Make a ppt with intresting slide back ground and add photos and diagrams to explain properly according to the given information Physiological Roles of Endocannabinoids Mediators of Endocannabinoid Action The lipophilic nature of THC delayed the identification of its mech- anism of action for many years. The first convincing evidence that its actions were mediated by a G protein-coupled receptor (GPCR) came from the pioneering work of Allyn Howlett and colleagues (Howlett et al., 1990; Howlett and Abood, 2017). These studies showed that THC and related synthetic cannabinoids inhibited adenylyl cyclase via a per- tussis toxin–sensitive GPCR and that this receptor was highly expressed in many brain regions, consistent with the psychotropic effects of THC. Subsequent autoradiographic mapping using high-affinity synthetic cannabinoids confirmed the widespread and high levels of this cann- abinoid receptor across the brain (Herkenham et al., 1991). This receptor (now designated as the CB1 cannabinoid receptor) was cloned and its distribution, actions, and regulation characterized (Howlett et al., 2002). Within a few years, a second cannabinoid receptor, the CB2 receptor, was cloned from an immune cell line. The psychoactivity after consumption of cannabis is likely mediated by CB1 cannabinoid receptors, whereas the immune modulatory effects are likely CB2 cannabinoid receptor medi- ated (Mackie, 2008). CB1 Cannabinoid Receptors CB1 receptors are highly expressed in presynaptic terminals of a sub- set of cortical GABAergic interneurons (often coexpressing the neuro- modulator, CCK) and at lower levels in many other nerve terminals (Hu and Mackie, 2015). The role of these presynaptic as well as somatic CB1 receptors in mediating synaptic plasticity and neuronal excitability is discussed below. CB1 receptor expression changes with age, potentially explaining effects of cannabinoids on the developing CNS (Bara et al., 2021). CB1 receptors are also expressed in nonneuronal cell types such as astrocytes and outside the brain in hepatocytes, adipocytes, skeletal mus- cle, and endocrine cells (Covelo et al., 2021; Fong and Heymsfield, 2009). CB2 Cannabinoid Receptors CB2 receptors are highly expressed in immune cells (including micro- glia) and are expressed at lower levels in other cell types such as neu- rons, endothelial cells, pericytes, and keratinocytes. CB2 receptors may mediate immunomodulatory effects of THC and could be important for reducing drug craving and pain. CB1 and CB2 Receptor Signaling CB1 and CB2 are GPCRs and usually couple to inhibitory G proteins and arrestins, although coupling to Gs to activate adenylyl cyclase or Gq/11 to activate PLC has been observed in some experimental conditions. As Gi-coupled receptors, the canonical CB1 and CB2 signaling pathways include inhibition of adenylyl cyclase and voltage-gated Ca2+ channels and activation of mitogen-activated protein kinases (MAP kinases) and inwardly rectifying K+ channels (Howlett et al., 2002; Mackie, 2008). Both CB1 and CB2 receptors show functional selectivity or biased agonism, whereby certain ligands favor activating specific subsets of G proteins and/or arrestin signaling pathways. This functional selectivity needs to be considered when evaluating the behavioral and physiological conse- quences of structurally diverse cannabinoids acting at cannabinoid recep- tors, particularly CB2 receptors (Atwood et al., 2012). Non-CB1/CB2 Targets of Endocannabinoids Endocannabinoids and some synthetic ligands can engage other targets in addition to CB1 and CB2, including ion channels (discussed below), peroxisome proliferator-activated receptors (PPARs), and synthetic cannabinoid receptor ligands. Among PPARs, PPARα and PPARγ are activated by eCBs and may contribute to the pharmacological effects of cannabinoids (Pistis and O’Sullivan, 2017). Genes targeted by PPARs include those involved in the regulation of metabolism, inflammation, neuroprotection, and cellular differentiation. eCBs as Retrograde Messengers. Endocannabinoids are major retro- grade messengers in the nervous system and mediate several forms of synaptic plasticity (Chevaleyre et al., 2006; Ohno-Shosaku and Kano, 2014). As retrograde messengers, eCBs are synthesized “on demand” by the postsynaptic neuron and travel retrogradely across the synapse to activate presynaptic CB1 receptors, suppressing neurotransmission from CB1-expressing nerve terminals (Figure 26–3). Depending on the duration of eCB production, eCB-mediated synaptic plasticity may be transient or sustained (Figure 26–4). Both forms of plasticity involve stimulation of the postsynaptic neuron (by depolarization and Ca2+ influx via voltage-sensitive Ca2+ channels and/or activation of a Gq/11- linked GPCR and release of Ca2+ from intracellular stores). This activates diacylglycerol lipase α to produce 2-AG (Figures 26–2 and 26–3). Two well-described transient forms of eCB-mediated synaptic plasticity are depolarization-stimulated suppression of excitation (if excitatory transmis- sion is suppressed) or depolarization-stimulated suppression of inhibition (if inhibitory transmission is suppressed) and metabotropic-stimulated suppression of excitation (if excitatory transmission is suppressed) or metabotropic-stimulated suppression of inhibition (if inhibitory trans- mission is suppressed). These transient forms of plasticity start within a second of stimulation of the postsynaptic neurons and can last for tens of seconds (Wilson et al., 2001). Sustained low-frequency activity of excitatory synapses may lead to a persistent eCB-mediated long-term depression (LTD) (Chevaleyre et al., 2006). Induction of LTD depends on sustained eCB production. However, established LTD is maintained independent of eCBs or CB1 receptors. The network implications of eCB-mediated synaptic plasticity depend on the activity of the CB1-expressing synapse: If the synapse is not active, there will be little effect; it also depends on whether the inhibited syn- apse is excitatory or inhibitory in nature and the relationship between the inputs driving eCB synthesis and the presynaptic terminals expressing CB1 receptors (Soltesz et al., 2015). Nonretrograde Effects of eCBs on Neuronal Excitability. In addition to their role as retrograde messengers, eCBs may modify neuronal excit- ability in diverse ways. The best characterized include: • Direct modulation of ion channels • Activation of G protein-coupled inwardly rectifying K+ channels (GIRKs) • Enhancement of a hyperpolarization-activated cation channel (Ih) Endocannabinoids may directly modulate ion channels, including 5HT3, TRPV1, GABAA, glycine, and others (Soderstrom et al., 2017). When relating in vitro reports to what occurs in vivo, it is important to appreciate that some of these reported effects only occur with high eCB concentrations that are unlikely to be reached in vivo. Levels of eCBs produced by intense neuronal activity activate somatic CB1 receptors to open GIRK channels to hyperpolarize the neuron (Bacci et al., 2004). Ih is a cation channel regulating dendritic excitability and playing a cen- tral role in synaptic plasticity and learning. Enhancing Ih activity impairs learning, and Ih activation by CB1 receptors is a possible mechanism for THC impairment of learning. CB1 enhancement of Ih involves a signaling cascade consisting of c-Jun-N-terminal kinase 1 (JNK1), guanylyl cyclase, cyclic GMP, and hyperpolarization-activated cyclic nucleotide-gated (HCN) channels (Maroso et al., 2016). Physiological Roles of Endocannabinoids Reward Intoxication with cannabis does produce a state of mild euphoria, and Stress and Its Resolution cannabis possesses addiction potential, albeit less than what is seen with Regular users of cannabis cite its ability to reduce stress and anxiety as a drugs such as opiates. Rodents will self-administer cannabis vapor and primary motivation for its use. Similarly, eCB signaling can reduce stress will exert effort to seek cannabis vapor, both hallmark traits of substances and anxiety. Research in both humans and rodents has found that expo- that are reinforcing (Ferland and Hurd, 2020; Freels et al., 2020). The abil- sure to stress results in the mobilization of eCBs, both in the brain and ity of cannabinoids to enhance reward is mediated by their actions in the the periphery, and that glucocorticoids are an integral mediator in this ventral tegmental area (VTA; see Figure 26–5), a small brain nucleus with response. This release of eCBs following stress is important for the ter- a high density of dopaminergic neurons. CB1 receptors in the VTA are mination of the stress response. As such, increasing eCB function can primarily localized to the axon terminals of inhibitory GABA neurons restrict or limit responses to stress. Within the brain, eCBs gate stress- that impinge upon VTA dopaminergic neurons. Activation of CB1 in the induced excitation in brain regions such as the amygdala (Figure 26–5), VTA inhibits GABA release, which disinhibits dopaminergic neurons, which restricts the development of anxiety and the release of stress hor- promoting the release of dopamine within the nucleus accumbens, a pro- mones (Gray et al., 2015; Morena et al., 2016). CB1 receptors are also cess known to be central for the encoding of rewarding salient events and localized to sympathetic nerve terminals in the periphery, and activation for the motivation to engage in rewarding actions (Dubreucq et al., 2013; of these receptors by eCBs following stress exposure is important for Wenzel and Cheer, 2018). Reinforcing stimuli, including both cocaine restricting the autonomic response to stress. Exposure to chronic stress and voluntary exercise, require eCB signaling in the VTA to produce impairs eCB function. A loss of the ability of eCB signaling to restrict their rewarding effects. Disruption of eCB signaling inhibits motivation stress responses likely contributes to the development of stress-induced for rewarding stimuli and reduces engagement in pleasurable activities. allostatic load (Morena et al., 2016). Human studies have found that the In humans, the elevated AEA signaling associated with the P129T variant P129T genetic variant in FAAH, which reduces FAAH and elevates AEA of FAAH increases neural reactivity of the nucleus accumbens to reward- signaling, is associated with lower levels of trait anxiety, enhanced top- ing cues (Hariri et al., 2009). Pharmacological antagonism of CB1 recep- down emotional control, improved inhibition of fear, and blunted neu- tors has been linked to the development of depression with anhedonia, an ral and physiological responses to stress (Hariri et al., 2009; Petrie et al., https://ebooksmedicine.net/ inability to experience pleasure (Christensen et al., 2007 Appetite and Metabolism been noted in rodent models of obesity and in human obese populations. Elevated eCB activity can promote the development of obesity and met- An increase in the consumption of sweet, palatable food, often referred to abolic disorders; conversely, blockade of CB1 receptors produces anorec- as “the munchies,” is one of the prototypical effects of cannabis consump- tic effects, weight loss, and the prevention of metabolic consequences of tion in humans. eCB signaling is prominent within feeding circuits in the obesity, such as insulin resistance and the development of type 2 diabetes brain (see Figure 26–5). Within the hypothalamus, eCB levels fluctuate in in multiple species including humans (Lau et al., 2017; Ruiz de Azua response to nutritional status, where fasting elevates eCB levels and subse- and Lutz, 2019). Curiously, however, cannabis use in humans is generally quent feeding and satiety decrease these levels (Lau et al., 2017). eCB sig- not associated with obesity. Several large-scale population studies report naling regulates feeding through regulation of the excitability of neurons that cannabis users have a lower body mass index and lower rates of within the arcuate nucleus of the hypothalamus, which are known to drive obesity than noncannabis users. Because THC is a partial agonist at CB1 food intake (the AgRP/NPY neurons) and inhibit food intake (the POMC/ receptors, THC may occlude CB1 activation by 2-AG, a full agonist and MCH4 neurons). Thus, eCB signaling can rapidly increase or suppress thus limit some of the negative metabolic effects driven by elevated eCB food-seeking behavior and consumption. eCB signaling is also embedded function (Le Foll et al., 2013; Sidney, 2016). into canonical hormonal cascades involved in regulating feeding. Leptin, a potent anorectic peptide produced by adipose tissue, rapidly suppresses Pain hypothalamic eCB signaling to inhibit feeding. Hunger-stimulating hor- Management of chronic pain and chemotherapy-induced nausea are the mones, such as ghrelin or glucocorticoids, promote food intake via recruit- most common and most scientifically established therapeutic uses of ment of eCB signaling (Balsevich et al., 2018; Lau et al., 2017). cannabis in humans (Committee on the Health Effects of Marijuana, 2017; Peripheral eCB signaling also influences food intake and metabolic see also Chapter 54). CB1 receptors are distributed throughout multiple processes (Maccarrone et al., 2015; Ruiz de Azua and Lutz, 2019). Stimu- levels of pain circuits, including cortical, midbrain, spinal, and periph- lation of cannabinoid receptors on vagal afferents and sympathetic nerve eral sites of action. CB1 receptors are synthesized within many dorsal terminals can enhance food intake. Excess eCB activity in peripheral root ganglion neurons and transported to peripheral afferent fibre nerve organs can have adverse effects on metabolic processes. Activation of terminals. Peripheral eCB signaling can suppress pain initiation directly hepatic CB1 receptors promotes the development of fatty liver and hepatic through activation of these receptors (Piomelli et al., 2014). eCBs also can steatosis. Adipose tissue CB1 receptor activation can augment adipo- act on CB1 receptors, and in some situations at TRPV1 receptors, within genesis and fat accumulation. Elevated levels of endocannabinoids have spinal networks to influence pain processing (Woodhams et al., 2017). Cannabinoids can produce analgesia through activation of CB1 receptors within the periaqueductal gray (PAG; see Figure 26–5) and rostral ventro- medial medulla of the descending pain circuit. eCBs act in higher-order brain circuits, primarily the cortical-amygdalar pathway, to influence pain processing, likely by influencing the affective component of pain. Exposure to noxious stimuli can enhance release of eCBs both in the periphery and within this distributed supraspinal pain circuit to act as endogenous regula- tors of pain initiation and sensitivity (Piomelli et al., 2014; Woodhams et al., 2017). Acute stress exposure produces transient analgesia via local release of eCBs within the PAG (Hohmann et al., 2005). A Scottish woman was dis- covered to possess both the P129T FAAH mutation as well as an upstream deletion in an FAAH pseudogene, which collectively resulted in robust ele- vations in AEA. These mutations were associated with a phenotype of pain insensitivity and accelerated healing (Habib et al., 2019). Inflammation CB2 receptors are primarily localized to immune cells and tissue, both in the periphery and in the brain. Most immune cells express CB2 recep- tors at varying levels, including T cells, monocytes, natural killer cells, and neutrophils, as well as microglia within the CNS. Activation of CB2 receptors on immune cells acts to reduce inflammation, primarily via the suppression of the release of proinflammatory cytokines, as well as by inhibiting cell proliferation and migration. Within the brain, CB2 recep- tors on microglia are rapidly induced by inflammation or damage and act to suppress the release of inflammatory cytokines and promote the release of anti-inflammatory cytokines. Within the periphery, CB2 recep- tors on T cells gate migration into tissues, such as the CNS, by reducing expression of adhesion factors. Deficits in T-cell CB2 receptors are asso- ciated with their enhanced infiltration into the CNS in pathological con- ditions such as multiple sclerosis (Malfitano et al., 2014). CB2-mediated activation of MAP kinases is integral to its ability to promote the release of anti-inflammatory cytokines and engage in reparative functions (Eljaschewitsch et al., 2006). CB1 receptors are also localized on some immune cells, but CB2 receptors appear to be the primary mechanism for most of the anti-inflammatory actions of eCBs. eCB molecules can also regulate inflammation in the brain indepen- dently of cannabinoid receptors. 2-AG in the brain is predominately seques- tered to cell membrane domains where it acts as a reservoir for arachidonic acid. In response to inflammatory stimuli, MAGL activity rapidly increases, metabolizing this membrane-associated 2-AG and liberating arachidonic acid, which is then converted to inflammatory prostaglandins via COX-2 (Nomura et al., 2011). MAGL localized within astrocytes (but not neurons) in the brain mediates the generation of neuroinflammatory molecules from 2-AG catabolism (Viader et al., 2015). Sleep The self-reported prosomnogenic effects of cannabis are often cited as a primary reason for continued consumption among recreational and medical cannabis users (Kesner and Lovinger, 2020). Cannabis can reduce the latency to onset of sleep and nighttime awakenings as well as promote non–rapid eye movement (NREM) sleep, while reducing the percentage of time spent in rapid eye movement (REM) sleep. eCB levels fluctuate in the brain and in the circulation in a circadian man- ner, and this diurnal cycle is disrupted following sleep. Elevating 2-AG signaling via MAGL inhibition similarly increases time spent sleeping and enhances NREM sleep while suppressing REM sleep (Kesner and Lovinger, 2020). Administration of a CB1 receptor antagonist promotes wakefulness and arousal and reduces NREM sleep. In humans, there have been multiple reports of sleep disruption following administration of the CB1 receptor antagonist rimonabant. eCB signaling may contrib- ute to normative sleep-wake cycles. Pls make simple slide and within 4 to 5 slide all this topics should be covered.
endocannabinoid system diagram CB1 CB2 receptors retrograde signaling image
endocannabinoid system brain reward pain appetite diagram image free use
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{ text: "eCB-mediated LTD (maintained independent of eCBs)", options: { color: "CCCCCC" } }
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slide.addText([
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{ text: "• Ih (HCN channel) enhancement\n → impairs learning (THC mechanism)\n", options: { color: "E0E0E0" } },
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// Retrograde signaling image
if (images[0] && !images[0].error) {
slide.addImage({ data: images[0].base64, x: 5.3, y: 4.05, w: 4.3, h: 1.4 });
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}
// ─────────────────────────────────────────────
// SLIDE 4 – REWARD, STRESS, APPETITE & PAIN
// ─────────────────────────────────────────────
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color: "C0392B",
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items: [
"VTA dopaminergic disinhibition via CB1 on GABA terminals",
"CB1 activation → inhibits GABA → dopamine release in nucleus accumbens",
"Required for reinforcing effects of cocaine & exercise",
"P129T FAAH variant → elevated AEA → heightened reward reactivity"
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x: 5.1, y: 0.7,
items: [
"Stress mobilizes eCBs in brain & periphery (glucocorticoid mediated)",
"eCBs gate amygdala excitation → reduce anxiety & stress hormones",
"CB1 on sympathetic terminals limits autonomic stress response",
"P129T FAAH variant → lower trait anxiety, improved fear inhibition"
]
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{
title: "🍽️ Appetite & Metabolism",
color: "27AE60",
bg: "101E12",
x: 0.2, y: 3.1,
items: [
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"eCBs regulate AgRP/NPY (appetite-ON) & POMC/MCH4 (appetite-OFF) neurons",
"Leptin suppresses eCB signaling; ghrelin & glucocorticoids promote it",
"Peripheral: hepatic CB1 → fatty liver; adipose CB1 → fat accumulation"
]
},
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title: "💊 Pain",
color: "F39C12",
bg: "1E1600",
x: 5.1, y: 3.1,
items: [
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"Spinal CB1/TRPV1 modulates pain processing",
"PAG & RVM CB1 activation produces descending analgesia",
"Cortical-amygdalar pathway modulates affective pain component"
]
}
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// ─────────────────────────────────────────────
// SLIDE 5 – INFLAMMATION, SLEEP + KEY TAKEAWAYS
// ─────────────────────────────────────────────
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slide.addText([
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{ text: "• CB2 on microglia: induced by inflammation → anti-inflammatory cytokines\n", options: { color: "D0D0D0" } },
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const takeaways = [
["Retrograde Control", "eCBs synthesized on-demand suppress presynaptic neurotransmitter release via CB1"],
["CB1 Distribution", "Presynaptic GABAergic terminals (brain), hepatocytes, adipocytes, muscle, endocrine cells"],
["CB2 in Immunity", "Primary immunomodulatory receptor — reduces cytokines, migration, and inflammation"],
["Broad Roles", "Reward, stress, appetite, pain, inflammation, sleep — all modulated by eCB signaling"],
["Therapeutic Target", "CB1 blockade → anorexia, weight loss; CB2 agonism → anti-inflammatory; FAAH inhibition → anxiolysis"]
];
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// ECS infographic image
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// skip - just use the diagram space
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// Save
pres.writeFile({ fileName: "/home/daytona/workspace/endocannabinoid-ppt/Endocannabinoids_Physiological_Roles.pptx" })
.then(() => console.log("DONE: Presentation saved successfully."))
.catch(err => console.error("ERROR saving:", err));
cd /home/daytona/workspace/endocannabinoid-ppt && node create_ppt.js 2>&1
ls -lh /home/daytona/workspace/endocannabinoid-ppt/Endocannabinoids_Physiologica…
Endocannabinoids Physiological Roles
Presentation · PPTX
| Slide | Title | Highlights |
|---|---|---|
| 1 | Title Slide | Dark navy background, green accents, molecular decoration, ECS brain diagram image |
| 2 | CB1 & CB2 Receptors + Signaling | Side-by-side receptor cards (teal / green), 4 signaling pathway boxes (cAMP, Ca²⁺, MAPK, GIRK), CB1/CB2 image |
| 3 | eCBs as Retrograde Messengers | 4-step numbered flow (synthesis → retrograde travel → CB1 → suppression), non-retrograde effects panel, retrograde signaling diagram image |
| 4 | Reward, Stress, Appetite & Pain | 4-quadrant layout - each physiological role in its own color-coded card with bullet points |
| 5 | Inflammation, Sleep & Key Takeaways | Left: inflammation (teal) + sleep (purple) boxes; Right: 5 key takeaway summary cards in gold |