Posted on Authorea 11 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159986420.00633539 — This a preprint and has not been peer reviewed. Data may be preliminary. iodr.Tu,i hsrve,w ics h oeo anbni eetratvto niflmainand inflammation in activation receptor system cannabinoid Endocannabinoid of 2.0 role the immune discuss and we ligands inflammatory review, of of development immunobiology. management this the the in in in Thus, activity aid receptor will disorders. cannabinoid associated, al., modulate pathways et selectively signaling can Zhao homeostatic various that of 2015; the modulation al., and receptor-mediated functions et cannabinoid (Wen defensive in sclerosis and involved multiple mechanisms the and Understanding injury CB 2009; 2010). reperfusion al., the ischemic et neo- of atherosclerosis, (Ligresti neuroinflammation, Activation in as pain outcomes such 2014). and processes depression al., the pathological anxiety, of et in colitis, physiology role McPartland ulcerative normal a diseases, plays the cardiovascular also in diseases, involved It plastic processes function. critical immune in as such roles body, al., crucial plays et Turcotte system 2019; endocannabinoid The al., et and synthesis (Zeng the system 1995). for endocannabinoid al., the responsible 2016). et constitute enzymes with (Galiegue endocannabinoids, together of endocannabinoids CB receptors, metabolism and 1993). their cannabinoids al., and et by endocannabinoids (Munro Collectively, activation the of brain following the discovery in immunomodulation in the distributed expression in of by ubiquitously level receptors confirmed some with cannabinoid is of This CB CB subfamily the the as receptor. a known this for system, nervous ligands for central which high-affinity ligand arachidonoylethanolamide, as a and endogenous 2-arachidonoyl-glycerol function over suggested one mediators, al., cannabinoids lipid for by et least activated synthesized Turcotte selectively medicine endogenously at 2016; is two (McCoy, that traditional of body, effects human in psychotropic presence within its receptor sativa the a by of Cannabis promoted discovery The use of widespread 2016). use its with the years, shown thousand have studies disease Ethnopharmacological in pathways peripheral trials. and clinical Introduction central and 1.0 its preclinical several understood, both in fully exploiting promise not in great is the potential shown in system already great target endocannabinoid has drug a the therapy a towards of Cannabinoid as its in heavily role management. potential receptors leans exact and its cannabinoid the found as body of Though well evidence role the as conditions. the critical responses of the inflammatory pathway, inflammatory physiology some cannabinoid other of scientific normal endogenous and of amelioration the neurodegeneration the subjects on of been in focus mediation have and authors role pain signaling the and Its depression review neoplasm, this diseases, system. In interest cardiovascular generated as interest. endocannabinoid has such ligands the states endogenous pathological understanding their in and implication finally CB2 to and CB1 regards receptors with cannabinoid endogenous of discovery eventual The Abstract 2020 11, September 1 Osafo Newman Inflammation and Receptor Cannabinoid wm kua nvriyo cec n Technology and Science of University Nkrumah Kwame 2 a ic encoe,caatrsdaddsoee ob rmrl itiue nimn cells immune in distributed primarily be to discovered and characterised cloned, been since has , 1 dr Yeboah Oduro , 1 ao Antwi Aaron , 1 eetr Trot ta. 06.Ascn anbni receptor, cannabinoid second A 2016). al., et (Turcotte receptors 2 eetrhsbe eotdt eascae ihpositive with associated be to reported been has receptor 1 1 n ereAinooson George and , 2 eetri hsblee ob involved be to believed thus is receptor 1 Posted on Authorea 11 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159986420.00633539 — This a preprint and has not been peer reviewed. Data may be preliminary. n at cdaiehdoae(AH,rsetvl Brti n uir 09 lnmnadCravatt, and Blankman 2009; (MAGL) Zurier, and lipase inactivated and 2-AG monoacylglycerol are (Burstein system, enzymes molecules respectively nervous (FAAH), hydrolase the endogenous hydrolase serine in these amide the instance, acid space, For by the fatty synaptic primarily regulate and environment. the inactivated and intracellular Manolios, diffuse, from are the and endocannabinoids within anandamide uptake (Barrie these enzymes messengers cellular retrograde release, specific after as by Upon locally Soon acting 2011). by manner Kim, messengers 2017). activity-dependent presynaptic and an multiple endocannabinoids in Alger of where sites biogenesis, 2010; release storage demand” al., and/or “on Rather, as precursors et to 2012). phospholipid transported (Min referred Freund, membrane process be and from a (Katona to in liberated hydrophobicity mobilized not are their be believed to to thought due are are synthesis they endocannabinoids following storage neurotransmitters, for other vesicles into and hormones 1. most figure Unlike in diacylglycerol summarized sn-1-selective are by endocannabinoids hydrolysed di- for then of pathways is production Diacylglycerol subsequent with 2005). lipases- position al., sn-2 et the (Hashimotodani 2013. at Cravatt, acylglycerol and species Blankman (PIP2) PLC by 4,5-bisphosphate phosphoinositol extensively reviewed 2-AG, phosphatidylinositol also of and synthesis et suggested the (Okamoto been During enzyme have 2006; of Cravatt, D others, and phospholipase among O-deacylation (Simon phosphatidylethanolamine-selective 2004), GDE1 N-acyl al., sequential glycerophosphodiesterase by the as liberation by direct bond such phosphodiester 2008), a the anandamide of of cleavage of phosphatidylethanolamine)-lipase 1994). and position (N-acyl 4 of production al., lyso sn-1 et the formation the Marzo by the by for the arachidonoylphosphatidylethanolamine (Di dissimilar hydrolysed from pathways in anandamide then largely biosynthetic AA yield is resulting arachi- Other are to of NAPE phosphatidylethanolamine, D pathways of transfer 2016). phospholipase amine Wiley, biosynthetic breakdown the -acylphosphatidylethanolamine-hydrolyzing and primary their the catalyses (Sharke the (NAPE) membrane, from N-acyltransferase arachidonoylphosphatidylethanolamine to cell synthesized phospholipid 2019). the molecules donor al., from lipid et liberated both and (Argenziano (AA) analogs are in synthetic acid presented 2-AG of are donic structures and chemical endocannabinoids anandamide elucidated the common presents fully Although most also be 1 of to figure yet structures however, purposes, chemical illustration is, phytocannabinoids. The For functions biological 1. 2019). other exact Figure of al., dopamine their number a N-arachidonoyl on et ligands, and Knowledge these (Argenziano ether to identified. addition 2-AG In been virodhamine, 2019). have canine including al., from endocannabinoids, et isolated Argenziano similar initially capacity 2000; biochemically 2-AG, al., the hand, et to pleasure (Sugiura other alludes receptors the and these This On motivation CB pleasure. signaling. increase to and binds endocannabinoid to motivation intestines, basal ability increase maintaining to its anandamide for to of responsible due is was named and AEA) so receptors ethanolamine, investigated and (arachidonoyl Anandamide most brain, from endogenous 1995). two porcine (derived al., these from the et Of isolated Mechoulam represent 2012). 1992; initially (2-AG) Freund, al., and 2-arachidonoylglycerol et Katona (Devane and 2017; ligands anandamide signals Manolios, specific and molecules, to (Barrie signaling response signals in inflammatory lipids as membrane such from synthesized inactivation N-acylethanolamines and are Of synthesis Endocannabinoids their processes. ligands, neuromodulatory cannabinoid inflammatory This Endogenous as 2.1 2018). well al., as et homeostasis, CB Bie to system CB 2019; compared receptors, immune al., cannabinoid maintaining et two in the (Argenziano important hydrolase) is amide 2- system acid as fatty such and cannabinoids (CB lipase C- endogenous receptors (phospholipase of cognate synthesis consists their their that system anandamide, neuromodulator and arachidonoylglycerol a is system Endocannabinoid α n - and β Α ¯ (DAGL ad,aSnki odfrbis Mneen ta. 05.I id obt CB both to binds It 2015). al., et (Monteleone bliss) for word Sanskrit a nanda, 1 eetr Agnin ta. 2019). al., et (Argenziano receptors 1 α n CB and n - and β eutn ntepouto f2A Ldn ta. 99.Tebiosynthetic The 1999). al., et (Ledent 2-AG of production the in resulting ) 2 ihgetrant hnaadmd ic tfntosa ulaoitfor agonist full a as functions it since anandamide than affinity greater with β 2 (PLC oagetretn,i novdi h euaino mueresponse immune of regulation the in involved is extent, greater a to , β n ,-icllcrllps)adiatvto (monoglyceride inactivation and lipase) 1,2-diacylglycerol and ) β 2 sfis ciae edn ohdoye farachidonoyl of hydrolyses to leading activated first is 1 n CB and 2 ,adteezmsinvolved enzymes the and ), α-β 1 hydrolase n CB and N N N 2 - - Posted on Authorea 11 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159986420.00633539 — This a preprint and has not been peer reviewed. Data may be preliminary. ytei cannabinoids Synthetic Phytocannabinoids 2009). Ueda, and (Wang 2 figure in shown as while glycerol to ethanolamine yields addition and enzyme Endocannabinoids acid In respective arachidonic by Alhouayek yields 2-AG 2014; 2007). anandamide al., of active al., of et degradation biologically inactivation (Hermanson et the Enzymatic form inflammation (Blankman of to 2014). degradation regulation Muccioli, 2-AG the enzyme and oxygenates in involved the also esters, of (COX2) glyceryl 15% prostaglandin cyclooxygenase-2 about transformation, enzymatic for account the MAGL, by to inactivated known mostly are is 2-AG Although 2013). 3 α/β yrls oancnann rti- n -12 and protein-6 domain-containing hydrolase Posted on Authorea 11 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159986420.00633539 — This a preprint and has not been peer reviewed. Data may be preliminary. h eihr n irgi nteCS(bai ta. 2003). al., acti- et hyperalgesia, (Ibrahim inflammatory CNS or the pain in neuropathic microglia of and settings periphery the 2017). the CB Manolios, in inhibited peripheral and that, thus Barrie of proposed 1999; cells, vation been al., non-neural et therefore CB by (Hanus has selective terminals factors It neuronal CB a pro-inflammatory nociceptive HU-308, of model. neighbouring that of pain secretion discovery sensitization inflammatory local on the rodent suppressed by periphery formalin-induced activation supported the in process- ceptor is in behaviour pain This inflammatory distribution nociceptive as decreases wide 2017). such significantly Their Manolios, processes inflammatory and 2008). modulating (Barrie al., for ing targets et Wright them makes 2015; cells Sharkey, immune and (Trautmann tract GI soitdwt eta n eihrlnrossseseet Bri n aois 2017). Manolios, and (Barrie effects CB dis- produced systems CB widespread targeting nervous effects the peripheral therapies biological With and that of central supplied. surprising array with exogenously not associated wide and is the expressed (Trautmann it explains endogenously neurons tribution, distribution both motor inhibitory ligands, widespread except cannabinoid Their neurons by enteric of 2015). classes Sharkey, CB all et a and on (Martin regulate 2017). and neuroinflammation tract they Manolios, and (GI) where and gastrointestinal transmission regions Barrie pain supraspinal including 1995; processes and the al., gray, neurotransmission Within of periaqueductal 2016). variety Wiley, and wide and (Sharke hippocampus, brain thalamus, the ganglia, in receptors G-protein–coupled CB abundant most CNS, the of one CB is receptors, CB surface cell receptors. main G-protein-coupled two via signal Endocannabinoids subtypes investigated receptor most Cannabinoid the of 2.2 inactivation 2-AG. enzymatic and and biosynthesis anandamide the ligands: for pathways endocannabinoid prominent Most 2. 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No reuse without permission. — https://doi.org/10.22541/au.159986420.00633539 — This a preprint and has not been peer reviewed. Data may be preliminary. aeatasto rmnuortciet ertxcpeoyedpnigo h nest fteneuronal the of may intensity microglia the that on proposed depending been phenotype also neurotoxic has to with it neuroprotective However, primed from in when 2007). transition hand, response Glass, a other and healing make the (Ashton the On neurotoxic during become 2003). central hence al., et are (Schwartz received 2006). activities injury al., stimuli glutamate IFN- et their of (Schwartz of and type one models neurotoxic neuroprotective the transection or nerve are on phenotype neuroprotective microglia Depending Glial a instance, inflammation. either 2018). 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CD4 In of al., supresses balance et ligands the (Yuan shifting endogenous by cells by activity T activation anti-inflammatory Th2 ‘Helper’ receptor promotes cannabinoid and and inflammation, activity macrophages pro-inflammatory anandamide modulating from Th1 In both release NO Moreover, 2001). and THC al., 1997). production et concentrations, al., IL-6 micromolar lipopolysaccharide-induced et at inhibit is (Berdyshev THC while synthesis This synthesis, cytokine cytokine pro-inflammatory 2005). stimulates pro-inflammatory inhibits (Klein, it cytokines concentrations, (IFN)- pro-inflammatory interferon and of IL-12 of CB synthesis suppression used the the cannabinoid of of reversal enhance γ. SR144528-mediated dose also and employed, rimonabant- may model by supported inflammatory probe, of drug type the and on depending however, (Eljaschewitsch pathway Cannabinoids, (MAPK) kinase protein 2006). mitogen-activated ethanolamine, the al., and through et production acid (NO) arachidonic oxide of tric conjugate re- (NF amide immune factor B necrosis adaptive The kappa tumor and inhibits innate anandamide 2009). directly both Griffin-Thomas, instance, anandamide, in For and different cytokines Endoge- (Cabral at anti-inflammatory 2009). sponses them enhance 2005). Griffin-Thomas, release and Klein, IL-10, cytokines and and anti-inflammatory, 2018; inflammatory production (Cabral the al., cytokines response of et regulate inflammatory release (Donvito and to the the system able is endocannabinoid during are example the stages ligands activated by classic awry, receptor regulated A going cannabinoid part, nous from damage. in it cytokines tissue preventing pro-inflammatory is, the to and which to check response addition in in in mediators anti-inflammatory injury produced release tissue and produce to cells immune responses inflammatory inflammation keeping acute In and signaling receptor Cannabinoid 3.0 2 ioaatpoue eetv naoimo CB of antagonism selective produces Rimonabant Δ γ eetr Kene l,18) H’ ffc nctkn synthesis cytokine on effect THC’s 1985). al., et (Klein receptors sas(aedt ta. 00.Cnaiod aeas endmntae oihbtcell-specific inhibit to demonstrated been also have Cannabinoids 2000). al., et (Sacerdote assays 9 n hnamnsee ihLS irgi dp hntp utdfrdfnieimnt,and immunity, defensive for suited phenotype a adopt microglia LPS, with administered then and ttayrcnaio ( -tetrahydrocannabinol 2 eetr rtce ieaantln shmcrpruinijr ydmeigiflmainin inflammation dampening by injury reperfusion ischemic lung against mice protected receptor, κ )vadrc niiino h I the of inhibition direct via B) 1 Δ n CB and 9- H) h rmr ciecnttetin constituent active primary the THC), 2 erae h irto frtmcohgsin macrophages rat of migration the decreased , κ iae(acoe l,20) n loihbt irgilni- microglial inhibits also and 2003), al., et (Sancho kinase B α 5 (TNF- 1 2 eetr hl R458slcieyantagonises selectively SR144528 while receptors eetratvto nln inflammation. lung in activation receptor α ciaino h rncito ula factor nuclear transcription the of activation ) 2 tmlto yJH3,a agonist an JWH133, by stimulation nvitro in anbssativa Cannabis sbpai.I nanomolar In biphasic. is nvitro in nvivo in upespro- suppress , (Chang and in + Posted on Authorea 11 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159986420.00633539 — This a preprint and has not been peer reviewed. Data may be preliminary. n MAijr oes(hhr ta. 05.A ro fcnet h xrsino akr fmicroglial of markers of expression the concept, of an proof As 2005). following al., activation et (Ehrhart models NMDA-injury and the of CB activation of Thus, activation in phenotype. including microglia, neurotoxic phenotype a to benign differentiation the microglial CB of blocks also migration microglia and in proliferation receptors stimulating to CB system addition of In bulb expression of zone-olfactory CB levels subventricular that the argued the in authors changes and the polarisation, hippocampus microglial of the CB (2004) terms in In not al. neurons 2007). et Glass, new Jin and of by (Ashton and CB study production (Ashton in a the brain neurogenesis including adult to of studies, the process numerous in the from neurogenesis CB with evidence stimulate by associated 2-AG, supported defects as is such where 2018). This cannabinoids, al., that 2007). et fact Glass, Bie known 2005; a al., is et It virus-induced Benito immunodeficiency neurode- 2005; and al., of pain sclerosis et pathogenesis lateral neuropathic (Ramirez amyotrophic sclerosis, the (PD), encephalitis multiple in disease (HD), et Parkinson’s implicated disease (Bie (AD), thus events Huntington’s disease damage (ALS), downstream is Alzheimer’s neuronal to neuroinflammation as subsequent such and leads and diseases with receptors activation receptors generative chemokines P2X4 Microglial these and purinergic of 2018). as cytokines Activation al., such pro-inflammatory 2012). receptors several subse- al., several release with expresses et pro-inflammatory cells, that latter rogue (Naguib microglial The the (TLRs) priming 2013; to of receptors 2017). al., Toll-like anti-inflammatory capable et al., protective, Wake is et 2011; or signals from (Lan noxious al., phenotype structure phenotype of intensity et microglial synaptic array (Paolicelli the of of wide neurodegeneration transition such, maintenance A of quent As the onset 2013). the to al., 2013). and et central processes synapse Kettenmann Stevens, is through the and pruning plasticity, of Schafer synaptic synaptic destruction of the of microglial-mediated 2011; environment maintenance of Majewska, local and nature and the induction (Tremblay and and in phagocytosis role structure as essential synaptic such an modify play microglia thus conditions, neurons, 2006). Aktas, physiological and normal (Zipp Under it of duration also and insult Sbe ta. 09 cml ta. 05.Mroe,tegtas otisezmso h endocannabinoid the of enzymes 2018). contains al., also FAAH et D, gut (Grill phospholipase the MAGL phosphatidylethanolamine-specific Moreover, N-acyl the and and 2015). Within lipase al., diacylglycerol et including 2008). Schmole system al., 2009; et al., et (Lauckner G (Sibaev stores involve (IP3R)-gated CB CB to receptor system, classical shown GI 1,4,5-triphosphate the been inositol to has from addition mechanism released In This system. 2018). endocannabinoid the of CB components in rich is CB tract GI inflammatory inflammation function. The to cognitive Gut response for demonstrated and in crucial activity (2013) matter areas Cannabinoid gray in CB 5.0 of especially al. encodes degeneration matter, et that white increased gene Rossi the with of of associated sclerosis, lesions polymorphism was multiple 6) repeat of chromosome tandem model on short rodent trinucleotide AAT a microglia CB of study, in of reversal of ablation Moreover, (Ashton result genetic phenotype a that anti-inflammatory as 2007). neuroprotective is a effect Glass, to this and pro-inflammatory if cytotoxic determined the be from to phenotype, remains however, It, TNF- phenotype. including microglia mediators, pro-inflammatory of release the nvivo in 2 2 1 2 eetr,tegtas xrse rti-ope eetr5 GR5,acnaiodrsosv non- cannabinoid-responsive a (GPR55), 55 receptor protein-coupled G /CB expresses also gut the receptors, eetrihbt irgilmdae ernldmg nanme fnuoeeeaiedsaemodels, disease neurodegenerative of number a in damage neuronal microglial-mediated inhibits receptor eetrsiuaini soitdwt peuaino ergnssi erlgcldsae leading disease, neurological in neurogenesis of upregulation with associated is stimulation receptor 1 lsl orlt Cba n acaoCba,20) nasuyb arladCba (2005), Cabral and Cabral by study a In 2005). 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All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159986420.00633539 — This a preprint and has not been peer reviewed. Data may be preliminary. al .Ohrcnaiodrcpo iad nmrn oeso netnlinflammation intestinal of models murine 2017). in al., ligands et receptor (Leinward cannabinoid inflammation Other intestinal 1. in Table system As CB endocannabinoid 2017). of the al., Activation of et effect patients. 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In on TNBS-induced to antagonistic 2018). of shown al., model et been psychotropic (Grill rat have inflammation the phytocannabinoids intestinal both as of (2010), models well animal as in endocannabinoids inflammation of Shamran sulfate analogs 2016; 2017). sodium al., in Synthetic al., dextran et deficiency et that as (Pagano genetic such Zhao colitis demonstrated or 2017; colitis (TNBS)-induced that acid MAGL al., experimental gut studies sulfonic et against or from worsens trinitrobenzene FAAH protective evident or receptors is of is colitis enzymes, inhibition these (DSS)-induced This these following of encodes 2-AG, 2008). ablation that and al., genes genetic anandamide et or of Storr levels antagonism 2004; shown increased al., pharmacological been et has while system (Massa It 2009), endocannabinoid inflammation 2006). al., the al., CB et et of of D’Argenio Storr components 2004; activation the al., al., pharmacological in et et (Massa that, alterations (Grill inflammation shows progress intestinal disease models experimental during with animal correlate from al., variations et data such Chen Functional if 2011; al., determined et are be Sabatino lipids to (Di endocannabinoids-like remains cancer 2018). and however colorectal endocannabinoids and It of (IBD) levels subset 2015). disease (Treg) the bowel cell in inflammatory T changes in regulatory Karwad that implicated the 2016; unsurprising of al., expansion is CX3CR1 the et it of of (Cani Thus, regulation presence commensals through en- the achieved to is these and tolerant barrier, latter Tr1 that cells epithelial The apparent immune the 2017). most the of al., integrity keeping is et the and it maintaining integrity, microbiota including, gut gut roles maintaining regulating regulatory in multiple have endocannabinoids ligands of dogenous role the examining By 2 RAwsrltvl xrse 1fl oeo rg scmae oTeetrcls hl nwild- in while cells, effector T to compared as Tregs on more 11-fold expressed relatively was mRNA 2 nacsteatvto fTe-xrse CB Treg-expressed of activation the enhances 2 receptors 1 rCB or nvitro in Δ 2 9 hi TCadtennpyhtoi anbdo eue ooi nuyi a in injury colonic reduced cannabidiol non-psychotropic the and -THC ic -62lcsant o CB for affinity lacks O-1602 since nimnsprsiemcohg ouain(cay ta. 2017). al., et (Acharya population macrophage immunosuppressive an , 2 P1 oee i o tmlt CB stimulate not did however GP-1a . a oneuae nbt hoial nae TNF inflamed chronically both in downregulated was R 1 n CB and ΔΑΡΕ/+ 2 eetraoit csa CB at acts agonist, receptor 2 2 anbssativa Cannabis eetr niie lii nmc,tu salsigthe establishing thus mice, in ileitis inhibited receptors teutseprmna oii Kmale l,2006; al., et (Kimball colitis experimental attenuates 7 iecmae ihcnrl.I TNF In controls. with compared mice 2 eetr yedcnaiod,wt subsequent with endocannabinoids, by receptors 1 n CB and ahrta igeeet(aaoet (Pagano effect single a than rather 1 2 eetr.Teivreagonism inverse The receptors. Rbr ta. 07.Several 2007). al., et (Ryberg 2 sa nes gns,thus agonist, inverse an as γ D iipse al., et Filippis (De 1 n CB and ΔΑΡΕ/+ ΔΑΡΕ/+ 2 n is and , 2 mice, mice and Posted on Authorea 11 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159986420.00633539 — This a preprint and has not been peer reviewed. Data may be preliminary. nii rptnit tmlto fTP1b t iad Hrane l,20) eas cAMP-dependent Because 2003). al., cyclic et not (Hermann or ligands whether its on by CB TRPV1 Depending po- of of 2013). as stimulation stimulation al., activated, function potentiate also et is or pathway Starowicz products, inhibit responses signaling 2003; lipoxygenation inflammatory (cAMP) al., its of et monophosphate of modulation (Ahluwalia some adenosine TRPV1 the and on anandamide in ligands instance, role For tent potential 2018). a al., play et may (Mlost systems endovanilloid CB and that nabinoid arthritis shown the rheumatoid been within in 2011). has bradykinins, inflammation al., It joint and et of (Raychaudhuri factor sustenance TRPV1 growth and sensitizing nerve development by the prostaglandins, (RA) to as contributes such also inflammation synovium terminals and of peripheral (Rosa horn, mediators from (B´anv response dorsal neuropeptides other expression inflammatory the these TRPV1 the in of increased release neurons amplifies via subsequent which of joint, then branches loop A arthritic released of feedback of the histamine varicosities positive In The terminal a 2013). 2017). from Fantozzi, creating Manolios, SP thus and additional CGRP, (Barrie of and histamine adjacent release on of act the neurons release afferent induces peptide subsequent local gene-related by with calcitonin inflammation cells neurogenic (SP), during mast P released substance A, neurokinin including and neuropeptides, (CGRP) as such mediators Inflammatory inflammation joint factor and growth Cannabinoids endothelial protein 6.0 G vascular mitogen-activated VEGF, GPR55, MAPK, receptor; toll-like acid; rapamycin; PPAR TLR, dinitrobenzenesulfonic of oxide; species; target DNBS, nitric mammalian NO, sulfate; mTOR, kinase; sodium 55; dextran receptor DSS, protein-coupled receptor; cannabinoid CB, MAPK p38 of inhibits Partly and colitis DSS-induced and colitis DSS-induced Mechanism in production NO Inhibits colitis Palmitoylethanolamide DSS-induced in production NO Decrease colitis DNBS-induced model Animal HU210 colitis DNBS-induced 55,212-2 WIN Cannabichromene Cannabigerol Ligand δ n -br euti h eeomn flclnuoei namto,adas erpti pain neuropathic also and inflammation, neurogenic local of development the in result C-fibers and 1 n CB and α, eoioepoieao-ciae eetrapa O,ratv oxygen reactive ROS, alpha; receptor proliferator-activated peroxisome 2 NSidcdcolitis DNBS-induced colitis DNBS-induced olclz ihTP1 n hta nepa ewe h endocan- the between interplay an that and TRPV1, with co-localize ly ta. 04 eplanadPwwk 97.Terlaeof release The 1997). Pawlwak, and Heppelmann 2004; al., et ¨ olgyi 8 PPAR selective a in pathway Akt/mTOR the via signaling VEGF inflammation-associated of modulation and CB of activation via integrity barrier maintains and inflammation intestinal Inhibits 2004) Massa al., 2017, et al., et (Lin activation MAPK p38 TLR4-mediated via that effects anti-inflammatory extraintestinal produces but TLR4, of independent integrity barrier intestinal Maintains Brel ta. 05 49-52) 2015; al., et (Borrelli 2016) al., et (Feng 2013) al., et (Romano macrophages 2013) al., et (Borrelli cells epithelial intestinal in formation ROS and macrophages α- eedn manner dependent 1 eetr a either may receptors 2 GPR55 , Posted on Authorea 11 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159986420.00633539 — This a preprint and has not been peer reviewed. Data may be preliminary. neligteihbto fpobletridcdaueiflmainb CB mechanisms by possible are inflammation PPARs acute of ester-induced activation and phorbol CXL10, of and inhibition CCL8, the CCL2, CB underlying as interferon 2014). such and al., chemokines IL-17 et of cytokines, Harvey duction pro-inflammatory 2015; mentioned previously al., to et addition (Kozela in polyi- inhibits, TNF- on also and and study cytes IL-8 and reduced a IL-6, cannabidiol cytokines In protein-2, vitro molecules of various chemotactic cannabinoids. 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Data may be preliminary. hw ordc aclrclae eoisadpeetmcohg nlrto n bols migration fibroblast and IL- CB been infiltration and has of macrophage cannabinoid, Activation infiltration synthetic prevent increased macrophage a scleroderma. and and VCE-004.8, of of IL-23, deposits 2019). models and al., collagen mouse 22 et vascular in IL, (Du reduce 10 IL-17, and to as 9 such shown ligands cytokines profile motif) particular Th17-derived a (C-X-C decreased displays chemokine collagen, function, of Treg deposition cytokines patent reduced excessive by inflammatory of a caused of scleroderma, In 2019). inhibition localised these in Anastassov, the Inflammation 2013). and that pro- through (Changoer showed al., between also factors balance was et and growth of it (Ramot Th2, angiogenic restoration cannabigerol, and samples anti-inflammatory the and via and skin course CBD Th1 human disease topical inflammatory cultured the with inhibits organ treatment dose-dependently in psoriasis phytocannabinoids K16 for and filed be K6 (20190060250) to of appears and expression Th2 receptors, anti-inflammatory the CB CB the of synthetic independent to are a however, lymphocytes PPAR effects, by Th1 These predominantly of 2019). mediated conversion al., et the (Sheriff promoting phenotype by inflammation of associated administration the psoriasis, In 2018). al., et ciain(la ta. 04.Teat-namtr ffcsapa ob eedn nA on and dependent 3 be TRPV1, to of activation appear the effects anti-inflammatory through instance, For The sebocytes activation. 2014). receptor proliferation al., CB pso- of the (Ol´ah of in et proliferation and independent activation observed the be secretion As 4 and to 2016). sebum appear sebum al., decreases (Ol´ah cannabinoids of et cytokines of CBD production effects pro-inflammatory the positive of 2015; the inhibits expression Akhtar, riasis, the safely and reduce (Ali Phytocannabinoids and weeks 12 2008). sebocytes 12-O-tetradecanoylphorbol-13-acetate for of al., application model topical et mouse involving decreas- Dobrosi pre-clinical in trials effective in human are shown and they as erythema psoriasis, (TPA)-induced sebum of 2017). skin management and al., the in erythema et effective ing (Martyanov phytocannabinoids decreases eicosanoids topical acid are pro-resolving only lipid- of ajulemic Not increases production that, and revealed the fibrosis, for trials for relevant these important genes genes in synthetic metabolising matrix-related a enrolled extracellular anabasum, patients and that from genes shows biopsies syntheticinflammation-related trials skin Another clinical Analysing 2 and 2016). 2017;). 1 al., Phase et and of studies, Rio analog preclinical (del from VCE-004.8 Evidence of 2018). effects antifibrotic CB the non-psychoactive for accounting production, significant a a using observed CB CB (2018) neuroinflammation of against al. et activation cannabinoids Braun of selective CB injury, effects brain CB of protective in traumatic of of studies the role CB upregulation Additional model evaluate between the impact to 2016). relation cortical on study al., controlled the et a murine elucidate questions Duru In fully 2013; to to fibrosis. al., needed door et of thus (He the is fibrosis area promotes opens activation this however, M2 CB whereas argument, of 2018) activation phenotype This al., M2 since anti-inflammatory fibrosis, cytokines the in 2018). toward numerous macrophages polarisation al., of enhance also et release and TNF- subsequent (Luo polarisation polarisation and M1 macrophages with inhibit IL-12 signals, phenotype, to IL-8, inflammatory shown M1 to IL-6, in pro-inflammatory exposed as IL-1, such the When including damage toward tissue 2011). and favoured al., pathogens is et to response (Brancato effects. inflammatory tissues cytotoxic the cannabidiol necrotic no in players Thus, or important minimal 2013). are with Macrophages al., ACD et of (Gaffal component ACD inflammatory 2,4-dinitrofluorobenzene-induced suppress can in especially reported, been CB Non 2 eetratgns ffcieyrvre CB reversed effectively antagonist receptor 1 /CB Δ 8 TC1-i cd saueu lentv ntetn ceoem Mne l,21;Sir tal., et Spiera 2017; al., et (Man scleroderma treating in alternative useful a is acid, -THC-11-oic 2 mdae niiflmaoyeet fcnaiod uha topical as such cannabinoids of effects anti-inflammatory -mediated 1 gns,dcessbt eaioyecl proliferation cell keratinocyte both decreases agonist, 2 eetrwti nlrtn yli el fe 2hus h emas bevdthat observed also team The hours. 72 after cells myeloid infiltrating within receptor 2 eetraoitueu nteteteto ceoem sauei cd(Burstein, acid ajulemic is scleroderma of treatment the in useful agonist receptor 2 niie 1plrsto n eue eerlodm.Amnsrto fa of Administration oedema. cerebral reduced and polarisation M1 inhibited Δ γ β 9 WlisnadWlimo,20) Arachidonoyl-chloro-ethanolamide, 2007). Williamson, and (Wilkinson TCadCDihbttepoieaino eaioyeadmodulate and keratinocyte of proliferation the inhibit CBD and -THC erto.Truhitrcinwt md,PPAR Smads, with interaction Through secretion. α DqeadDsoeu,21) ciaino CB of Activation 2014). Descoteaux, and (Duque 2 2 niisfirss(ie l,21;Wn ta. 06 aget Tang 2016; al., et Wang 2016; al., et (Li fibrosis inhibits mdae erpoeto n osndotoe (Braun outcomes worsened and neuroprotection -mediated 2 10 per omdaeteat-namtr component anti-inflammatory the mediate to appears 2 2mcohgsadtedevelopment the and macrophages M2 , nsitu in nhmnsi utrs and cultures, skin human in Δ 9 TCi C aealso have ACD in -THC γ niisTGF- inhibits 2A 2 2 adenosine a been has n M2 and β Posted on Authorea 11 Sep 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159986420.00633539 — This a preprint and has not been peer reviewed. Data may be preliminary. thsbe eosrtdta u namto lesteepeso fmtblzn nye fteen- the of enzymes metabolizing of expression the 2018). alters al., inflammation URB597 et gut (Mlost inhibitor that FAAH osteoarthritis demonstrated of the management been as the has such in It molecules SB366791 small antagonist single-target receptor evidenced over TRPV1 development partly the OMDM198 drug as and therapy of multi-target single-target effectiveness disorders, to inflammatory the compared advantageous of by be process. pathophysiology may immunomodulatory the strategies molecules, and pharmacotherapy of adhesion and inflammatory complexity the molecules, the in co-stimulatory to roles ether Owing on their 2-AG effects ascertain virodhamine, to possible cytokines, endocannabinoids their and “not-so-popular” for and chemokines the affinities dopamine increased of N-arachidonoyl with effects and molecules biological novel exact of the identification investigate future or challenges, synthesis therapeutic the and CB on social the focus legal, pose therefore cannabinoids may Interestingly, of studies effects immunosuppression. psychotropic the profound Since without cotherapy. immunomodulation selective produce CB to shown been ran- risks well-controlled long-term disorders. Additional and CB inflammatory efficacy clinical clinic. in true therapy the the cannabinoid to evaluate comprehensively with research to pointed associated pre-clinical required largely however pharmacologi- have of are re- studies translation potential trials conditions, these patient domized successful from the disease in findings potential variations inflammatory to reported, individual the several points been Although to of have evidence therapy management disorders. cannabinoid-inclusive or inflammatory of to treatment peripheral sponse pool the and a central in both endocannabinoid system elucidated, the including this fully of of role not regula- modulation exact the is the in cal involved though inflammation be Even to in studies responses. clinical system immunomodulatory and and preclinical inflammatory several of in shown tion been has system cannabinoid The Scheau studies Future 2013; and Hagemann, Conclusion and 2019). several (Candido 8.0 al., carcinogenesis of et fuelling Cioni release of 2019; the al., capable et inflammation and of TGF- transition 2020). mediators inhibiting al., epithelial–mesenchymal other by et of cancers (Scheau enhancement skin sarcoma with metalloproteinase-mediated Kaposi associated and processes carcinomas inflammatory basal β- inhibit and cannabinoids cell summary, squamous Both skin In certain melanoma, carcinogenesis. with as in associated inflammation inflammation such attenuate treatment of cancers cannabinoids role the exogenous complex in and the system alternate in endocannabinoid implicated useful the also a is represents signaling 2020). thus CB receptor al., Cannabinoid efficient addition, et and In (Scheau tolerable, conditions skin. safe, skin dermatomyositis be inflammatory lesional to of in shown activities CB been IFN a have 2 lenabasum, nists and that 1 identified type was downregulates it (2017), vasculopa- al. to et lead TNF- also CB inflammatory as may the in such and of results release regeneration, subsequently Administration and This 2015). necrosis (Volc-Platzer, factors. cells tissue thy complement dendritic muscle and and typical IFNs by lymphocytes characterised of of myopathy, activation production the the by increases driven 2016). which therefore is al., dermatomyositis may (Ol´ah et with cannabigerovarin syndrome syn- associated and dry-skin lipid Inflammation CBG of sebaceous treatment increase inflammation. cannabigerovarin the inhibit and for in significantly CBG useful potential to contrast, be significant ability In show sig- their treatment. may despite cannabinoids acne thus thesis, non-psychotropic in agents These lipogenesis, novel acne-like as sebocytes. use acid-induced SZ95 arachidonic in inhibited inflammation nificantly and decreases cannabichromene and NF- CBD, production p65 to lipid the Similar of 2012). inhibition al., the thus activation, receptor eitdimnsprsinadtmrgot,TNF- growth, tumor and immunosuppression mediated 2 2 eetr r rmrl xrse nimn el,adpamclgcltreigo hs eetr have receptors these of targeting pharmacological and cells, immune on expressed primarily are receptors eetratvto swtotpyhtoi ieeet,tu aigi utbetre o pharma- for target suitable a it making thus effects, side psychotropic without is activation receptor 2 eetrfruei namtr n uomuedsae.I diin oesuisaerqie to required are studies more addition, In diseases. autoimmune and inflammatory in use for receptor α, n lotepouto fIFN- of production the also and Δ 2 11 2 9 eetraoit erae r-namtr cytokine pro-inflammatory decreases agonists receptor ttayrcnaiai,ihbt xesv sebaceous excessive inhibits -tetrahydrocannabivarin, α eetraoit erae D elppltosand populations cell CD4 decreases agonist, receptor κ n IFN- and aha pnamnsrto D ercli et Petrocellis (De administration upon pathway B α- eitdcl uvvladpoieain matrix proliferation, and survival cell mediated β Sha ta. 00.I td yChen by study a In 2020). al., et (Scheau 2 eetrago- receptor Posted on Authorea 11 Sep 2020 — The copyright holder is the author/funder. 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