{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T19:45:11Z","timestamp":1791229511340,"version":"4.1.0"},"reference-count":185,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2022,9,2]],"date-time":"2022-09-02T00:00:00Z","timestamp":1662076800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health to LSP","award":["DA028017"],"award-info":[{"award-number":["DA028017"]}]},{"name":"National Institutes of Health to LSP","award":["R43DK117674"],"award-info":[{"award-number":["R43DK117674"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The most common medicinal claims for cannabis are relief from chronic pain, stimulation of appetite, and as an antiemetic. However, the mechanisms by which cannabis reduces pain and prevents nausea and vomiting are not fully understood. Among more than 450 constituents in cannabis, the most abundant cannabinoids are \u03949-tetrahydrocannabinol (THC) and cannabidiol (CBD). Cannabinoids either directly or indirectly modulate ion channel function. Transient receptor potential vanilloid 1 (TRPV1) is an ion channel responsible for mediating several modalities of pain, and it is expressed in both the peripheral and the central pain pathways. Activation of TRPV1 in sensory neurons mediates nociception in the ascending pain pathway, while activation of TRPV1 in the central descending pain pathway, which involves the rostral ventral medulla (RVM) and the periaqueductal gray (PAG), mediates antinociception. TRPV1 channels are thought to be implicated in neuropathic\/spontaneous pain perception in the setting of impaired descending antinociceptive control. Activation of TRPV1 also can cause the release of calcitonin gene-related peptide (CGRP) and other neuropeptides\/neurotransmitters from the peripheral and central nerve terminals, including the vagal nerve terminal innervating the gut that forms central synapses at the nucleus tractus solitarius (NTS). One of the adverse effects of chronic cannabis use is the paradoxical cannabis-induced hyperemesis syndrome (HES), which is becoming more common, perhaps due to the wider availability of cannabis-containing products and the chronic use of products containing higher levels of cannabinoids. Although, the mechanism of HES is unknown, the effective treatment options include hot-water hydrotherapy and the topical application of capsaicin, both activate TRPV1 channels and may involve the vagal-NTS and area postrema (AP) nausea and vomiting pathway. In this review, we will delineate the activation of TRPV1 by cannabinoids and their role in the antinociceptive\/nociceptive and antiemetic\/emetic effects involving the peripheral, spinal, and supraspinal structures.<\/jats:p>","DOI":"10.3390\/ijms231710016","type":"journal-article","created":{"date-parts":[[2022,9,6]],"date-time":"2022-09-06T05:17:23Z","timestamp":1662441443000},"page":"10016","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":53,"title":["TRPV1: A Common Denominator Mediating Antinociceptive and Antiemetic Effects of Cannabinoids"],"prefix":"10.3390","volume":"23","author":[{"given":"Kathleen","family":"Louis-Gray","sequence":"first","affiliation":[{"name":"Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Srinivasan","family":"Tupal","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Southern Illinois University School of Medicine, Springfield, IL 62794, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louis S.","family":"Premkumar","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Southern Illinois University School of Medicine, Springfield, IL 62794, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2474","DOI":"10.1001\/jama.2015.6199","article-title":"Medical Marijuana for Treatment of Chronic Pain and Other Medical and Psychiatric Problems: A Clinical Review","volume":"313","author":"Hill","year":"2015","journal-title":"JAMA"},{"key":"ref_2","first-page":"e78","article-title":"Systematic review of systematic reviews for medical cannabinoids: Pain, nausea and vomiting, spasticity, and harms","volume":"64","author":"Allan","year":"2018","journal-title":"Can. Fam. Physician"},{"key":"ref_3","first-page":"1","article-title":"Phytochemistry of Cannabis sativa L","volume":"103","author":"ElSohly","year":"2017","journal-title":"Prog. Chem. Org. Nat. Prod."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1089\/can.2016.0027","article-title":"A Short Guide for Nonbotanists","volume":"1","author":"Pollio","year":"2016","journal-title":"Cannabis Cannabinoid Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1038\/sj.bjp.0707442","article-title":"The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: Delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin","volume":"153","author":"Pertwee","year":"2008","journal-title":"Br. J. Pharmacol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/bs.apha.2017.03.007","article-title":"CB1 and CB2 Receptor Pharmacology","volume":"201","author":"Howlett","year":"2017","journal-title":"Adv. Pharmacol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1089\/can.2016.0037","article-title":"Cannabinoid CB1 and CB2 Receptor Signaling and Bias","volume":"2","author":"Ibsen","year":"2017","journal-title":"Cannabis Cannabinoid Res."},{"key":"ref_8","first-page":"e3278","article-title":"Epilepsy and Cannabis: A Literature Review","volume":"10","author":"Zaheer","year":"2018","journal-title":"Cureus"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1111\/epi.12631","article-title":"Cannabidiol: Pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders","volume":"55","author":"Devinsky","year":"2014","journal-title":"Epilepsia"},{"key":"ref_10","doi-asserted-by":"crossref","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. Neurosci."},{"key":"ref_11","doi-asserted-by":"crossref","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":"ref_12","doi-asserted-by":"crossref","first-page":"1479","DOI":"10.1111\/j.1476-5381.2010.01166.x","article-title":"Effects of cannabinoids and cannabinoid-enriched Cannabis extracts on TRP channels and endocannabinoid metabolic enzymes","volume":"163","author":"Ligresti","year":"2011","journal-title":"Br. J. Pharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"234","DOI":"10.12688\/f1000research.16515.1","article-title":"Epidiolex as adjunct therapy for treatment of refractory epilepsy: A comprehensive review with a focus on adverse effects","volume":"8","author":"Sekar","year":"2019","journal-title":"F1000Research"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.eplepsyres.2016.10.016","article-title":"TRPV1 deletion exacerbates hyperthermic seizures in an age-dependent manner in mice","volume":"128","author":"Barrett","year":"2016","journal-title":"Epilepsy Res."},{"key":"ref_15","doi-asserted-by":"crossref","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":"ref_16","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1038\/35050121","article-title":"Induction of vanilloid receptor channel activity by protein kinase C","volume":"408","author":"Premkumar","year":"2000","journal-title":"Nature"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.resp.2004.08.001","article-title":"Substance P expression in TRPV1 and trkA-positive dorsal root ganglion neurons innervating the mouse lung. Respir","volume":"144","author":"Dinh","year":"2004","journal-title":"Physiol. Neurobiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1159\/000087656","article-title":"Spinal and supraspinal contributions to central sensitization in peripheral neuropathy","volume":"14","author":"Suzuki","year":"2005","journal-title":"Neurosignals"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1016\/j.lfs.2012.08.010","article-title":"TRP channels and analgesia","volume":"92","author":"Premkumar","year":"2013","journal-title":"Life Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1097\/j.pain.0000000000001386","article-title":"Cannabidiol modulates serotonergic transmission and reverses both allodynia and anxiety-like behavior in a model of neuropathic pain","volume":"160","author":"McLaughlin","year":"2019","journal-title":"Pain"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1146\/annurev-cellbio-101011-155833","article-title":"TRP channels and pain","volume":"29","author":"Julius","year":"2013","journal-title":"Annu. Rev. Cell. Dev. Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.coph.2011.10.022","article-title":"Transient receptor potential vanilloid type 1 and pain development","volume":"12","author":"Palazzo","year":"2012","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1093\/chemse\/bjh180","article-title":"TRP channels and thermosensation","volume":"30","author":"Patapoutian","year":"2005","journal-title":"Chem. Senses"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1146\/annurev.biochem.75.103004.142819","article-title":"TRP channels","volume":"76","author":"Venkatachalam","year":"2007","journal-title":"Annu. Rev. Biochem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/j.ceca.2005.06.028","article-title":"TRP channels: An overview","volume":"38","author":"Pedersen","year":"2005","journal-title":"Cell Calcium"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e7021","DOI":"10.1371\/journal.pone.0007021","article-title":"Selective targeting of TRPV1 expressing sensory nerve terminals in the spinal cord for long lasting analgesia","volume":"9","author":"Jeffry","year":"2009","journal-title":"PLoS ONE"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1113\/jphysiol.2005.087874","article-title":"Activation of transient receptor potential vanilloid 1 (TRPV1) by resiniferatoxin","volume":"567","author":"Raisinghani","year":"2005","journal-title":"J. Physiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1113\/jphysiol.2002.016352","article-title":"Single-channel properties of native and cloned rat vanilloid receptors","volume":"545","author":"Premkumar","year":"2002","journal-title":"J. Physiol."},{"key":"ref_29","doi-asserted-by":"crossref","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":"ref_30","doi-asserted-by":"crossref","first-page":"32879","DOI":"10.1074\/jbc.M603220200","article-title":"Cannabinoid WIN 55,212-2 regulates TRPV1 phosphorylation in sensory neurons","volume":"281","author":"Jeske","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"11393","DOI":"10.1073\/pnas.0603861103","article-title":"The cannabinoid WIN 55,212-2 inhibits transient receptor potential vanilloid 1 (TRPV1) and evokes peripheral antihyperalgesia via calcineurin","volume":"103","author":"Patwardhan","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.eplepsyres.2016.02.005","article-title":"Involvement of TRPV1 channels in the activity of the cannabinoid WIN 55,212-2 in an acute rat model of temporal lobe epilepsy","volume":"122","author":"Carletti","year":"2016","journal-title":"Epilepsy Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1339","DOI":"10.2174\/1381612003399473","article-title":"Ajulemic acid (CT3): A potent analog of the acid metabolites of THC","volume":"6","author":"Burstein","year":"2000","journal-title":"Curr. Pharm. Des."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1446","DOI":"10.1038\/nn1210-1446","article-title":"Anandamide serves two masters in the brain","volume":"13","year":"2010","journal-title":"Nat. Neurosci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"12198","DOI":"10.1073\/pnas.96.21.12198","article-title":"Pain modulation by release of the endogenous cannabinoid anandamide","volume":"96","author":"Walker","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e6493","DOI":"10.7717\/peerj.6493","article-title":"Dual mechanism of TRKB activation by anandamide through CB1 and TRPV1 receptors","volume":"7","author":"Diniz","year":"2019","journal-title":"PeerJ"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1007\/978-3-540-34891-7_9","article-title":"Capsaicin receptor: TRPV1 a promiscuous TRP channel","volume":"179","author":"Pingle","year":"2007","journal-title":"Handb. Exp. Pharmacol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"7658","DOI":"10.1073\/pnas.96.14.7658","article-title":"Ion channels gated by heat","volume":"96","author":"Cesare","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"7407","DOI":"10.1523\/JNEUROSCI.3721-12.2013","article-title":"Disrupting sensitization of transient receptor potential vanilloid subtype 1 inhibits inflammatory hyperalgesia","volume":"33","author":"Fischer","year":"2013","journal-title":"J. Neurosci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1007\/s00406-019-01068-z","article-title":"Cannabis use and psychosis: A review of reviews","volume":"270","author":"Hasan","year":"2020","journal-title":"Eur. Arch. Psychiatry Clin. Neurosci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"833","DOI":"10.3389\/fpsyg.2020.00833","article-title":"Unraveling the Intoxicating and Therapeutic Effects of Cannabis Ingredients on Psychosis and Cognition","volume":"11","author":"Colizzi","year":"2020","journal-title":"Front. Psychol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1308","DOI":"10.1177\/0269881118799953","article-title":"The dose-dependent psychomotor effects of intravenous delta-9-tetrahydrocannabinol (\u03949THC) in humans","volume":"32","author":"Boggs","year":"2018","journal-title":"J. Psychopharmacol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1016\/j.mehy.2005.08.026","article-title":"A tale of two cannabinoids: The therapeutic rationale for combining tetrahydrocannabinol and cannabidiol","volume":"66","author":"Russo","year":"2006","journal-title":"Med. Hypotheses."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1558","DOI":"10.1038\/sj.npp.1300496","article-title":"The psychotomimetic effects of intravenous delta-9-tetrahydrocannabinol in healthy individuals: Implications for psychosis","volume":"29","author":"Perry","year":"2004","journal-title":"Neuropsychopharmacology"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1007\/s00213-006-0508-y","article-title":"The acute effects of cannabinoids on memory in humans: A review","volume":"188","author":"Ranganathan","year":"2006","journal-title":"Psychopharmacology"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1007\/s11920-015-0657-y","article-title":"Cannabis and Psychosis: A Critical Overview of the Relationship","volume":"18","author":"Ksir","year":"2016","journal-title":"Curr. Psychiatry Rep."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1016\/0091-3057(90)90028-G","article-title":"Acute and residual effects of marijuana: Profiles of plasma THC levels, physiological, subjective, and performance measures","volume":"37","author":"Heishman","year":"1990","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1007\/BF00690920","article-title":"Increased susceptibility to memory intrusions and the Stroop interference effect during acute marijuana intoxication","volume":"91","author":"Hooker","year":"1987","journal-title":"Psychopharmacology"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1159\/000026487","article-title":"The effects of tetrahydrocannabinol on the recognition of emotionally charged words: An analysis using event-related brain potentials","volume":"37","author":"Leweke","year":"1998","journal-title":"Neuropsychobiology"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1054\/plef.2001.0351","article-title":"Endocannabinoids in cognition and dependence","volume":"66","author":"Lichtman","year":"2002","journal-title":"Prostaglandins Leukot. Essent. Fatty Acids"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1126\/science.1063545","article-title":"Endocannabinoid signaling in the brain","volume":"296","author":"Wilson","year":"2002","journal-title":"Science"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"429","DOI":"10.3949\/ccjm.82a.14023","article-title":"Cannabinoid hyperemesis syndrome: Marijuana is both antiemetic and proemetic","volume":"82","author":"Lu","year":"2015","journal-title":"Clevel. Clin. J. Med."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1080\/23328940.2015.1043042","article-title":"The involvement of TRPV1 in emesis and anti-emesis","volume":"21","author":"Rudd","year":"2015","journal-title":"Temperature"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1146\/annurev-med-050214-013454","article-title":"Marijuana Legalization: Impact on Physicians and Public Health","volume":"67","author":"Wilkinson","year":"2016","journal-title":"Annu. Rev. Med."},{"key":"ref_55","unstructured":"Allen, E. (2019). Congressional Research Service Informing the legislative debate since 1914. Libr. Congr. Mag."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"10184","DOI":"10.1523\/JNEUROSCI.19-22-10184.1999","article-title":"Functional attributes discriminating mechanoinsensitive and mechano-responsive C nociceptors in human skin","volume":"19","author":"Weidner","year":"1999","journal-title":"J. Neurosci."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"3102","DOI":"10.1016\/j.celrep.2017.11.066","article-title":"Functional and molecular characterization of mechanoinsensitive \u201csilent\u201d nociceptors","volume":"21","author":"Prato","year":"2017","journal-title":"Cell Rep."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1016\/j.jht.2018.01.011","article-title":"Peripheral nerve injuries, pain, and neuroplasticity","volume":"31","author":"Osborne","year":"2018","journal-title":"J. Hand. Ther."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1148","DOI":"10.1111\/jdi.13105","article-title":"Painful and non-painful diabetic polyneuropathy: Clinical characteristics and diagnostic issues","volume":"10","author":"Gylfadottir","year":"2019","journal-title":"J. Diabetes Investig."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1111\/j.1526-4637.2008.00555.x","article-title":"Neuropathic pain in diabetes, prediabetes and normal glucose tolerance: The MONICA\/KORA Augsburg Surveys S2 and S3","volume":"10","author":"Ziegler","year":"2009","journal-title":"Pain Med."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.pain.2010.04.002","article-title":"Natural history of cutaneous innervation following herpes zoster","volume":"150","author":"Petersen","year":"2010","journal-title":"Pain"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/S0304-3959(00)00481-4","article-title":"The density of remaining nerve endings in human skin with and without postherpetic neuralgia after shingles","volume":"92","author":"Oaklander","year":"2001","journal-title":"Pain"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1212\/WNL.58.1.115","article-title":"Reduced intraepidermal nerve fiber density in HIV-associated sensory neuropathy","volume":"58","author":"Polydefkis","year":"2002","journal-title":"Neurology"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/j.pain.2005.09.036","article-title":"Evidence of focal small-fiber axonal degeneration in complex regional pain syndrome-I (reflex sympathetic dystrophy)","volume":"120","author":"Oaklander","year":"2006","journal-title":"Pain"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1089\/met.2005.3.113","article-title":"Small fiber neuropathy is associated with the metabolic syndrome","volume":"3","author":"Pittenger","year":"2005","journal-title":"Metab. Syndr. Relat. Disord."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1249","DOI":"10.1212\/WNL.52.6.1249","article-title":"Quantitative analysis of epidermal innervation in Fabry disease","volume":"52","author":"Scott","year":"1999","journal-title":"Neurology"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1016\/j.ygyno.2015.01.524","article-title":"Basic science and clinical management of painful and non-painful chemotherapy-related neuropathy","volume":"136","author":"Kim","year":"2015","journal-title":"Gynecol. Oncol."},{"key":"ref_68","unstructured":"(2022, August 28). Clinical Trial Identifier: NCT03687970, A New Method for Identifying Sensory Changes in Painful Chemotherapy-Induced Peripheral Neuropathy (CIPN), Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT03687970."},{"key":"ref_69","unstructured":"Abrams, D.I., Jay, C., Petersen, K., Shade, S., Vizoso, H., Reda, H., Benowitz, N., and Rowbotham, M. (2003). The Effects of Smoked Cannabis in Painful Peripheral Neuropathy and Cancer Pain Refractory to Opioids, International Association of Cannabis as Medicine, Cologne."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1097\/00126334-200401010-00005","article-title":"Patterns of marijuana use among patients with HIV\/AIDS followed in a public health care setting","volume":"35","author":"Prentiss","year":"2004","journal-title":"J. Acquir. Immune Defic. Syndr."},{"key":"ref_71","first-page":"9","article-title":"Cannabinoid-Induced Tetrad in Mice","volume":"80","author":"Grel","year":"2017","journal-title":"Curr. Protoc. Neurosci."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1124\/jpet.105.093286","article-title":"Elevation of endocannabinoid levels in the ventrolateral periaqueductal grey through inhibition of fatty acid amide hydrolase affects descending nociceptive pathways via both cannabinoid receptor type 1 and transient receptor potential vanilloid type-1 receptors","volume":"316","author":"Maione","year":"2006","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1111\/j.1476-5381.2010.01063.x","article-title":"Non-psychoactive cannabinoids modulate the descending pathway of antinociception in anaesthetized rats through several mechanisms of action","volume":"162","author":"Maione","year":"2011","journal-title":"Br. J. Pharmacol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1111\/bph.13333","article-title":"Neural correlates of interactions between cannabidiol and \u0394(9) -tetrahydrocannabinol in mice: Implications for medical cannabis","volume":"173","author":"Todd","year":"2016","journal-title":"Br. J. Pharmacol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.brainres.2007.09.090","article-title":"Cannabidiol potentiates pharmacological effects of Delta(9)-tetrahydrocannabinol via CB(1) receptor-dependent mechanism","volume":"1188","author":"Hayakawa","year":"2008","journal-title":"Brain Res."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1007\/BF00429130","article-title":"Modification of delta9-THC-actions by cannabinol and cannabidiol in the rat","volume":"38","author":"Fernandes","year":"1974","journal-title":"Psychopharmacologia"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1113\/jphysiol.2006.118620","article-title":"Potentiation of glutamatergic synaptic transmission by protein kinase C-mediated sensitization of TRPV1 at the first sensory synapse","volume":"581","author":"Sikand","year":"2007","journal-title":"J. Physiol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"151","DOI":"10.2174\/157015908784533888","article-title":"TRPV1: A target for next generation analgesics","volume":"2","author":"Premkumar","year":"2008","journal-title":"Curr. Neuropharmacol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"2192","DOI":"10.2174\/156802611796904834","article-title":"Disease-related changes in TRPV1 expression and its implications for drug development","volume":"11","author":"Premkumar","year":"2011","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.neulet.2015.12.060","article-title":"Effect of cannabinoids on CGRP release in the isolated rat lumbar spinal cord","volume":"614","author":"Milne","year":"2016","journal-title":"Neurosci. Lett."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/j.npep.2011.03.005","article-title":"Inhibitory CB1 and activating\/desensitizing TRPV1-mediated cannabinoid actions on CGRP release in rodent skin","volume":"45","author":"Engel","year":"2011","journal-title":"Neuropeptides"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"5067","DOI":"10.1523\/JNEUROSCI.6451-10.2011","article-title":"Trpv1 reporter mice reveal highly restricted brain distribution and functional expression in arteriolar smooth muscle cells","volume":"31","author":"Cavanaugh","year":"2011","journal-title":"J. Neurosci."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1007\/3-540-26573-2_20","article-title":"Cardiovascular pharmacology of cannabinoids","volume":"168","author":"Pacher","year":"2005","journal-title":"Handb. Exp. Pharmacol."},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Feng, L., Uteshev, V.V., and Premkumar, L.S. (2019). Expression and Function of Transient Receptor Potential Ankyrin 1 Ion Channels in the Caudal Nucleus of the Solitary Tract. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20092065"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.neuropharm.2017.12.013","article-title":"Differential neuromodulatory role of endocannabinoids in the rodent trigeminal sensory ganglion and cerebral cortex relevant to pain processing","volume":"131","author":"Eroli","year":"2018","journal-title":"Neuropharmacology"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"R134","DOI":"10.1152\/ajpregu.00049.2018","article-title":"Activation of TRPV1 in nucleus tractus solitarius reduces brown adipose tissue thermogenesis, arterial pressure, and heart rate","volume":"315","author":"Mohammed","year":"2018","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jchemneu.2015.12.003","article-title":"Localization of TRPV1 and P2X3 in unmyelinated and myelinated vagal afferents in the rat","volume":"72","author":"Hermes","year":"2016","journal-title":"J. Chem. Neuroanat."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"6","DOI":"10.3389\/fnins.2014.00006","article-title":"Isolation of TRPV1 independent mechanisms of spontaneous and asynchronous glutamate release at primary afferent to NTS synapses","volume":"8","author":"Fenwick","year":"2014","journal-title":"Front. Neurosci."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1111\/joa.12529","article-title":"TRPV1 receptor in the human trigeminal ganglion and spinal nucleus: Immunohistochemical localization and comparison with the neuropeptides CGRP and SP","volume":"229","author":"Quartu","year":"2016","journal-title":"J. Anat."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.jchemneu.2012.09.005","article-title":"The role of calcitonin gene-related peptide on the increase in transient receptor potential vanilloid-1 levels in trigeminal ganglion and trigeminal nucleus caudalis activation of rat","volume":"47","author":"Chatchaisak","year":"2013","journal-title":"J. Chem. Neuroanat."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1152\/jn.01023.2006","article-title":"TRPV1 receptor mediates glutamatergic synaptic input to dorsolateral periaqueductal gray (dl-PAG) neurons","volume":"97","author":"Xing","year":"2007","journal-title":"J. Neurophysiol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.brainres.2010.02.077","article-title":"Diabetic thermal hyperalgesia: Role of TRPV1 and CB1 receptors of periaqueductal gray","volume":"1328","author":"Sahebgharani","year":"2010","journal-title":"Brain Res."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1186\/1744-8069-6-66","article-title":"Moving towards supraspinal TRPV1 receptors for chronic pain relief","volume":"6","author":"Palazzo","year":"2010","journal-title":"Mol. Pain."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1241","DOI":"10.1097\/j.pain.0000000000000905","article-title":"Neuropathic pain-induced enhancement of spontaneous and pain-evoked neuronal activity in the periaqueductal gray that is attenuated by gabapentin","volume":"158","author":"Samineni","year":"2017","journal-title":"Pain"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1016\/j.bbr.2015.07.023","article-title":"Role of TRPV1 channels of the dorsal periaqueductal gray in the modulation of nociception and open elevated plus maze-induced antinociception in mice","volume":"292","author":"Mascarenhas","year":"2015","journal-title":"Behav. Brain Res."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.phrs.2016.08.011","article-title":"Genotype-dependent responsivity to inflammatory pain: A role for TRPV1 in the periaqueductal grey","volume":"113","author":"Madasu","year":"2016","journal-title":"Pharmacol. Res."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1124\/jpet.107.125674","article-title":"Repeated administration of vanilloid receptor TRPV1 antagonists attenuates hyperthermia elicited by TRPV1 blockade","volume":"323","author":"Gavva","year":"2007","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1111\/bph.12944","article-title":"Are cannabidiol and \u0394(9)-tetrahydrocannabivarin negative modulators of the endocannabinoid system? Asystematic review","volume":"172","author":"McPartland","year":"2015","journal-title":"Br. J. Pharmacol."},{"key":"ref_99","doi-asserted-by":"crossref","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":"ref_100","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1002\/ptr.2625","article-title":"Cannabidiol in medicine: A review of its therapeutic potential in CNS disorders","volume":"23","author":"Scuderi","year":"2009","journal-title":"Phytother. Res."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.pharmthera.2011.09.002","article-title":"Phytocannabinoids as novel therapeutic agents in CNS disorders","volume":"133","author":"Hill","year":"2012","journal-title":"Pharmacol. Ther."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1921","DOI":"10.3389\/fimmu.2019.01921","article-title":"Combination of Cannabinoids, \u03949- Tetrahydrocannabinol and Cannabidiol, Ameliorates Experimental Multiple Sclerosis by Suppressing Neuroinflammation Through Regulation of miRNA-Mediated Signaling Pathways","volume":"10","author":"Miranda","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"399","DOI":"10.2147\/JPR.S240011","article-title":"A Review of Scientific Evidence for THC:CBD Oromucosal Spray (Nabiximols) in the Management of Chronic Pain","volume":"13","year":"2020","journal-title":"J. Pain Res."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.ejim.2018.01.004","article-title":"Practical considerations in medical cannabis administration and dosing","volume":"49","author":"MacCallum","year":"2018","journal-title":"Eur. J. Intern. Med."},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Urasaki, Y., Beaumont, C., Workman, M., Talbot, J.N., Hill, D.K., and Le, T.T. (2020). Potency Assessment of CBD Oils by Their Effects on Cell Signaling Pathways. Nutrients, 12.","DOI":"10.3390\/nu12020357"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1932","DOI":"10.1097\/j.pain.0000000000001293","article-title":"Cannabis and cannabinoids for the treatment of people with chronic noncancer pain conditions: A systematic review and meta-analysis of controlled and observational studies","volume":"159","author":"Stockings","year":"2018","journal-title":"Pain"},{"key":"ref_107","unstructured":"National academies of sciences engineering and medicine (2017). The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research, The National Academies Press."},{"key":"ref_108","first-page":"9","article-title":"Influence of TRPV1 on diabetes-induced alterations in thermal pain sensitivity","volume":"1","author":"Pabbidi","year":"2008","journal-title":"Mol. Pain"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1016\/j.jpain.2011.03.005","article-title":"Preservation of acute pain and efferent functions following intrathecal resiniferatoxin-induced analgesia in rats","volume":"12","author":"Bishnoi","year":"2011","journal-title":"J. Pain"},{"key":"ref_110","unstructured":"(2022). Resiniferatoxin to Treat Severe Pain Associated with Advanced Cancer Dec 2008\u2013Dec 2014 (Standard No. NCT00804154)."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1016\/j.pain.2014.01.007","article-title":"Nociception and inflammatory hyperalgesia evaluated in rodents using infrared laser stimulation after Trpv1 gene knockout or resiniferatoxin lesion","volume":"155","author":"Mitchell","year":"2014","journal-title":"Pain"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"1018","DOI":"10.1097\/j.pain.0000000000000115","article-title":"Intrathecal resiniferatoxin in a dog model: Efficacy in bone cancer pain","volume":"156","author":"Brown","year":"2015","journal-title":"Pain"},{"key":"ref_113","first-page":"2453","article-title":"Local Resiniferatoxin Induces Long-Lasting Analgesia in a Rat Model of Full Thickness Thermal Injury","volume":"18","author":"Salas","year":"2017","journal-title":"Pain Med."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"1","DOI":"10.2174\/1876386301508010001","article-title":"Ablation and regeneration of peripheral and Central TRPV1 Expressing Nerve Terminals and the Consequence of Nociception","volume":"8","author":"Yu","year":"2015","journal-title":"The Open Pain J."},{"key":"ref_115","unstructured":"(2022, August 28). ClinicalTrials.gov Identifier: NCT04044742, A Phase 3 Study to Evaluate the Efficacy and Safety of Resiniferatoxin for Pain Due to Osteoarthritis of the Knee, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT04044742."},{"key":"ref_116","unstructured":"(2022, August 28). Clinical Trials.gov Identifier: NCT00804154, Resiniferatoxin to Treat Severe Pain Associated with Advanced Cancer, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT00804154."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1016\/S1474-4422(19)30185-1","article-title":"Migraine and the trigeminovascular system\u201440 years and counting","volume":"18","author":"Ashina","year":"2019","journal-title":"Lancet Neurol."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1038\/s41582-018-0003-1","article-title":"CGRP as the target of new migraine therapies-successful translation from bench to clinic","volume":"14","author":"Edvinsson","year":"2018","journal-title":"Nat. Rev. Neurol."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1002\/phar.1673","article-title":"Effects of Medical Marijuana on Migraine Headache Frequency in an Adult Population","volume":"36","author":"Rhyne","year":"2016","journal-title":"Pharmacotherapy"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"172","DOI":"10.3389\/fnins.2018.00172","article-title":"Endocannabinoid System and Migraine Pain: An Update","volume":"12","author":"Greco","year":"2018","journal-title":"Front Neurosci."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"1303","DOI":"10.2165\/00003495-200060060-00005","article-title":"Cannabinoids in clinical practice","volume":"60","author":"Williamson","year":"2000","journal-title":"Drugs"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/j.pain.2003.11.009","article-title":"Local application of the cannabinoid receptor agonist, WIN 55,212\u20132, to spinal trigeminal nucleus caudalis differentially affects nociceptive and non-nociceptive neurons","volume":"107","author":"Papanastassiou","year":"2004","journal-title":"Pain"},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1038\/sj.bjp.0706093","article-title":"The expanding field of cannabimimetic and related lipid mediators","volume":"144","author":"Bradshaw","year":"2005","journal-title":"Br. J. Pharmacol."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1124\/pr.58.3.2","article-title":"The endocannabinoid system as an emerging target of pharmacotherapy","volume":"58","author":"Pacher","year":"2006","journal-title":"Pharmacol. Rev."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1016\/j.tips.2009.06.006","article-title":"The therapeutic potential of the endocannabinoid system for the development of a novel class of antidepressants","volume":"30","author":"Hill","year":"2009","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1038\/nrn1247","article-title":"The molecular logic of endocannabinoid signalling","volume":"4","author":"Piomelli","year":"2003","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1007\/3-540-26573-2_5","article-title":"The biosynthesis, fate and pharmacological properties of endocannabinoids","volume":"168","author":"Bisogno","year":"2005","journal-title":"Handb. Exp. Pharmacol."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1186\/s41232-018-0086-5","article-title":"Endocannabinoids and related N-acylethanolamines: Biological activities and metabolism","volume":"38","author":"Tsuboi","year":"2018","journal-title":"Inflamm Regen."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1016\/j.neuropharm.2005.02.013","article-title":"Oleoylethanolamide, an endogenous PPAR-alpha agonist, lowers body weight and hyperlipidemia in obese rats","volume":"48","author":"Fu","year":"2005","journal-title":"Neuropharmacology"},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"30429","DOI":"10.1074\/jbc.M305051200","article-title":"Activation of TRPV1 by the satiety factor oleoylethanolamide","volume":"278","author":"Ahern","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1016\/j.bcp.2009.04.024","article-title":"N-acylethanolamines, anandamide and food intake","volume":"78","author":"Hansen","year":"2009","journal-title":"Biochem. Pharmacol."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1111\/j.1476-5381.2011.01214.x","article-title":"Capsaicin in the periaqueductal gray induces analgesia via metabotropic glutamate receptor-mediated endocannabinoid retrograde disinhibition","volume":"163","author":"Liao","year":"2011","journal-title":"Br. J. Pharmacol."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1016\/S0301-0082(02)00009-6","article-title":"Descending control of pain","volume":"66","author":"Millan","year":"2002","journal-title":"Prog. Neurobiol."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1016\/j.brainresrev.2008.12.009","article-title":"Descending control of nociception: Specificity, recruitment and plasticity","volume":"60","author":"Heinricher","year":"2009","journal-title":"Brain Res. Rev."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1016\/0306-4522(96)00180-7","article-title":"Endogenous opioids acting at a medullary mu-opioid receptor contribute to the behavioral antinociception produced by GABA antagonism in the midbrain periaqueductal gray","volume":"74","author":"Roychowdhury","year":"1996","journal-title":"Neuroscience"},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.pharmthera.2007.01.005","article-title":"Biochemistry and pharmacology of endovanilloids","volume":"114","author":"Starowicz","year":"2007","journal-title":"Pharmacol Ther."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/S0014-2999(96)00909-0","article-title":"Dipyrone into the nucleus raphe magnus inhibits the rat nociceptive tail-flick reflex","volume":"318","author":"Jones","year":"1996","journal-title":"Eur. J. Pharmacol."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"1982","DOI":"10.1152\/jn.00411.2004","article-title":"Neural basis for the hyperalgesic action of cholecystokinin in the rostral ventromedial medulla","volume":"92","author":"Heinricher","year":"2004","journal-title":"J. Neurophysiol."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"7220","DOI":"10.1523\/JNEUROSCI.4362-08.2009","article-title":"Substance P drives endocannabinoid-mediated disinhibition in a midbrain descending analgesic pathway","volume":"29","author":"Drew","year":"2009","journal-title":"J. Neurosci."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1016\/0306-4522(90)90035-3","article-title":"The effect of [Met] enkephalin on the periaqueductal gray neurons of the rat: An in vitro study","volume":"38","author":"Behbehani","year":"1990","journal-title":"Neuroscience"},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1038\/37610","article-title":"How opioids inhibit GABA-mediated neurotransmission","volume":"390","author":"Vaughan","year":"1997","journal-title":"Nature"},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1016\/S0028-3908(03)00235-1","article-title":"Effects of direct periaqueductal grey administration of a cannabinoid receptor agonist on nociceptive and aversive responses in rats","volume":"45","author":"Finn","year":"2003","journal-title":"Neuropharmacology"},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.ejphar.2011.11.034","article-title":"Effects of intra- ventrolateral periaqueductal grey palmitoylethanolamide on thermoceptive threshold and rostral ventromedial medulla cell activity","volume":"676","author":"Luongo","year":"2012","journal-title":"Eur. J. Pharmacol."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"1214","DOI":"10.1111\/j.1476-5381.2010.01157.x","article-title":"Inhibition of fatty acid amide hydrolase unmasks CB1 receptor and TRPV1 channel-mediated modulation of glutamatergic synaptic transmission in midbrain periaqueductal grey","volume":"163","author":"Kawahara","year":"2011","journal-title":"Br. J. Pharmacol."},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1007\/s000180300052","article-title":"Dual effect of cannabinoid CB1 receptor stimulation on a vanilloid VR1 receptor-mediated response","volume":"60","author":"Hermann","year":"2003","journal-title":"Cell. Mol. Life. Sci."},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1016\/j.neuropharm.2018.03.032","article-title":"Periaqueductal gray glutamatergic, cannabinoid and vanilloid receptor interplay in defensive behavior and aversive memoryformation","volume":"135","author":"Back","year":"2018","journal-title":"Neuropharmacology"},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1007\/s00213-008-1168-x","article-title":"Involvement of 5HT1A receptors in the anxiolytic- like effects of cannabidiol injected into the dorsolateral periaqueductal gray of rats","volume":"199","author":"Campos","year":"2008","journal-title":"Psychopharmacology"},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.expneurol.2017.10.007","article-title":"Monoaminergic descending pathways contribute to modulation of neuropathic pain by increasing-intensity treadmill exercise after peripheral nerve injury","volume":"299","author":"Puigdomenech","year":"2018","journal-title":"Exp. Neurol."},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1146\/annurev.neuro.24.1.737","article-title":"Contributions ofthe medullary raphe and ventromedial reticular region to pain modulation and other homeostatic functions","volume":"24","author":"Mason","year":"2001","journal-title":"Annu. Rev. Neurosci."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1016\/0361-9230(94)90143-0","article-title":"The dorsal raphe: An important nucleus in pain modulation","volume":"34","author":"Nakai","year":"1994","journal-title":"Brain. Res. Bull."},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"1209","DOI":"10.1016\/j.neuroscience.2010.09.058","article-title":"Phasic responses in dorsal raphe serotonin neurons to noxious stimuli","volume":"171","author":"Schweimer","year":"2010","journal-title":"Neuroscience"},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1016\/j.neuropharm.2015.06.003","article-title":"Enhanced serotonin and mesolimbic dopamine transmissions in a rat model of neuropathic pain","volume":"97","author":"Sagheddu","year":"2015","journal-title":"Neuropharmacology"},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"1501","DOI":"10.1016\/j.jpsychires.2012.08.012","article-title":"Cannabidiol blocks long-lasting behavioral consequences of predator threat stress: Possible involvement of 5HT1A receptors","volume":"46","author":"Campos","year":"2012","journal-title":"J. Psychiatr. Res."},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1007\/s11064-005-6978-1","article-title":"Agonistic properties of cannabidiol at 5-HT1a receptors","volume":"30","author":"Russo","year":"2005","journal-title":"Neurochem. Res."},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"1353","DOI":"10.1111\/j.1526-4637.2009.00703.x","article-title":"Systematic Review and Meta-analysis of Cannabis Treatment for Chronic Pain","volume":"10","author":"Furukawa","year":"2009","journal-title":"Pain Med."},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"1219","DOI":"10.1038\/npp.2011.6","article-title":"Cannabidiol Reduces the Anxiety Induced by Simulated Public Speaking in Treatment-Na\u00efve Social Phobia Patients","volume":"36","author":"Bergamaschi","year":"2011","journal-title":"Neuropsychopharmacology"},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1111\/j.1476-5381.2009.00521.x","article-title":"Antidepressant-like effects of cannabidiol in mice: Possible involvement of 5-HT1A receptors","volume":"159","author":"Zanelati","year":"2010","journal-title":"Br. J. Pharmacol."},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1016\/j.drugalcdep.2012.06.002","article-title":"Cannabis and depression: An integrative data analysis of four Australasian cohorts","volume":"126","author":"Horwood","year":"2012","journal-title":"Drug Alcohol Depend."},{"key":"ref_159","unstructured":"Mack, A., and Joy, J. (2000). Marijuana as Medicine? The Science Beyond the Controversy, National Academies Press."},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1523\/JNEUROSCI.14-02-00871.1994","article-title":"Emetic reflex arc revealed by expression of the immediate-early gene c-fos in the cat","volume":"14","author":"Miller","year":"1994","journal-title":"J. Neurosci."},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1159\/000112901","article-title":"The Perceived Effects of Smoked Cannabis on Patients with Multiple Sclerosis","volume":"38","author":"Consroe","year":"1997","journal-title":"Eur. Neurol."},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"413","DOI":"10.31887\/DCNS.2007.9.4\/nkogan","article-title":"Cannabinoids in health and disease","volume":"9","author":"Kogan","year":"2007","journal-title":"Dialogues Clin. Neurosci."},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1007\/s11916-020-00872-w","article-title":"Considerations and Implications of Cannabidiol Use During Pregnancy","volume":"24","author":"Sarrafpour","year":"2020","journal-title":"Curr. Pain Headache Rep."},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"1975","DOI":"10.1038\/s41593-019-0512-2","article-title":"Prenatal THC exposure produces a hyperdopaminergic phenotype rescued by pregnenolone","volume":"22","author":"Frau","year":"2019","journal-title":"Nat. Neurosci."},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.autneu.2006.01.008","article-title":"Signals for nausea and emesis: Implications for models of upper gastrointestinal diseases","volume":"125","author":"Andrews","year":"2006","journal-title":"Auton. Neurosci."},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"106S","DOI":"10.1016\/S0002-9343(01)00849-X","article-title":"Central neurocircuitry associated with emesis","volume":"111","author":"Hornby","year":"2001","journal-title":"Am. J. Med."},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1097\/00001756-200204160-00006","article-title":"Cannabidiol, a non-psychoactive component of cannabis and its synthetic dimethylheptyl homolog suppress nausea in an experimental model with rats","volume":"13","author":"Parker","year":"2002","journal-title":"NeuroReport"},{"key":"ref_168","first-page":"39S","article-title":"Central mechanisms of vomiting","volume":"44","author":"Miller","year":"1999","journal-title":"Dig. Dis. Sci."},{"key":"ref_169","first-page":"305","article-title":"Mechanism of action of cannabinoids: How it may lead to treatment of cachexia, emesis, and pain","volume":"2","author":"Martin","year":"2004","journal-title":"J. Support. Oncol."},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1097\/MCG.0000000000001164","article-title":"Practical Perspectives in the Treatment of Nausea and Vomiting","volume":"53","author":"Cangemi","year":"2019","journal-title":"J. Clin. Gastroenterol."},{"key":"ref_171","first-page":"1","article-title":"Cannabinoid hyperemesis syndrome: An unrecognized cause of nausea and vomiting","volume":"32","author":"Smith","year":"2019","journal-title":"JAAPA"},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1080\/15563650.2017.1349910","article-title":"Cannabinoid hyperemesis syndrome: Potential mechanisms for the benefit of capsaicin and hot water hydrotherapy in treatment","volume":"56","author":"Richards","year":"2018","journal-title":"Clin. Toxicol."},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1016\/j.jemermed.2017.12.010","article-title":"Cannabinoid Hyperemesis Syndrome: Pathophysiology and Treatment in the Emergency Department","volume":"54","author":"Richards","year":"2018","journal-title":"J. Emerg. Med."},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1080\/15563650.2017.1324166","article-title":"Resolution of cannabis hyperemesis syndrome with topical capsaicin in the emergency department: A case series","volume":"55","author":"Dezieck","year":"2017","journal-title":"Clin. Toxicol."},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1016\/j.coph.2007.08.008","article-title":"The endocannabinoid system and gut-brain signalling","volume":"7","author":"Storr","year":"2007","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.2217\/fon-2018-0530","article-title":"Cannabinoids: The lows and the highs of chemotherapy-induced nausea and vomiting","volume":"15","author":"Mortimer","year":"2019","journal-title":"Future Oncol."},{"key":"ref_177","first-page":"49","article-title":"Dronabinol for chemotherapy-induced nausea and vomiting unresponsive to antiemetics","volume":"8","author":"May","year":"2016","journal-title":"Cancer Manag. Res."},{"key":"ref_178","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.brainres.2005.01.050","article-title":"Nociceptive transmitter release in the dorsal spinal cord by capsaicin-sensitive fibers after noxious gastric stimulation","volume":"1039","author":"Schicho","year":"2005","journal-title":"Brain Res."},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/j.ejphar.2013.08.051","article-title":"Additive antiemetic efficacy of low-doses of the cannabinoid CB(1\/2) receptor agonist \u0394(9)-THC with ultralow-doses of the vanilloid TRPV1 receptor agonist resiniferatoxin in the least shrew (Cryptotis parva)","volume":"722","author":"Darmani","year":"2014","journal-title":"Eur. J. Pharmacol."},{"key":"ref_180","doi-asserted-by":"crossref","unstructured":"Peters, J.H., McDougall, S.J., Fawley, J.A., and Andresen, M.C. (2011). TRPV1 marks synaptic segregation of multiple convergent afferents at the rat medial solitary tract nucleus. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0025015"},{"key":"ref_181","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1113\/JP275127","article-title":"Activation of astrocytic PAR1 receptors in the rat nucleus of the solitary tract regulates breathing through modulation of presynaptic TRPV1","volume":"596","author":"Huda","year":"2018","journal-title":"J. Physiol."},{"key":"ref_182","doi-asserted-by":"crossref","first-page":"1247","DOI":"10.1038\/sj.bjp.0703428","article-title":"The emetic and anti-emetic effects of the capsaicin analogue resiniferatoxin in Suncus murinus, the house musk shrew","volume":"130","author":"Andrews","year":"2000","journal-title":"Br. J. Pharmacol."},{"key":"ref_183","doi-asserted-by":"crossref","first-page":"101853","DOI":"10.1016\/j.pupt.2019.101853","article-title":"Emerging targets for cough therapies; NK1 receptor antagonists","volume":"59","author":"Badri","year":"2019","journal-title":"Pulm. Pharmacol. Ther."},{"key":"ref_184","doi-asserted-by":"crossref","first-page":"21","DOI":"10.2147\/CE.S203634","article-title":"Management of Chemotherapy Induced Nausea and Vomiting (CINV): A Short Review on the Role of Netupitant- Palonosetron (NEPA)","volume":"15","author":"Lorusso","year":"2020","journal-title":"Core Evid."},{"key":"ref_185","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1111\/j.1399-6576.2009.02115.x","article-title":"The potential for mu-opioid receptor agonists to be anti-emetic in humans: A review of clinical data","volume":"54","author":"Johnston","year":"2010","journal-title":"Acta Anaesthesiol. Scand."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/17\/10016\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:22:16Z","timestamp":1760142136000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/17\/10016"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,2]]},"references-count":185,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2022,9]]}},"alternative-id":["ijms231710016"],"URL":"https:\/\/doi.org\/10.3390\/ijms231710016","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,2]]}}}