinally expressed cannabinoid receptors are unaffected following nerve injury.143 In such, manipulation of the cannabinoid system has been effective in alleviating signs of neuropathic pain in animal models of neuropathic pain5,22 144145 representing a possible therapeutic advantage of cannabinoids over opioids in neuropathic pain.

Opiate History

Opiates have been used for pain control for several thousands of years, dating back to the times of the ancient Sumerians. The Sumerians documented poppy in their pharmacopoeia and called it HU GIL, the plant of joy (Benedetti 1987). In the third century BC, Theophrastus has the first documented reference to poppy juice (Macht 1915). The word opium is derived from the Greek name for juice obtained from the poppy, Papaver, and the Latin name for sleep inducing, somniferum. Arab traders brought opium to the Orient, where it was used to treat the symptoms of dysentery. Opium contains approximately 20 distinct naturally occurring alkaloids, called opiates, such as morphine or codeine. In 1805, a German pharmacist Sertuner isolated a pure substance in opium and called it morphine. Morphine is named after Morpheus, the Greek god of dreams. After this initial discovery, many more opium alkaloids were discovered. Robiquet isolated codeine in 1832, and Merck isolated papaverine in 1848. In...

Introduction

It has been long established that compounds produced by the Cannabis sativa plant cause a range of psychological effects. The isolation of delta-9-tetrahydrocannabinol (D9THC) as the main psychoactive constituent (Gaoni and Mechoulam, 1964) led to many studies investigating its in vivo effects. However, it was not until 1990, when the first cannabinoid receptor was cloned (Matsuda et al., 1990), followed by the cloning of cannabinoid receptor 2 in 1993 (Munro et al., 1993) that research into the function of cannabinoids escalated. Anandamide was the first endogenous cannabinoid to be isolated and described (Devane et al., 1992) but a period of almost 10 years remained until evidence emerged of its physiological relevance. In 2001 the endo-cannabinoids were identified as the signal messengers responsible for the phenomenon of retrograde signaling, providing a physiological rationale for their presence in the central nervous system (CNS) (Ohno-Shosaku et al., 2001 Wilson and Nicoll,...

Other GPCRs

Anandamide binds to GPR55 and activates coupling to GTPgS with an EC50 of 18 nM (Drmota et al., 2004 Ryberg et al., 2007). Coupling of this GPCR to G13 as well as G12 and Gq subtypes of G proteins has been indicated (Baker et al., 2006 Brown and Wise, 2001 Lauckner et al., 2008 Ryberg et al., 2007). At micromolar concentrations, anandamide stimulation of GPR55 increases intracellular Ca2+ in transiently transfected HEK 293 cells (Lauckner et al., 2008). The same response, when elicited by alternative cannabinoids, was dependant on Gq, G12, PLC and RhoA activation and subsequent release of Ca2+ from internal stores by IP3 (Lauckner et al., 2008) and similarly, in GPR55 stably transfected HEK 293 cells, anandamide stimulation resulted in activation of cdc42, rac1, and RhoA (Ryberg et al., 2007).

Patent reports

A group from AstraZeneca (Drmota et al., 2004) reported the use of 3H CP55940 and 3H rimonabant as radiolabels for detecting ligands for GPR55 expressed in HEK293 cells. The cell membranes did not bind another cannabinoid ligand, 3H WIN55,212-2, and therefore showed some similarity with the functional studies which suggest that WIN55,212-2 is usually not active at the rimonabant-sensitive cardiovascular sites for cannabinoids which mediate non-CB1 non-CB2 activity (White and Hiley, 1998). Surprisingly, rimonabant, which shows antagonist or inverse agonist activity in functional assays of CB1 receptors or against the non-CB1 cannabinoid effects in the cardiovascular system, was an agonist in GTPgS-binding assays using membranes containing GPR55. Other agonists in this assay included other ligands at CB1 and CB2 receptors, not only

Ga12 and GM3

Ryberg et al. (2007) reported that the responses evoked by the cannabinoids in GPR55-expressing cells were insensitive to PTX. Therefore, to identify properly the G proteins involved, they performed a series ofexperiments in which C-terminal fragments of, or antibodies against, Ga proteins were used to assess their effects on the GTPgS binding induced by 0-1602 this showed that coupling was through Ga13 and not by means of Gai1 2 or Gas. This confirmed results reported both in the yeast assay (Brown and Wise, 2001) and in GPR55-HEK293 cells, where expression of a dominant-inhibitory mutant of Ga13 blocked the LPI-evoked oscillatory Ca2+ signals (Henstridge et al., 2009).

Nfat

Cell relaxation by increasing intracellular cyclic GMP, or of Ca2+-activated K+ channels, which bring about hyperpolarization of the smooth muscle cells and hence decrease developed tension (Lagaud et al., 1999). Therefore, if the ''endothelial anandamide receptor'' were GPR55, then increases in endothelial Ca2+ could result in blood vessel relaxation, but it should be noted that vasodilatation induced by cannabinoids shows varying degrees of dependence on the endothelium and it is by no means clear that endothelial mechanisms are dominant in cannabinoid-induced vasorelaxation (see, e.g.,

Adjuvants

Trauma victims may develop central or peripheral neuropathic pain, especially following traumatic amputations (> 50 after major limb amputation), spinal cord injury (> 50 ), vertebral fractures (> 25 ), and crush or burn injuries. Neuropathic pain is initiated or caused by a primary lesion or dysfunction in the nervous system and is often described as shooting, burning, or electrical like. Not infrequently, hyperalgesia, allodynia, or signs of autonomic dysfunction, such as sudomotor and vasomotor changes, are present. The identification of neuropathic pain as the primary cause or a contributor to trauma-related pain is essential in the formulation of an analgesic plan. First-line agents for neuropathic pain include tricyclic antidepressants (and serotonin-norepinephrine reuptake inhibitors in the elderly) and gabapentinoid membrane stabilizers. Second, third, and fourth line agents include NMDA receptor antagonists (e.g., ketamine and dextromethorphan), which may act...

Conclusions

A role for the endogenous cannabinoid system in several aspects of human (patho)physiology has been proposed through the activation of cannabinoid and vanilloid receptors, and or via nonreceptor-mediated actions. In the case of AEA, the role of FAAH in controlling its cellular activity seems more critical than that of NAT, NAPE-PLD, or EMT. Here, the activity of FSH, the biological relevance of Sertoli cells, and the main features of the ECS have been briefly described, to put in a better perspective the relevance of FAAH regulation by FSH for male reproduction. In particular, it is suggested that FAAH controls hormone level of AEA, by acting as a molecular integrator of fertility signals. In this context, since low FAAH levels in peripheral lymphocytes (Maccarrone ei a ., 2000), and hence high levels of AEA in blood of pregnant women (Habayeb ei a ., 2008), correlate with pregnancy failure, it can be suggested that FAAH is a critical sensor of reproductive abnormalities also on the...

Neurodegeneration

Exogenous and endogenous cannabinoids reduce hypoxic neuronal damage in cell culture and are neuroprotective in animal models of global and focal ischemia. These effects appear to be mediated via CB1 receptors and an induction of CB1 protein has been reported in an experimental stroke model (Jin et al. 2000). There is a major loss of cannabinoid receptor binding in post mortem brains from Huntington's patients. In particular, there is drop out of binding in the substantia nigra (Glass et al. 1993) and globus pallidus (Richfield and Herkenham 1994).

Feeding and satiety

Plant cannabinoids are well known, anecdotally, to increase food consumption in recreational users and preparations of THC are used therapeutically to increase appetite, for example, in AIDS patients (Mechoulam etal. 1998). In addition, anandamide, acting through the CB1 receptor, has been shown to increase feeding in laboratory animals (Hao etal. 2000). Food-deprived knockout mice have been reported to eat less than wild-type littermates and the nutritional regulator leptin reduces the levels of the endocannabinoids anandamide and

Abstract

Neutrophils are the earliest inflammatory cell to infiltrate tissue, playing an important role in early phagocytosis. Under pathological conditions, pro-inflammatory actions of neutrophils contribute to the development of various inflammatory diseases. Gi protein-coupled cell-surface receptors are an essential component of pro-migratory responses in leukocytes however, few investigations regarding inhibitors of cell migration have been reported. Kurihara etal. (2006) and McHugh etal. (2008) have revealed that certain endogenous cannabinoids and lipids are potent inhibitors ofinduced human neutrophil migration. McHugh et al. implicate a novel SR141716A-sensitive pharmacological target distinct from cannabinoid CB1 and CB2 receptors, which is antagonized by N-arachidonoyl-L-serine and that the CB2 receptor exerts negative tissue, neutrophils respond with chemotaxis, the process whereby cells sense soluble molecules and follow them along a concentration gradient to their source. Despite...

Conc Lusion

It is clear from the volume of empirical evidence contained in the literature that cell-surface receptors are an essential component of the majority of pro-migratory responses (Arai et al., 1997 Hwang et al., 2004 Neptune and Bourne, 1997 Wenzel-Seifert et al., 1998 Yokomizo et al., 2000). To date, few investigations regarding inhibitors of cell migration have been reported (Armstrong, 1995 De la Fuente et al., 1998 Garrido et al., 1996 Harvath et al., 1991 Mitsui et al., 1997 Okamoto et al., 2000) they include a m-opioid agonist, prostaglandin E, S1P and adenylyl cyclase-activating peptide, all of which act mainly on leukocytes, via cell-surface receptors. Together, the work of Kurihara et al. and McHugh et al. has revealed that certain endogenous cannabinoids and lipids are potent inhibitors ofinduced human neutro-phil migration. McHugh et al. implicate a novel SR141716A-sensitive pharmacological target distinct from cannabinoid CB1 and CB2 receptors, which is antagonized by the...

Chapter Sixteen

In the last few years several pieces of evidence have emerged suggesting that endocannabinoids may modulate innate as well as conditioned fear. The term endocannabinoid refers to a group of neurotransmitters that are the endogenous counterparts of A9-tetrahydrocannabinol (A9-THC), the compound that accounts for most of the effects induced by the herb Cannabis sativa (Howlett et al., 2002). In the central nervous system A particular feature of CB1 receptor is its location in presynaptic rather than in postsynaptic neurons (Egertova ei a ., 1998). This is in line with the proposal that endocannabinoids may be produced in postsynaptic neurons and act as retrograde neurotransmitters (Wilson and Nicoll, 2001). The functions of CB1 receptors have been investigated by selective pharmacological agents, such as the agonist arachidonoyl chloroethilamide and the antagonists inverse agonists rimonabant and AM251. By binding to CB1 receptors, cannabinoids can activate G-proteins (subtype Gi) that...

Chapter Eighteen

Targeting Degradation Enzymes of Cannabinoids as an Marijuana and its derivatives have been used in medicine for centuries, however, it was not until the isolation of the psychoactive component of Cannabis sativa -tetrahydrocannabinol A9-THC) and the subsequent discovery ofthe endogenous cannabinoid signaling system that research into the therapeutic value of this system reemerged. Ongoing research is determining that regulation of the endocannabinoid system may be effective in the treatment of pain (Calignano ei a ., 1998 Manzanares ei a ., 1999), glaucoma (Voth and Schwartz, 1997), and neurodegenerative disorders such as Parkinson's disease (Piomelli ei a ., 2000) and multiple sclerosis (Baker ei a ., 2000). In addition, cannabinoids might be effective antitumoral agents because of their ability to inhibit the growth of various types of cancer cell lines in culture (De Petrocellis ei a ., 1998 Ruiz ei a ., 1999 Sanchez ei a ., 1998, 2001) and in laboratory animals (Galve-Roperh...

M5 Receptors

The human M5 receptor gene (CHRM5) is located on chromosome 15q26 and consists of a single coding exon and three alternatively spliced 5'-UTRs (Anney et al. 2007). The NCBI database contains > 200 SNPs of this gene. We have identified only a single study linking a polymorphism of the M5 gene to phenotype (Anney et al. 2007). In that study, a non-coding C > T SNP (rs7162140) was reported to have a prevalence of 19 and to be associated with the number of cigarettes smoked and cannabis dependence but not with nicotine or alcohol dependence in a sample of 815 Australians of European descent.

Dronabinol

Dronabinol is a synthetic form of D9-tetrahydrocannabi-nol, the main psychoactive substance in marijuana cannabis. It is a cannabinoid agonist acting on cannabi-noid CB1 and CB2 receptors. The cannabinoid CB1 are mostly located in the brain and involved in addictive properties of marijuana the CB2 receptors are located in the periphery notably in the immune system, but may be also located in the brain. Dronabinol has been used in AIDS-related anorexia associated with weight loss and in nausea and vomiting associated with cancer chemotherapy. It has the potential to be abused and is a controlled substance.

Didier M Lambert

Cannabis, Cannabinoids, and Endocannabinoid The aim of this chapter is to briefly review the molecular pharmacology of cannabinoids and to present thereafter our main research interests (1) the synthesis and the pharmacological characterization of new cannabinoid-receptor antagonists and (2) the synthesis and biological evaluation of N-palmiloylethanolamine derivatives as new endocannabinoids interfering with the metabolism of anandamide. CANNABIS, CANNABINOIDS, AND ENDOCANNABINOID SIGNALING Among the plants known by humans since ancient times, the hemp Cannabis sativa has been widely used both for therapeutic, ritual, and recreational purposes. According to Chinese legend, the emperor Sheng Nung discovered the medicinal properties of three plants ephedra, ginseng, and cannabis. The Chinese pharmacopoeia already described, in 200 B.C., the beneficial effects of cannabis for human health as well as the psychotropic properties of abuse. However, the isolation of the psychoactive...

Prescription Drugs

The concern for prescription drug abuse has recently overshadowed that of illicit drug abuse, as the non-medical use of scheduled medications prescribed for pain, pain-related symptoms, and psychiatric disorders began rising in the mid-1990s. Non-medical use of prescription drugs was previously estimated in about 0.7 million individuals, 0.5 million of which used prescription pain relievers such as codeine, meperidine, morphine, fentanyl, hydro-morphone, hydrocodone, methadone, and oxycodone (Joranson et al. 2000). In 2003, the lifetime prevalence rates for non-medical use of opioids increased to about 3 million (Smith and Woody 2005). While opioid drug mentions decreased by 25 from 1990 to 1996, year 2000 and 2003 updates showed a significant increase in oxycodone mentions (Joranson et al. 2000, Office of Applied Studies, Substance Abuse and Mental Health Services Administration 2003). The prevalence of opioid abuse is now similar to that of cocaine and only second to that of...

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