{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T10:49:56Z","timestamp":1778237396429,"version":"3.51.4"},"reference-count":200,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,2,7]],"date-time":"2024-02-07T00:00:00Z","timestamp":1707264000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neuroinform."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>The endocannabinoid (eCB) system is named after the discovery that endogenous cannabinoids bind to the same receptors as the phytochemical compounds found in Cannabis. While endogenous cannabinoids include anandamide (AEA) and 2-arachidonoylglycerol (2-AG), exogenous phytocannabinoids include \u0394-9 tetrahydrocannabinol (THC) and cannabidiol (CBD). These compounds finely tune neurotransmission following synapse activation, via retrograde signaling that activates cannabinoid receptor 1 (CB1R) and\/or transient receptor potential cation channel subfamily V member 1 (TRPV1). Recently, the eCB system has been linked to several neurological diseases, such as neuro-ocular abnormalities, pain insensitivity, migraine, epilepsy, addiction and neurodevelopmental disorders. In the current study, we aim to: (i) highlight a potential link between the eCB system and neurological disorders, (ii) assess if THC exposure alters the expression of eCB-related genes, and (iii) identify evolutionary-conserved residues in CB1R or TRPV1 in light of their function.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>To address this, we used several bioinformatic approaches, such as transcriptomic (Gene Expression Omnibus), protein\u2013protein (STRING), phylogenic (BLASTP, MEGA) and structural (Phyre2, AutoDock, Vina, PyMol) analyzes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Using RNA sequencing datasets, we did not observe any dysregulation of eCB-related transcripts in major depressive disorders, bipolar disorder or schizophrenia in the anterior cingulate cortex, nucleus accumbens or dorsolateral striatum. Following <jats:italic>in vivo<\/jats:italic> THC exposure in adolescent mice, <jats:italic>GPR55<\/jats:italic> was significantly upregulated in neurons from the ventral tegmental area, while other transcripts involved in the eCB system were not affected by THC exposure. Our results also suggest that THC likely induces neuroinflammation following <jats:italic>in vitro<\/jats:italic> application on mice microglia. Significant downregulation of <jats:italic>TPRV1<\/jats:italic> occurred in the hippocampi of mice in which a model of temporal lobe epilepsy was induced, confirming previous observations. In addition, several transcriptomic dysregulations were observed in neurons of both epileptic mice and humans, which included transcripts involved in neuronal death. When scanning known interactions for transcripts involved in the eCB system (n\u2009=\u200912), we observed branching between the eCB system and neurophysiology, including proteins involved in the dopaminergic system. Our protein phylogenic analyzes revealed that CB1R forms a clade with CB2R, which is distinct from related paralogues such as sphingosine-1-phosphate, receptors, lysophosphatidic acid receptors and melanocortin receptors. As expected, several conserved residues were identified, which are crucial for CB1R receptor function. The anandamide-binding pocket seems to have appeared later in evolution. Similar results were observed for TRPV1, with conserved residues involved in receptor activation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The current study found that GPR55 is upregulated in neurons following THC exposure, while TRPV1 is downregulated in temporal lobe epilepsy. Caution is advised when interpreting the present results, as we have employed secondary analyzes. Common ancestors for CB1R and TRPV1 diverged from jawless vertebrates during the late Ordovician, 450 million years ago. Conserved residues are identified, which mediate crucial receptor functions.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fninf.2024.1294939","type":"journal-article","created":{"date-parts":[[2024,2,7]],"date-time":"2024-02-07T05:36:24Z","timestamp":1707284184000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["In silico analyses of the involvement of GPR55, CB1R and TRPV1: response to THC, contribution to temporal lobe epilepsy, structural modeling and updated evolution"],"prefix":"10.3389","volume":"18","author":[{"given":"Amy L.","family":"Cherry","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael J.","family":"Wheeler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karolina","family":"Mathisova","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mathieu","family":"Di Miceli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2024,2,7]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"1045","DOI":"10.1007\/s11064-020-02979-3","article-title":"Capsaicin exerts anti-convulsant and neuroprotective effects in Pentylenetetrazole-induced seizures","volume":"45","author":"Abdel-Salam","year":"2020","journal-title":"Neurochem. Res."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1002\/cne.900940104","article-title":"The nervous system of the earthworm Megascolex","volume":"94","author":"Adey","year":"1951","journal-title":"J. Comp. Neurol."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"736","DOI":"10.1002\/ajmg.b.30881","article-title":"Evidence for association between polymorphisms in the cannabinoid receptor 1 (CNR1) gene and cannabis dependence","author":"Agrawal","year":"2009","journal-title":"Am. J. Med. Genet. B Neuropsychiatr. Genet."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1111\/j.1535-7597.2004.04501.x","article-title":"Endocannabinoids and their implications for epilepsy","volume":"4","author":"Alger","year":"2004","journal-title":"Epilepsy Curr."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"1831","DOI":"10.1038\/sj.bjp.0702478","article-title":"Effects of the endogeneous cannabinoid, anandamide, on neuronal activity in rat hippocampal slices","volume":"126","author":"Ameri","year":"1999","journal-title":"Br. J. Pharmacol."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1186\/s13229-019-0256-6","article-title":"Lower circulating endocannabinoid levels in children with autism spectrum disorder","volume":"10","author":"Aran","year":"2019","journal-title":"Mol. Autism."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1016\/s0091-3057(01)00578-0","article-title":"Cannabinoid effects on anxiety-related behaviours and hypothalamic neurotransmitters","volume":"70","author":"Ar\u00e9valo","year":"2001","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"7486","DOI":"10.1038\/s41598-023-34754-z","article-title":"Two legume fatty acid amide hydrolase isoforms with distinct preferences for microbial- and plant-derived acylamides","volume":"13","author":"Arias-Gaguancela","year":"2023","journal-title":"Sci. Rep."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1002\/cne.20272","article-title":"Expression of vanilloid receptor TRPV1 in the rat trigeminal sensory nuclei","volume":"478","author":"Bae","year":"2004","journal-title":"J. Comp. Neurol."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"3383","DOI":"10.1093\/brain\/awac223","article-title":"Endocannabinoid dysfunction in neurological disease: neuro-ocular DAGLA-related syndrome","volume":"145","author":"Bainbridge","year":"2022","journal-title":"Brain"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"1521","DOI":"10.3389\/fphar.2018.01521","article-title":"Oral Cannabidiol use in children with autism Spectrum disorder to treat related symptoms and co-morbidities","volume":"9","author":"Barchel","year":"2018","journal-title":"Front. Pharmacol."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"2959","DOI":"10.1016\/j.lfs.2004.06.006","article-title":"The role of endogenous cannabinoids in the hypothalamo-pituitary-adrenal axis regulation: in vivo and in vitro studies in CB1 receptor knockout mice","volume":"75","author":"Barna","year":"2004","journal-title":"Life Sci."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"237","DOI":"10.2174\/092986607780090829","article-title":"Critical enzymes involved in endocannabinoid metabolism","volume":"14","author":"Basavarajappa","year":"2007","journal-title":"Protein Pept. Lett."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"10522","DOI":"10.1038\/s41598-017-11274-1","article-title":"Structural determinants of 5\u2032,6\u2032-epoxyeicosatrienoic acid binding to and activation of TRPV4 channel","volume":"7","author":"Berna-Erro","year":"2017","journal-title":"Sci. Rep."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1186\/s12916-022-02459-1","article-title":"Medical cannabinoids: a pharmacology-based systematic review and meta-analysis for all relevant medical indications","volume":"20","author":"Bilbao","year":"2022","journal-title":"BMC Med."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"2568","DOI":"10.1038\/npp.2013.165","article-title":"Peripheral endocannabinoid system dysregulation in first-episode psychosis","volume":"38","author":"Bioque","year":"2013","journal-title":"Neuropsychopharmacology"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"3540","DOI":"10.1111\/ejn.16122","article-title":"Cannabinoid receptor gene CNR1 is downregulated in subcortical brain samples and upregulated in blood samples of individuals with schizophrenia: a participant data systematic meta-analysis","volume":"58","author":"Bloch Priel","year":"2023","journal-title":"Eur. J. Neurosci."},{"key":"ref18","doi-asserted-by":"publisher","first-page":"3257","DOI":"10.1007\/s00213-019-05283-3","article-title":"The effects of cannabinoid 1 receptor compounds on memory: a meta-analysis and systematic review across species","volume":"236","author":"Borgan","year":"","journal-title":"Psychopharmacology"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"1074","DOI":"10.1001\/jamapsychiatry.2019.1427","article-title":"In vivo availability of cannabinoid 1 receptor levels in patients with first-episode psychosis","volume":"76","author":"Borgan","year":"","journal-title":"JAMA Psychiatry"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"677","DOI":"10.1007\/s00406-020-01191-2","article-title":"Association between cannabinoid 1 receptor availability and glutamate levels in healthy controls and drug-free patients with first episode psychosis: a multi-modal PET and 1H-MRS study","volume":"271","author":"Borgan","year":"2021","journal-title":"Eur. Arch. Psychiatry Clin. Neurosci."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"1337","DOI":"10.1007\/s00213-021-05914-8","article-title":"Cannabinoid receptor type 1 antagonists alter aspects of risk\/reward decision making independent of toluene-mediated effects","volume":"239","author":"Braunscheidel","year":"2022","journal-title":"Psychopharmacology"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"915","DOI":"10.1093\/sysbio\/syt043","article-title":"The Cambrian explosion: the reconstruction of animal biodiversity.\u2014 by Douglas H. Erwin and James W. Valentine","volume":"62","author":"Budd","year":"2013","journal-title":"Syst. Biol."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1126\/science.ade5645","article-title":"Syncytial nerve net in a ctenophore adds insights on the evolution of nervous systems","volume":"380","author":"Burkhardt","year":"2023","journal-title":"Science"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1016\/j.neuron.2012.09.020","article-title":"Endocannabinoid signaling and synaptic function","volume":"76","author":"Castillo","year":"2012","journal-title":"Neuron"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"816","DOI":"10.1038\/39807","article-title":"The capsaicin receptor: a heat-activated ion channel in the pain pathway","volume":"389","author":"Caterina","year":"1997","journal-title":"Nature"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"304","DOI":"10.1016\/j.neuroimage.2013.04.052","article-title":"Increased ventral striatal CB1 receptor binding is related to negative symptoms in drug-free patients with schizophrenia","volume":"79","author":"Ceccarini","year":"2013","journal-title":"NeuroImage"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"e13167","DOI":"10.1111\/adb.13167","article-title":"Cannabinoid receptor availability modulates the magnitude of dopamine release in vivo in the human reward system: a preliminary multitracer positron emission tomography study","volume":"27","author":"Ceccarini","year":"2022","journal-title":"Addict. Biol."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"542","DOI":"10.1038\/s41593-023-01288-6","article-title":"Lipid-accumulated reactive astrocytes promote disease progression in epilepsy","volume":"26","author":"Chen","year":"2023","journal-title":"Nat. Neurosci."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"412","DOI":"10.1038\/s41586-019-1522-7","article-title":"Death march of a segmented and trilobate bilaterian elucidates early animal evolution","volume":"573","author":"Chen","year":"2019","journal-title":"Nature"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"e0220025","DOI":"10.1371\/journal.pone.0220025","article-title":"Cannabidiol binding and negative allosteric modulation at the cannabinoid type 1 receptor in the presence of delta-9-tetrahydrocannabinol: an in silico study","volume":"14","author":"Chung","year":"2019","journal-title":"PLoS One"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1007\/978-1-4939-3578-9_5","article-title":"The gene expression omnibus database","volume":"1418","author":"Clough","year":"2016","journal-title":"Methods Mol. Biol."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1038\/sj.bjp.0705920","article-title":"Vanilloid TRPV1 receptor mediates the antihyperalgesic effect of the nonpsychoactive cannabinoid, cannabidiol, in a rat model of acute inflammation","volume":"143","author":"Costa","year":"2004","journal-title":"Br. J. Pharmacol."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1038\/s41582-019-0284-z","article-title":"Cannabinoids and the expanded endocannabinoid system in neurological disorders","volume":"16","author":"Cristino","year":"2020","journal-title":"Nat. Rev. Neurol."},{"key":"ref34","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1016\/S2215-0366(18)30427-9","article-title":"Efficacy and safety of a fatty acid amide hydrolase inhibitor (PF-04457845) in the treatment of cannabis withdrawal and dependence in men: a double-blind, placebo-controlled, parallel group, phase 2a single-site randomised controlled trial","volume":"6","author":"D\u2019Souza","year":"2019","journal-title":"Lancet Psychiatry"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1186\/s12859-022-04675-1","article-title":"Statistical power for cluster analysis","volume":"23","author":"Dalmaijer","year":"2022","journal-title":"BMC Bioinformatics"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"1620","DOI":"10.1038\/npp.2011.43","article-title":"Paranoid schizophrenia is characterized by increased CB1 receptor binding in the dorsolateral prefrontal cortex","volume":"36","author":"Dalton","year":"2011","journal-title":"Neuropsychopharmacology"},{"key":"ref37","doi-asserted-by":"publisher","first-page":"33","DOI":"10.3389\/fneur.2020.00033","article-title":"Top common differentially expressed genes in the epileptogenic nucleus of two strains of rodents susceptible to Audiogenic seizures: WAR and GASH\/Sal","volume":"11","author":"Damasceno","year":"2020","journal-title":"Front. Neurol."},{"key":"ref38","doi-asserted-by":"publisher","first-page":"420","DOI":"10.1002\/bab.2119","article-title":"CBD activation of TRPV1 induces oxidative signaling and subsequent ER stress in breast cancer cell lines","volume":"69","author":"de la Harpe","year":"2022","journal-title":"Biotechnol. Appl. Biochem."},{"key":"ref39","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1186\/1476-511X-2-5","article-title":"Endocannabinoid signalling in the blood of patients with schizophrenia","volume":"2","author":"De Marchi","year":"2003","journal-title":"Lipids Health Dis."},{"key":"ref40","doi-asserted-by":"publisher","first-page":"2031","DOI":"10.1038\/oby.2011.135","article-title":"Variants at the endocannabinoid receptor CB1 gene (CNR1) and insulin sensitivity, type 2 diabetes, and coronary heart disease","volume":"19","author":"de Miguel-Yanes","year":"2011","journal-title":"Obesity (Silver Spring)"},{"key":"ref41","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1111\/j.1748-1716.2011.02338.x","article-title":"Cannabinoid actions at TRPV channels: effects on TRPV3 and TRPV4 and their potential relevance to gastrointestinal inflammation","volume":"204","author":"De Petrocellis","year":"2012","journal-title":"Acta Physiol (Oxf.)"},{"key":"ref42","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/S0306-4522(00)00552-2","article-title":"Studies on [3H]CP-55940 binding in the human central nervous system: regional specific changes in density of cannabinoid-1 receptors associated with schizophrenia and cannabis use","volume":"103","author":"Dean","year":"2001","journal-title":"Neuroscience"},{"key":"ref43","doi-asserted-by":"publisher","first-page":"220115","DOI":"10.1098\/rsos.220115","article-title":"Internal anatomy of a fossilized embryonic stage of the Cambrian-Ordovician scalidophoran Markuelia","volume":"9","author":"Dong","year":"2022","journal-title":"R. Soc. Open Sci."},{"key":"ref44","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1093\/nar\/30.1.207","article-title":"Gene expression omnibus: NCBI gene expression and hybridization array data repository","volume":"30","author":"Edgar","year":"2002","journal-title":"Nucleic Acids Res."},{"key":"ref45","doi-asserted-by":"publisher","first-page":"660","DOI":"10.1002\/cne.21331","article-title":"Localization of CiCBR in the invertebrate chordate Ciona intestinalis: evidence of an ancient role for cannabinoid receptors as axonal regulators of neuronal signalling","volume":"502","author":"Egertov\u00e1","year":"2007","journal-title":"J. Comp. Neurol."},{"key":"ref46","doi-asserted-by":"publisher","first-page":"772","DOI":"10.1001\/archpsyc.65.7.772","article-title":"Reduced cortical cannabinoid 1 receptor messenger RNA and protein expression in schizophrenia","volume":"65","author":"Eggan","year":"2008","journal-title":"Arch. Gen. Psychiatry"},{"key":"ref47","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1016\/S0006-8993(97)01297-3","article-title":"An invertebrate G-protein coupled receptor is a chimeric cannabinoid\/melanocortin receptor","volume":"780","author":"Elphick","year":"1998","journal-title":"Brain Res."},{"key":"ref48","doi-asserted-by":"publisher","first-page":"3201","DOI":"10.1098\/rstb.2011.0394","article-title":"The evolution and comparative neurobiology of endocannabinoid signalling","volume":"367","author":"Elphick","year":"2012","journal-title":"Philos. Trans. R. Soc. Lond. Ser. B Biol. Sci."},{"key":"ref49","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1016\/s0378-1119(02)01094-6","article-title":"The invertebrate ancestry of endocannabinoid signalling: an orthologue of vertebrate cannabinoid receptors in the urochordate Ciona intestinalis","volume":"302","author":"Elphick","year":"2003","journal-title":"Gene"},{"key":"ref50","doi-asserted-by":"publisher","first-page":"120582","DOI":"10.1016\/j.lfs.2022.120582","article-title":"Pharmacological effects of cannabidiol by transient receptor potential channels","volume":"300","author":"Etemad","year":"2022","journal-title":"Life Sci."},{"key":"ref51","doi-asserted-by":"publisher","first-page":"7845","DOI":"10.1073\/pnas.2001045117","article-title":"Discovery of the oldest bilaterian from the Ediacaran of South Australia","volume":"117","author":"Evans","year":"2020","journal-title":"Proc. Natl. Acad. Sci."},{"key":"ref52","doi-asserted-by":"publisher","first-page":"649","DOI":"10.1097\/00001756-199702100-00014","article-title":"Cannabinoids excite dopamine neurons in the ventral tegmentum and substantia nigra","volume":"8","author":"French","year":"1997","journal-title":"Neuroreport"},{"key":"ref53","doi-asserted-by":"publisher","first-page":"10943","DOI":"10.1523\/JNEUROSCI.0190-17.2017","article-title":"CB1-dependent Long-term depression in ventral tegmental area GABA neurons: a novel target for marijuana","volume":"37","author":"Friend","year":"2017","journal-title":"J. Neurosci."},{"key":"ref54","doi-asserted-by":"publisher","first-page":"107740","DOI":"10.1016\/j.neuropharm.2019.107740","article-title":"Cannabidiol attenuates the rewarding effects of cocaine in rats by CB2, 5-HT1A and TRPV1 receptor mechanisms","volume":"167","author":"Galaj","year":"2020","journal-title":"Neuropharmacology"},{"key":"ref55","doi-asserted-by":"publisher","first-page":"762738","DOI":"10.3389\/fphar.2021.762738","article-title":"Reviewing the role of the endocannabinoid system in the pathophysiology of depression","volume":"12","author":"Gallego-Landin","year":"2021","journal-title":"Front. Pharmacol."},{"key":"ref56","doi-asserted-by":"publisher","first-page":"110096","DOI":"10.1016\/j.pnpbp.2020.110096","article-title":"Endocannabinoid system in psychotic and mood disorders, a review of human studies","volume":"106","author":"Garani","year":"2021","journal-title":"Prog. Neuro-Psychopharmacol. Biol. Psychiatry"},{"key":"ref57","doi-asserted-by":"publisher","first-page":"685","DOI":"10.1093\/oxfordjournals.molbev.a025808","article-title":"BIONJ: an improved version of the NJ algorithm based on a simple model of sequence data","volume":"14","author":"Gascuel","year":"1997","journal-title":"Mol. Biol. Evol."},{"key":"ref58","doi-asserted-by":"publisher","first-page":"5249","DOI":"10.1523\/JNEUROSCI.5403-12.2013","article-title":"The zebrafish Ortholog of TRPV1 is required for heat-induced locomotion","volume":"33","author":"Gau","year":"2013","journal-title":"J. Neurosci."},{"key":"ref59","doi-asserted-by":"publisher","first-page":"2108","DOI":"10.1038\/sj.npp.1300558","article-title":"Cerebrospinal anandamide levels are elevated in acute schizophrenia and are inversely correlated with psychotic symptoms","volume":"29","author":"Giuffrida","year":"2004","journal-title":"Neuropsychopharmacology"},{"key":"ref60","doi-asserted-by":"publisher","first-page":"e86166","DOI":"10.7554\/eLife.86166","article-title":"Cannabidiol sensitizes TRPV2 channels to activation by 2-APB","volume":"12","author":"Gochman","year":"2023","journal-title":"elife"},{"key":"ref61","doi-asserted-by":"publisher","first-page":"56","DOI":"10.3390\/genes7090056","article-title":"Possible therapeutic doses of cannabinoid type 1 receptor antagonist reverses key alterations in fragile X syndrome mouse model","volume":"7","author":"Gomis-Gonz\u00e1lez","year":"2016","journal-title":"Genes (Basel)"},{"key":"ref62","doi-asserted-by":"publisher","first-page":"1519","DOI":"10.1038\/nn.2685","article-title":"Postsynaptic TRPV1 triggers cell type-specific long-term depression in the nucleus accumbens","volume":"13","author":"Grueter","year":"2010","journal-title":"Nat. Neurosci."},{"key":"ref63","doi-asserted-by":"publisher","first-page":"e249","DOI":"10.1016\/j.bja.2019.02.019","article-title":"Microdeletion in a FAAH pseudogene identified in a patient with high anandamide concentrations and pain insensitivity","volume":"123","author":"Habib","year":"2019","journal-title":"Br. J. Anaesth."},{"key":"ref64","doi-asserted-by":"publisher","first-page":"373","DOI":"10.1523\/JNEUROSCI.1493-22.2022","article-title":"Cannabinoid CB1 receptors are expressed in a subset of dopamine neurons and underlie cannabinoid-induced aversion, Hypoactivity, and anxiolytic effects in mice","volume":"43","author":"Han","year":"2023","journal-title":"J. Neurosci."},{"key":"ref65","doi-asserted-by":"publisher","first-page":"3115","DOI":"10.1038\/s41598-020-59948-7","article-title":"An endocannabinoid catabolic enzyme FAAH and its paralogs in an early land plant reveal evolutionary and functional relationship with eukaryotic orthologs","volume":"10","author":"Haq","year":"2020","journal-title":"Sci. Rep."},{"key":"ref66","doi-asserted-by":"publisher","first-page":"e45530","DOI":"10.7554\/eLife.45530","article-title":"The genetic factors of bilaterian evolution","volume":"9","author":"Heger","year":"2020","journal-title":"elife"},{"key":"ref67","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1002\/ajmg.b.30325","article-title":"Association study of the CNR1 gene exon 3 alternative promoter region polymorphisms and substance dependence","author":"Herman","year":"2006","journal-title":"Am. J. Med. Genet. B Neuropsychiatr. Genet."},{"key":"ref68","doi-asserted-by":"publisher","first-page":"1013","DOI":"10.1001\/jamapsychiatry.2021.1471","article-title":"Development over time of the population-attributable risk fraction for Cannabis use disorder in schizophrenia in Denmark","volume":"78","author":"Hjorth\u00f8j","year":"2021","journal-title":"JAMA Psychiatry"},{"key":"ref69","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1186\/2041-9139-4-27","article-title":"Evolution of bilaterian central nervous systems: a single origin?","volume":"4","author":"Holland","year":"2013","journal-title":"EvoDevo"},{"key":"ref70","doi-asserted-by":"publisher","first-page":"655","DOI":"10.1016\/j.cell.2020.01.008","article-title":"Activation and signaling mechanism revealed by cannabinoid receptor-Gi complex structures","volume":"180","author":"Hua","year":"2020","journal-title":"Cell"},{"key":"ref71","doi-asserted-by":"publisher","first-page":"468","DOI":"10.1038\/nature23272","article-title":"Crystal structures of agonist-bound human cannabinoid receptor CB1","volume":"547","author":"Hua","year":"2017","journal-title":"Nature"},{"key":"ref72","doi-asserted-by":"publisher","first-page":"1131","DOI":"10.1021\/cn5000524","article-title":"Nonpsychotropic plant cannabinoids, Cannabidivarin (CBDV) and Cannabidiol (CBD), activate and desensitize transient receptor potential Vanilloid 1 (TRPV1) channels in vitro: potential for the treatment of neuronal Hyperexcitability","volume":"5","author":"Iannotti","year":"2014","journal-title":"ACS Chem. 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Lett."},{"key":"ref82","doi-asserted-by":"publisher","first-page":"e61462","DOI":"10.1371\/journal.pone.0061462","article-title":"Microarray and pathway analysis reveal distinct mechanisms underlying cannabinoid-mediated modulation of LPS-induced activation of BV-2 microglial cells","volume":"8","author":"Juknat","year":"2013","journal-title":"PLoS One"},{"key":"ref83","doi-asserted-by":"publisher","first-page":"1080","DOI":"10.1038\/ncomms2045","article-title":"Uncoupling of the endocannabinoid signalling complex in a mouse model of fragile X syndrome","volume":"3","author":"Jung","year":"2012","journal-title":"Nat. Commun."},{"key":"ref84","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1152\/physrev.00019.2008","article-title":"Endocannabinoid-mediated control of synaptic transmission","volume":"89","author":"Kano","year":"2009","journal-title":"Physiol. Rev."},{"key":"ref85","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1186\/s13229-018-0203-y","article-title":"Plasma anandamide concentrations are lower in children with autism spectrum disorder","volume":"9","author":"Karhson","year":"2018","journal-title":"Mol. Autism."},{"key":"ref86","doi-asserted-by":"publisher","first-page":"845","DOI":"10.1038\/nprot.2015.053","article-title":"The Phyre2 web portal for protein modeling, prediction and analysis","volume":"10","author":"Kelley","year":"2015","journal-title":"Nat. Protoc."},{"key":"ref87","doi-asserted-by":"publisher","first-page":"363","DOI":"10.1038\/nprot.2009.2","article-title":"Protein structure prediction on the web: a case study using the Phyre server","volume":"4","author":"Kelley","year":"2009","journal-title":"Nat. Protoc."},{"key":"ref88","doi-asserted-by":"publisher","first-page":"975","DOI":"10.3390\/ijms23020975","article-title":"New insights and potential therapeutic targeting of CB2 cannabinoid receptors in CNS disorders","volume":"23","author":"Kibret","year":"2022","journal-title":"Int. J. Mol. Sci."},{"key":"ref89","doi-asserted-by":"publisher","first-page":"442","DOI":"10.3389\/fncel.2019.00442","article-title":"Activation of TRPV1 contributes to recurrent febrile seizures via inhibiting the microglial M2 phenotype in the immature brain","volume":"13","author":"Kong","year":"2019","journal-title":"Front. Cell. Neurosci."},{"key":"ref90","doi-asserted-by":"publisher","first-page":"2672","DOI":"10.1038\/s41467-023-37864-4","article-title":"Structural basis for activation of CB1 by an endocannabinoid analog","volume":"14","author":"Krishna Kumar","year":"2023","journal-title":"Nat. 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Evol."},{"key":"ref94","doi-asserted-by":"publisher","first-page":"6079","DOI":"10.3390\/ijms20236079","article-title":"The interplay between the endocannabinoid system, epilepsy and cannabinoids","volume":"20","author":"Kwan Cheung","year":"2019","journal-title":"Int. J. Mol. Sci."},{"key":"ref95","doi-asserted-by":"publisher","first-page":"2874","DOI":"10.1038\/s41467-022-30602-2","article-title":"Vanilloid-dependent TRPV1 opening trajectory from cryoEM ensemble analysis","volume":"13","author":"Kwon","year":"2022","journal-title":"Nat. Commun."},{"key":"ref96","doi-asserted-by":"publisher","first-page":"649","DOI":"10.1093\/bja\/aei098","article-title":"Characterization and comparison of recombinant human and rat TRPV1 receptors: effects of exo- and endocannabinoids\u2020","volume":"94","author":"Lam","year":"2005","journal-title":"Br. J. Anaesth."},{"key":"ref97","doi-asserted-by":"publisher","first-page":"2693","DOI":"10.4103\/1673-5374.335821","article-title":"Cannabidiol preferentially binds TRPV2: a novel mechanism of action","volume":"17","author":"Landucci","year":"2022","journal-title":"Neural Regen. Res."},{"key":"ref98","doi-asserted-by":"publisher","first-page":"4790","DOI":"10.1111\/bph.13250","article-title":"Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor","volume":"172","author":"Laprairie","year":"2015","journal-title":"Br. J. Pharmacol."},{"key":"ref99","doi-asserted-by":"publisher","first-page":"2699","DOI":"10.1073\/pnas.0711278105","article-title":"GPR55 is a cannabinoid receptor that increases intracellular calcium and inhibits M current","volume":"105","author":"Lauckner","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref100","doi-asserted-by":"publisher","first-page":"416","DOI":"10.3390\/biomedicines10020416","article-title":"Increased TRPV1 channels and FosB protein expression are associated with chronic epileptic seizures and Anxiogenic-like behaviors in a preclinical model of temporal lobe epilepsy","volume":"10","author":"Lazarini-Lopes","year":"2022","journal-title":"Biomedicines"},{"key":"ref101","doi-asserted-by":"publisher","first-page":"634","DOI":"10.1016\/j.neuint.2011.01.027","article-title":"Capsaicin prevents kainic acid-induced epileptogenesis in mice","volume":"58","author":"Lee","year":"2011","journal-title":"Neurochem. Int."},{"key":"ref102","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1016\/j.schres.2007.04.025","article-title":"Anandamide levels in cerebrospinal fluid of first-episode schizophrenic patients: impact of cannabis use","volume":"94","author":"Leweke","year":"2007","journal-title":"Schizophr. Res."},{"key":"ref103","doi-asserted-by":"publisher","first-page":"581","DOI":"10.1242\/jeb.110817","article-title":"Elements of a \u201cnervous system\u201d in sponges","volume":"218","author":"Leys","year":"2015","journal-title":"J. Exp. Biol."},{"key":"ref104","doi-asserted-by":"publisher","first-page":"731","DOI":"10.1038\/s41467-022-28417-2","article-title":"Differential activation mechanisms of lipid GPCRs by lysophosphatidic acid and sphingosine 1-phosphate","volume":"13","author":"Liu","year":"2022","journal-title":"Nat. Commun."},{"key":"ref105","doi-asserted-by":"publisher","first-page":"516","DOI":"10.1016\/j.biopsych.2015.07.028","article-title":"An introduction to the endogenous cannabinoid system","volume":"79","author":"Lu","year":"2016","journal-title":"Biol. Psychiatry"},{"key":"ref106","doi-asserted-by":"publisher","first-page":"1488","DOI":"10.1002\/ajmg.b.30693","article-title":"Association of the cannabinoid receptor gene (CNR1) with ADHD and post-traumatic stress disorder","author":"Lu","year":"2008","journal-title":"Am. J. Med. Genet. B Neuropsychiatr. Genet."},{"key":"ref107","doi-asserted-by":"publisher","first-page":"2976","DOI":"10.1523\/JNEUROSCI.4465-07.2008","article-title":"Downregulation of the CB1 cannabinoid receptor and related molecular elements of the endocannabinoid system in epileptic human hippocampus","volume":"28","author":"Lud\u00e1nyi","year":"2008","journal-title":"J. Neurosci."},{"key":"ref108","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1038\/sj.bjp.0705931","article-title":"Marijuana and cannabinoid regulation of brain reward circuits","volume":"143","author":"Lupica","year":"2004","journal-title":"Br. J. Pharmacol."},{"key":"ref109","doi-asserted-by":"publisher","first-page":"841","DOI":"10.1126\/science.288.5467.841","article-title":"Age of Neoproterozoic bilatarian body and trace fossils, White Sea, Russia: implications for metazoan evolution","volume":"288","author":"Martin","year":"2000","journal-title":"Science"},{"key":"ref110","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1038\/nature25030","article-title":"Convergent evolution of bilaterian nerve cords","volume":"553","author":"Mart\u00edn-Dur\u00e1n","year":"2018","journal-title":"Nature"},{"key":"ref111","doi-asserted-by":"publisher","first-page":"172","DOI":"10.1016\/j.neuroscience.2021.12.013","article-title":"Targeting endocannabinoid system in epilepsy: for good or for bad","volume":"482","author":"Mart\u00ednez-Aguirre","year":"2022","journal-title":"Neuroscience"},{"key":"ref112","doi-asserted-by":"publisher","first-page":"561","DOI":"10.1038\/346561a0","article-title":"Structure of a cannabinoid receptor and functional expression of the cloned cDNA","volume":"346","author":"Matsuda","year":"1990","journal-title":"Nature"},{"key":"ref113","doi-asserted-by":"publisher","first-page":"151","DOI":"10.3390\/foods10010151","article-title":"A luminescence-based human TRPV1 assay system for quantifying pungency in spicy foods","volume":"10","author":"Matsuyama","year":"2021","journal-title":"Food Secur."},{"key":"ref114","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1016\/j.neuropharm.2007.05.028","article-title":"Identification of the sites of 2-arachidonoylglycerol synthesis and action imply retrograde endocannabinoid signaling at both GABAergic and glutamatergic synapses in the ventral tegmental area","volume":"54","author":"M\u00e1ty\u00e1s","year":"2008","journal-title":"Neuropharmacology"},{"key":"ref115","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1186\/1471-2202-11-44","article-title":"N-arachidonoyl glycine, an abundant endogenous lipid, potently drives directed cellular migration through GPR18, the putative abnormal cannabidiol receptor","volume":"11","author":"McHugh","year":"2010","journal-title":"BMC Neurosci."},{"key":"ref116","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1016\/j.brainresrev.2003.11.005","article-title":"Phylogenomic and chemotaxonomic analysis of the endocannabinoid system","volume":"45","author":"McPartland","year":"2004","journal-title":"Brain Res. Brain Res. Rev."},{"key":"ref117","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1038\/sj.bjp.0707399","article-title":"Meta-analysis of cannabinoid ligand binding affinity and receptor distribution: interspecies differences","volume":"152","author":"McPartland","year":"2007","journal-title":"Br. J. Pharmacol."},{"key":"ref118","first-page":"71","article-title":"The evolution of Cannabis and coevolution with the cannabinoid receptor - a hypothesis","volume-title":"The medicinal use of Cannabis","author":"McPartland","year":"2004"},{"key":"ref119","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1016\/j.gene.2005.11.004","article-title":"Evolutionary origins of the endocannabinoid system","volume":"370","author":"McPartland","year":"2006","journal-title":"Gene"},{"key":"ref120","doi-asserted-by":"publisher","first-page":"5295","DOI":"10.1523\/JNEUROSCI.4810-07.2008","article-title":"Mechanisms of prolonged presynaptic Ca2+ signaling and glutamate release induced by TRPV1 activation in rat sensory neurons","volume":"28","author":"Medvedeva","year":"2008","journal-title":"J. Neurosci."},{"key":"ref121","doi-asserted-by":"publisher","first-page":"3699","DOI":"10.1111\/bph.14435","article-title":"Sex-specific autistic endophenotypes induced by prenatal exposure to valproic acid involve anandamide signalling","volume":"175","author":"Melancia","year":"2018","journal-title":"Br. J. Pharmacol."},{"key":"ref122","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1016\/j.neulet.2019.05.033","article-title":"CB1R mediates oleamide\u2019s reward while 5HT2cR mediates aversion in the nucleus accumbens shell of rats","volume":"706","author":"M\u00e9ndez-D\u00edaz","year":"2019","journal-title":"Neurosci. Lett."},{"key":"ref123","doi-asserted-by":"publisher","first-page":"914","DOI":"10.1001\/jamapsychiatry.2019.0970","article-title":"Measuring disturbance of the endocannabinoid system in psychosis: a systematic review and Meta-analysis","volume":"76","author":"Minichino","year":"2019","journal-title":"JAMA Psychiatry"},{"key":"ref124","doi-asserted-by":"publisher","first-page":"50080","DOI":"10.1074\/jbc.M306619200","article-title":"Desensitization of capsaicin-activated currents in the Vanilloid receptor TRPV1 is decreased by the cyclic AMP-dependent protein kinase pathway*","volume":"278","author":"Mohapatra","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref125","doi-asserted-by":"publisher","first-page":"841190","DOI":"10.3389\/fmolb.2022.841190","article-title":"Targeting CB2 and TRPV1: computational approaches for the identification of dual modulators","volume":"9","author":"Morales","year":"2022","journal-title":"Front. Mol. Biosci."},{"key":"ref126","doi-asserted-by":"publisher","first-page":"362","DOI":"10.1016\/j.conb.2004.05.003","article-title":"TRP ion channels in the nervous system","volume":"14","author":"Moran","year":"2004","journal-title":"Curr. Opin. Neurobiol."},{"key":"ref127","doi-asserted-by":"publisher","first-page":"598","DOI":"10.1242\/jeb.110692","article-title":"Convergent evolution of neural systems in ctenophores","volume":"218","author":"Moroz","year":"2015","journal-title":"J. Exp. Biol."},{"key":"ref128","doi-asserted-by":"publisher","first-page":"1132","DOI":"10.1177\/0269881119857205","article-title":"Endocannabinoid system imbalance in the postmortem prefrontal cortex of subjects with schizophrenia","volume":"33","author":"Muguruza","year":"2019","journal-title":"J. Psychopharmacol."},{"key":"ref129","doi-asserted-by":"publisher","first-page":"144","DOI":"10.3389\/fmolb.2020.00144","article-title":"A closer look at anandamide interaction with TRPV1","volume":"7","author":"Muller","year":"2020","journal-title":"Front. Mol. Biosci."},{"key":"ref130","doi-asserted-by":"publisher","first-page":"487","DOI":"10.3389\/fnmol.2018.00487","article-title":"Cannabinoid ligands targeting TRP channels","volume":"11","author":"Muller","year":"2019","journal-title":"Front. Mol. Neurosci."},{"key":"ref131","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1038\/365061a0","article-title":"Molecular characterization of a peripheral receptor for cannabinoids","volume":"365","author":"Munro","year":"1993","journal-title":"Nature"},{"key":"ref132","doi-asserted-by":"publisher","first-page":"717","DOI":"10.1126\/science.abj2949","article-title":"Profiling cellular diversity in sponges informs animal cell type and nervous system evolution","volume":"374","author":"Musser","year":"2021","journal-title":"Science"},{"key":"ref133","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1093\/carcin\/bgs328","article-title":"Triggering of the TRPV2 channel by cannabidiol sensitizes glioblastoma cells to cytotoxic chemotherapeutic agents","volume":"34","author":"Nabissi","year":"2013","journal-title":"Carcinogenesis"},{"key":"ref134","doi-asserted-by":"publisher","first-page":"2154","DOI":"10.1038\/s41467-021-22507-3","article-title":"Extracellular cap domain is an essential component of the TRPV1 gating mechanism","volume":"12","author":"Nadezhdin","year":"2021","journal-title":"Nat. Commun."},{"key":"ref135","doi-asserted-by":"publisher","first-page":"4764","DOI":"10.3390\/ijms23094764","article-title":"Molecular alterations of the endocannabinoid system in psychiatric disorders","volume":"23","author":"Navarro","year":"2022","journal-title":"Int. J. Mol. Sci."},{"key":"ref136","doi-asserted-by":"publisher","first-page":"1744-8069-1-28","DOI":"10.1186\/1744-8069-1-28","article-title":"Acidification of rat TRPV1 alters the kinetics of capsaicin responses","volume":"1","author":"Neelands","year":"2005","journal-title":"Mol. Pain"},{"key":"ref137","doi-asserted-by":"publisher","first-page":"2451","DOI":"10.1038\/s41467-023-38162-9","article-title":"Human TRPV1 structure and inhibition by the analgesic SB-366791","volume":"14","author":"Neuberger","year":"2023","journal-title":"Nat. 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Commun."},{"key":"ref141","doi-asserted-by":"publisher","first-page":"1067493","DOI":"10.3389\/fnins.2022.1067493","article-title":"Chronic \u03949-tetrahydrocannabinol impact on plasticity, and differential activation requirement for CB1-dependent long-term depression in ventral tegmental area GABA neurons in adult versus young mice","volume":"16","author":"Ostlund","year":"2022","journal-title":"Front. Neurosci."},{"key":"ref142","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1016\/j.cmet.2006.02.004","article-title":"Deorphanization of a G protein-coupled receptor for oleoylethanolamide and its use in the discovery of small-molecule hypophagic agents","volume":"3","author":"Overton","year":"2006","journal-title":"Cell Metab."},{"key":"ref143","doi-asserted-by":"publisher","first-page":"eaax5858","DOI":"10.1126\/sciadv.aax5858","article-title":"Canadia spinosa and the early evolution of the annelid nervous system","volume":"5","author":"Parry","year":"2019","journal-title":"Sci. Adv."},{"key":"ref144","doi-asserted-by":"publisher","first-page":"104709","DOI":"10.1016\/j.neuint.2020.104709","article-title":"Capsaicin inhibits sodium currents and epileptiform activity in prefrontal cortex pyramidal neurons","volume":"135","author":"Pasierski","year":"2020","journal-title":"Neurochem. Int."},{"key":"ref145","doi-asserted-by":"publisher","first-page":"6969","DOI":"10.1038\/s41467-022-34204-w","article-title":"Ordovician opabiniid-like animals and the role of the proboscis in euarthropod head evolution","volume":"13","author":"Pates","year":"2022","journal-title":"Nat. Commun."},{"key":"ref146","doi-asserted-by":"publisher","first-page":"1693","DOI":"10.1126\/science.1216295","article-title":"Bilaterian burrows and grazing behavior at >585 million years ago","volume":"336","author":"Pecoits","year":"2012","journal-title":"Science"},{"key":"ref147","doi-asserted-by":"publisher","first-page":"6825","DOI":"10.1038\/srep06825","article-title":"Dampened neural activity and abolition of epileptic-like activity in cortical slices by active ingredients of spices","volume":"4","author":"Pezzoli","year":"2014","journal-title":"Sci. Rep."},{"key":"ref148","doi-asserted-by":"publisher","first-page":"232","DOI":"10.1038\/tpj.2009.59","article-title":"Association of polymorphisms of the cannabinoid receptor (CNR1) and fatty acid amide hydrolase (FAAH) genes with heroin addiction: impact of long repeats of CNR1","volume":"10","author":"Proudnikov","year":"2010","journal-title":"Pharmacogenomics J."},{"key":"ref149","doi-asserted-by":"publisher","first-page":"6231","DOI":"10.1523\/JNEUROSCI.0504-08.2008","article-title":"TRPV2 is activated by Cannabidiol and mediates CGRP release in cultured rat dorsal root ganglion neurons","volume":"28","author":"Qin","year":"2008","journal-title":"J. Neurosci."},{"key":"ref150","year":"2013"},{"key":"ref151","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1186\/s13073-017-0458-5","article-title":"Post-mortem molecular profiling of three psychiatric disorders","volume":"9","author":"Ramaker","year":"2017","journal-title":"Genome Med."},{"key":"ref152","doi-asserted-by":"publisher","first-page":"997","DOI":"10.1016\/j.biopsych.2015.08.021","article-title":"Reduced brain cannabinoid receptor availability in schizophrenia","volume":"79","author":"Ranganathan","year":"2016","journal-title":"Biol. Psychiatry"},{"key":"ref153","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1016\/j.pbb.2017.06.010","article-title":"\u03949-tetrahydrocannabinol (\u03949-THC) administration after neonatal exposure to phencyclidine potentiates schizophrenia-related behavioral phenotypes in mice","volume":"159","author":"Rodr\u00edguez","year":"2017","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref154","year":"2020"},{"key":"ref155","doi-asserted-by":"publisher","first-page":"2382","DOI":"10.1210\/jc.2006-2523","article-title":"Genetic variations at the endocannabinoid type 1 receptor gene (CNR1) are associated with obesity phenotypes in men","volume":"92","author":"Russo","year":"2007","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref156","doi-asserted-by":"publisher","first-page":"1092","DOI":"10.1038\/sj.bjp.0707460","article-title":"The orphan receptor GPR55 is a novel cannabinoid receptor","volume":"152","author":"Ryberg","year":"2007","journal-title":"Br. J. 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Biol. Chem."},{"key":"ref160","doi-asserted-by":"publisher","first-page":"msac180","DOI":"10.1093\/molbev\/msac180","article-title":"Evolutionary tuning of transient receptor potential Ankyrin 1 underlies the variation in heat avoidance behaviors among frog species inhabiting diverse thermal niches","volume":"39","author":"Saito","year":"2022","journal-title":"Mol. Biol. Evol."},{"key":"ref161","doi-asserted-by":"publisher","first-page":"100478","DOI":"10.1016\/j.xpro.2021.100478","article-title":"Analysis workflow of publicly available RNA-sequencing datasets","volume":"2","author":"Sanchis","year":"2021","journal-title":"STAR Protoc."},{"key":"ref162","doi-asserted-by":"publisher","first-page":"955","DOI":"10.1016\/j.euroneuro.2018.05.008","article-title":"Chronic exposure to cannabinoids before an emotional trauma may have negative effects on emotional function","volume":"28","author":"Sbarski","year":"2018","journal-title":"Eur. Neuropsychopharmacol."},{"key":"ref163","author":"Schr\u00f6dinger","year":"2020"},{"key":"ref164","doi-asserted-by":"publisher","first-page":"e0230238","DOI":"10.1371\/journal.pone.0230238","article-title":"Differential effects of \u03949-tetrahydrocannabinol dosing on correlates of schizophrenia in the sub-chronic PCP rat model","volume":"15","author":"Seillier","year":"2020","journal-title":"PLoS One"},{"key":"ref165","doi-asserted-by":"publisher","first-page":"e902","DOI":"10.1038\/tp.2016.182","article-title":"Targeting anandamide metabolism rescues core and associated autistic-like symptoms in rats prenatally exposed to valproic acid","volume":"6","author":"Servadio","year":"2016","journal-title":"Transl. 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Commun."},{"key":"ref169","doi-asserted-by":"publisher","first-page":"108","DOI":"10.3390\/biom12010108","article-title":"Early blockade of CB1 receptors ameliorates schizophrenia-like alterations in the neurodevelopmental MAM model of schizophrenia","volume":"12","author":"Stark","year":"2022","journal-title":"Biomol. Ther."},{"key":"ref170","doi-asserted-by":"publisher","first-page":"172","DOI":"10.1080\/19336950.2019.1619436","article-title":"Diverse TRPV1 responses to cannabinoids","volume":"13","author":"Starkus","year":"2019","journal-title":"Channels (Austin)"},{"key":"ref171","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1016\/s0006-8993(96)01484-9","article-title":"Identification and characterization of the leech CNS cannabinoid receptor: coupling to nitric oxide release","volume":"753","author":"Stefano","year":"1997","journal-title":"Brain Res."},{"key":"ref172","doi-asserted-by":"publisher","first-page":"1.30.1","DOI":"10.1002\/cpbi.5","article-title":"The GeneCards suite: from gene data mining to disease genome sequence analyzes","volume":"54","author":"Stelzer","year":"2016","journal-title":"Curr. Protoc. Bioinformatics"},{"key":"ref173","doi-asserted-by":"publisher","first-page":"9610","DOI":"10.1038\/s41598-023-36710-3","article-title":"A collection of cannabinoid-related negative findings from autaptic hippocampal neurons","volume":"13","author":"Straiker","year":"2023","journal-title":"Sci. Rep."},{"key":"ref174","doi-asserted-by":"publisher","first-page":"734837","DOI":"10.3389\/fpsyt.2021.734837","article-title":"Endocannabinoid system unlocks the puzzle of autism treatment via microglia","volume":"12","author":"Su","year":"2021","journal-title":"Front. Psych."},{"key":"ref175","doi-asserted-by":"publisher","first-page":"781113","DOI":"10.3389\/fncir.2021.781113","article-title":"Endocannabinoid-mediated control of neural circuit excitability and epileptic seizures","volume":"15","author":"Sugaya","year":"2022","journal-title":"Front. Neural Circuits"},{"key":"ref176","doi-asserted-by":"publisher","first-page":"5193","DOI":"10.1073\/pnas.1211204110","article-title":"Cannabinoid- and lysophosphatidylinositol-sensitive receptor GPR55 boosts neurotransmitter release at central synapses","volume":"110","author":"Sylantyev","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref177","doi-asserted-by":"publisher","first-page":"D607","DOI":"10.1093\/nar\/gky1131","article-title":"STRING v11: protein\u2013protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets","volume":"47","author":"Szklarczyk","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref178","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1016\/j.neulet.2016.09.020","article-title":"Decreased CB receptor binding and cannabinoid signaling in three brain regions of a rat model of schizophrenia","volume":"633","author":"Sz\u0171cs","year":"2016","journal-title":"Neurosci. Lett."},{"key":"ref179","doi-asserted-by":"publisher","first-page":"87","DOI":"10.3389\/fneur.2020.00087","article-title":"Endocannabinoid modulation of microglial phenotypes in neuropathology","volume":"11","author":"Tanaka","year":"2020","journal-title":"Front. Neurol."},{"key":"ref180","doi-asserted-by":"publisher","first-page":"613","DOI":"10.1038\/sj.bjp.0707133","article-title":"Cannabidiol displays unexpectedly high potency as an antagonist of CB1 and CB2 receptor agonists in vitro","volume":"150","author":"Thomas","year":"2007","journal-title":"Br. J. Pharmacol."},{"key":"ref181","doi-asserted-by":"publisher","first-page":"531","DOI":"10.1016\/s0896-6273(00)80564-4","article-title":"The cloned capsaicin receptor integrates multiple pain-producing stimuli","volume":"21","author":"Tominaga","year":"1998","journal-title":"Neuron"},{"key":"ref182","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization and multithreading","volume":"31","author":"Trott","year":"2010","journal-title":"J. Comput. Chem."},{"key":"ref183","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1007\/s00213-009-1608-2","article-title":"Immunodensity and mRNA expression of A2A adenosine, D2 dopamine, and CB1 cannabinoid receptors in postmortem frontal cortex of subjects with schizophrenia: effect of antipsychotic treatment","volume":"206","author":"Urig\u00fcen","year":"2009","journal-title":"Psychopharmacology"},{"key":"ref184","doi-asserted-by":"publisher","first-page":"410a","DOI":"10.1016\/j.bpj.2019.11.2321","article-title":"Inhibition of inositol Monophosphatase enhances TRPV1 function in vivo","volume":"118","author":"Vasquez","year":"2020","journal-title":"Biophys. J."},{"key":"ref185","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1186\/1744-8069-2-22","article-title":"The \u03bc opioid agonist morphine modulates potentiation of capsaicin-evoked TRPV1 responses through a cyclic AMP-dependent protein kinase a pathway","volume":"2","author":"Vetter","year":"2006","journal-title":"Mol. Pain"},{"key":"ref186","doi-asserted-by":"publisher","first-page":"748","DOI":"10.1038\/nature02732","article-title":"The principle of temperature-dependent gating in cold- and heat-sensitive TRP channels","volume":"430","author":"Voets","year":"2004","journal-title":"Nature"},{"key":"ref187","doi-asserted-by":"publisher","first-page":"214","DOI":"10.1186\/s12974-019-1618-x","article-title":"TRPV1 translocated to astrocytic membrane to promote migration and inflammatory infiltration thus promotes epilepsy after hypoxic ischemia in immature brain","volume":"16","author":"Wang","year":"2019","journal-title":"J. Neuroinflammation"},{"key":"ref188","doi-asserted-by":"publisher","first-page":"434","DOI":"10.1038\/nature01807","article-title":"Anandamide and arachidonic acid use epoxyeicosatrienoic acids to activate TRPV4 channels","volume":"424","author":"Watanabe","year":"2003","journal-title":"Nature"},{"key":"ref189","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1089\/can.2015.0008","article-title":"Enhancement of anandamide-mediated endocannabinoid signaling corrects autism-related social impairment","volume":"1","author":"Wei","year":"2016","journal-title":"Cannabis Cannabinoid Res."},{"key":"ref190","doi-asserted-by":"publisher","first-page":"588","DOI":"10.1038\/35069076","article-title":"Endogenous cannabinoids mediate retrograde signalling at hippocampal synapses","volume":"410","author":"Wilson","year":"2001","journal-title":"Nature"},{"key":"ref191","doi-asserted-by":"publisher","first-page":"1505","DOI":"10.1016\/j.neuroimage.2010.04.034","article-title":"Quantification of cerebral cannabinoid receptors subtype 1 (CB1) in healthy subjects and schizophrenia by the novel PET radioligand [11C]OMAR","volume":"52","author":"Wong","year":"2010","journal-title":"NeuroImage"},{"key":"ref192","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1016\/j.celrep.2014.12.005","article-title":"Input- and cell type-specific endocannabinoid-dependent LTD in the striatum","volume":"10","author":"Wu","year":"2015","journal-title":"Cell Rep."},{"key":"ref193","doi-asserted-by":"publisher","first-page":"107736","DOI":"10.1016\/j.neuropharm.2019.107736","article-title":"Targeting the inhibition of fatty acid amide hydrolase ameliorate the endocannabinoid-mediated synaptic dysfunction in a valproic acid-induced rat model of autism","volume":"162","author":"Wu","year":"2020","journal-title":"Neuropharmacology"},{"key":"ref194","doi-asserted-by":"publisher","first-page":"msac051","DOI":"10.1093\/molbev\/msac051","article-title":"Premetazoan origin of neuropeptide signaling","volume":"39","author":"Ya\u00f1ez-Guerra","year":"2022","journal-title":"Mol. Biol. Evol."},{"key":"ref195","doi-asserted-by":"publisher","first-page":"2988","DOI":"10.1073\/pnas.1522434113","article-title":"Fuxianhuiid ventral nerve cord and early nervous system evolution in Panarthropoda","volume":"113","author":"Yang","year":"2016","journal-title":"Proc. Natl. Acad. Sci."},{"key":"ref196","doi-asserted-by":"publisher","first-page":"468","DOI":"10.1038\/nature11874","article-title":"Specialized appendages in fuxianhuiids and the head organization of early euarthropods","volume":"494","author":"Yang","year":"2013","journal-title":"Nature"},{"key":"ref197","doi-asserted-by":"publisher","first-page":"367","DOI":"10.3389\/fncel.2019.00367","article-title":"Cannabidivarin treatment ameliorates autism-like behaviors and restores hippocampal endocannabinoid system and glia alterations induced by prenatal Valproic acid exposure in rats","volume":"13","author":"Zamberletti","year":"2019","journal-title":"Front. Cell. 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