{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T19:33:12Z","timestamp":1768591992310,"version":"3.49.0"},"reference-count":62,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2022,10,2]],"date-time":"2022-10-02T00:00:00Z","timestamp":1664668800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004166","name":"Medical University of Warsaw","doi-asserted-by":"publisher","award":["FW3\/PM1\/17"],"award-info":[{"award-number":["FW3\/PM1\/17"]}],"id":[{"id":"10.13039\/501100004166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004166","name":"Medical University of Warsaw","doi-asserted-by":"publisher","award":["S.I.1.3"],"award-info":[{"award-number":["S.I.1.3"]}],"id":[{"id":"10.13039\/501100004166","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Institute of Genetics and Animal Biotechnology at the Polish Academy of Sciences","award":["FW3\/PM1\/17"],"award-info":[{"award-number":["FW3\/PM1\/17"]}]},{"name":"Institute of Genetics and Animal Biotechnology at the Polish Academy of Sciences","award":["S.I.1.3"],"award-info":[{"award-number":["S.I.1.3"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>In this work we strived to determine whether endocannabinoid system activity could account for the differences in acute inflammatory pain sensitivity in mouse lines selected for high (HA) and low (LA) swim-stress-induced analgesia (SSIA). Mice received intraplantar injections of 5% formalin and the intensity of nocifensive behaviours was scored. To assess the contribution of the endocannabinoid system, mice were intraperitoneally (i.p.) injected with rimonabant (0.3\u20133 mg\/kg) prior to formalin. Minocycline (45 and 100 mg\/kg, i.p.) was administered to investigate microglial activation. The possible involvement of the endogenous opioid system was investigated with naloxone (1 mg\/kg, i.p.). Cannabinoid receptor types 1 and 2 (Cnr1, Cnr2) and opioid receptor subtype (Oprm1, Oprd1, Oprk1) mRNA levels were quantified by qPCR in the structures of the central nociceptive circuit. Levels of anandamide (AEA) and 2-arachidonoylglycerol (2-AG) were measured by liquid chromatography coupled with the mass spectrometry method (LC-MS\/MS). In the interphase, higher pain thresholds in the HA mice correlated with increased spinal anandamide and 2-AG release and higher Cnr1 transcription. Downregulation of Oprd1 and Oprm1 mRNA was noted in HA and LA mice, respectively, however no differences in naloxone sensitivity were observed in either line. As opposed to the LA mice, inflammatory pain sensitivity in the HA mice in the tonic phase was attributed to enhanced microglial activation, as evidenced by enhanced Aif1 and Il-1\u03b2 mRNA levels. To conclude, Cnr1 inhibitory signaling is one mechanism responsible for decreased pain sensitivity in HA mice in the interphase, while increased microglial activation corresponds to decreased pain thresholds in the tonic inflammatory phase.<\/jats:p>","DOI":"10.3390\/ijms231911686","type":"journal-article","created":{"date-parts":[[2022,10,8]],"date-time":"2022-10-08T22:19:27Z","timestamp":1665267567000},"page":"11686","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Mechanisms Underlining Inflammatory Pain Sensitivity in Mice Selected for High and Low Stress-Induced Analgesia\u2014The Role of Endocannabinoids and Microglia"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1321-2235","authenticated-orcid":false,"given":"Piotr","family":"Poznanski","sequence":"first","affiliation":[{"name":"Department of Experimental Genomics, Institute of Genetics and Animal Biotechnology, Polish Academy of Sciences in Jastrzebiec, Postepu 36A Str., 05-552 Magdalenka, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2567-4453","authenticated-orcid":false,"given":"Joanna","family":"Giebultowicz","sequence":"additional","affiliation":[{"name":"Department of Bioanalysis and Drugs Analysis, Faculty of Pharmacy, Medical University of Warsaw, Centre for Preclinical Research and Technology, Banacha 1 Str., 02-097 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Justyna","family":"Durdzinska","sequence":"additional","affiliation":[{"name":"Department of Pharmacodynamics, Faculty of Pharmacy, Medical University of Warsaw, Banacha 1 Str., 02-097 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7587-2626","authenticated-orcid":false,"given":"Tomasz","family":"Kocki","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Pharmacology, Medical University of Lublin, Jaczewskiego 8b Str., 20-090 Lublin, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mariusz","family":"Sacharczuk","sequence":"additional","affiliation":[{"name":"Department of Experimental Genomics, Institute of Genetics and Animal Biotechnology, Polish Academy of Sciences in Jastrzebiec, Postepu 36A Str., 05-552 Magdalenka, Poland"},{"name":"Department of Pharmacodynamics, Faculty of Pharmacy, Medical University of Warsaw, Banacha 1 Str., 02-097 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Magdalena","family":"Bujalska-Zadrozny","sequence":"additional","affiliation":[{"name":"Department of Pharmacodynamics, Faculty of Pharmacy, Medical University of Warsaw, Banacha 1 Str., 02-097 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Lesniak","sequence":"additional","affiliation":[{"name":"Department of Pharmacodynamics, Faculty of Pharmacy, Medical University of Warsaw, Banacha 1 Str., 02-097 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1186\/s13075-020-2096-3","article-title":"Combatting joint pain and inflammation by dual inhibition of monoacylglycerol lipase and cyclooxygenase-2 in a rat model of osteoarthritis","volume":"22","author":"Philpott","year":"2020","journal-title":"Arthritis Res. Ther."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1016\/j.chembiol.2009.02.013","article-title":"Discovery and characterization of a highly selective FAAH inhibitor that reduces inflammatory pain","volume":"16","author":"Ahn","year":"2009","journal-title":"Chem. Biol."},{"key":"ref_3","doi-asserted-by":"crossref","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":"ref_4","doi-asserted-by":"crossref","first-page":"9371","DOI":"10.1073\/pnas.161191698","article-title":"Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase","volume":"98","author":"Cravatt","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1124\/jpet.109.158162","article-title":"Blockade of 2-Arachidonoylglycerol Hydrolysis by Selective Monoacylglycerol Lipase Inhibitor 4-Nitrophenyl 4-(Dibenzo[d][1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate (JZL184) Enhances Retrograde Endocannabinoid Signaling","volume":"331","author":"Pan","year":"2009","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"946","DOI":"10.1136\/gut.2005.076372","article-title":"Neural contractions in colonic strips from patients with diverticular disease: Role of endocannabinoids and substance P","volume":"55","author":"Guagnini","year":"2006","journal-title":"Gut"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"112858","DOI":"10.1016\/j.ejmech.2020.112858","article-title":"The endocannabinoid system dual-target ligand N-cycloheptyl-1,2-dihydro-5-bromo-1-(4-fluorobenzyl)-6-methyl-2-oxo-pyridine-3-carboxamide improves disease severity in a mouse model of multiple sclerosis","volume":"208","author":"Arena","year":"2020","journal-title":"Eur. J. Med. Chem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"9918","DOI":"10.1021\/acs.jmedchem.2c00582","article-title":"Design, Synthesis, and Biological Activity of New CB2 Receptor Ligands: From Orthosteric and Allosteric Modulators to Dualsteric\/Bitopic Ligands","volume":"65","author":"Gado","year":"2022","journal-title":"J. Med. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2948","DOI":"10.1038\/npp.2015.148","article-title":"A Cannabinoid CB1 Receptor-Positive Allosteric Modulator Reduces Neuropathic Pain in the Mouse with No Psychoactive Effects","volume":"40","author":"Baillie","year":"2015","journal-title":"Neuropsychopharmacology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1016\/j.pain.2004.01.022","article-title":"Mice lacking fatty acid amide hydrolase exhibit a cannabinoid receptor-mediated phenotypic hypoalgesia","volume":"109","author":"Lichtman","year":"2004","journal-title":"Pain"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"5780","DOI":"10.1073\/pnas.96.10.5780","article-title":"Increased mortality, hypoactivity, and hypoalgesia in cannabinoid CB1 receptor knockout mice","volume":"96","author":"Zimmer","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.bbr.2014.05.063","article-title":"Augmented tonic pain-related behavior in knockout mice lacking monoacylglycerol lipase, a major degrading enzyme for the endocannabinoid 2-arachidonoylglycerol","volume":"271","author":"Petrenko","year":"2014","journal-title":"Behav. Brain Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1744806916649192","DOI":"10.1177\/1744806916649192","article-title":"A pro-nociceptive phenotype unmasked in mice lacking fatty-acid amide hydrolase","volume":"12","author":"Carey","year":"2016","journal-title":"Mol. Pain"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/j.neuropharm.2005.07.022","article-title":"Development and expression of neuropathic pain in CB1 knockout mice","volume":"50","author":"Ledent","year":"2006","journal-title":"Neuropharmacology"},{"key":"ref_15","first-page":"535","article-title":"Correlation between magnitude and opioid mediation of stress-induced analgesia: Individual differences and the effect of selective breeding","volume":"50","author":"Panocka","year":"1990","journal-title":"Acta Neurobiol. Exp."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1016\/0091-3057(91)90553-E","article-title":"Tolerance and cross-tolerance with morphine in mice selectively bred for high and low stress-induced analgesia","volume":"40","author":"Panocka","year":"1991","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1016\/j.neuroscience.2019.02.015","article-title":"Divergent Response to Cannabinoid Receptor Stimulation in High and Low Stress-Induced Analgesia Mouse Lines Is Associated with Differential G-Protein Activation","volume":"404","author":"Lesniak","year":"2019","journal-title":"Neuroscience"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/0014-2999(94)90428-6","article-title":"Morphine analgesia and tolerance in mice selectively bred for divergent swim stress-induced analgesia","volume":"265","author":"Lufty","year":"1994","journal-title":"Eur. J. Pharmacol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"26","DOI":"10.55782\/ane-2014-1969","article-title":"Role of the blood-brain barrier in differential response to opioid peptides and morphine in mouse lines divergently bred for high and low swim stress-induced analgesia","volume":"74","author":"Kosson","year":"2014","journal-title":"Acta Neurobiol. Exp."},{"key":"ref_20","first-page":"311","article-title":"Blood-brain barrier permeability differentiates Sadowski mouse lines of high and low stress-induced analgesia: Electron microscopy analysis","volume":"49","author":"Gajkowska","year":"2011","journal-title":"Folia Neuropathol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"130639","DOI":"10.1155\/2015\/130639","article-title":"Anandamide, Acting viaCB2Receptors, Alleviates LPS-Induced Neuroinflammation in Rat Primary Microglial Cultures","volume":"2015","author":"Malek","year":"2015","journal-title":"Neural Plast."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/j.bbi.2015.06.002","article-title":"Endocannabinoids drive the acquisition of an alternative phenotype in microglia","volume":"49","author":"Mecha","year":"2015","journal-title":"Brain Behav. Immun."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1186\/s13578-020-00387-2","article-title":"Dynorphin activation of kappa opioid receptor promotes microglial polarization toward M2 phenotype via TLR4\/NF-\u03baB pathway","volume":"10","author":"Liu","year":"2020","journal-title":"Cell Biosci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1186\/s12974-017-0844-3","article-title":"Mu-opioid receptor and delta-opioid receptor differentially regulate microglial inflammatory response to control proopiomelanocortin neuronal apoptosis in the hypothalamus: Effects of neonatal alcohol","volume":"14","author":"Shrivastava","year":"2017","journal-title":"J. Neuroinflamm."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"5117","DOI":"10.1523\/JNEUROSCI.0866-05.2005","article-title":"Endogenous Opioids and Attenuated Hypothalamic-Pituitary-Adrenal Axis Responses to Immune Challenge in Pregnant Rats","volume":"25","author":"Brunton","year":"2005","journal-title":"J. Neurosci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/S0165-5728(02)00268-0","article-title":"Increased splenocyte proliferative response and cytokine production in \u03b2-endorphin-deficient mice","volume":"131","author":"Refojo","year":"2002","journal-title":"J. Neuroimmunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/0165-5728(94)00189-U","article-title":"The \u03b2-endorphin inhibition of mitogen-induced splenocytes proliferation is mediated by central and peripheral paracrine\/autocrine effects of the opioid","volume":"58","author":"Panerai","year":"1995","journal-title":"J. Neuroimmunol."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Nicolle, P., Liang, H., Reboussin, E., Rabut, G., Warcoin, E., Brignole-Baudouin, F., Melik-Parsadaniantz, S., Baudouin, C., Labbe, A., and Goazigo, A.R.-L. (2018). Proinflammatory Markers, Chemokines, and Enkephalin in Patients Suffering from Dry Eye Disease. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19041221"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1111\/j.1749-6632.2009.05294.x","article-title":"Endomorphins in rheumatoid arthritis, osteoarthritis, and experimental arthritis","volume":"1193","author":"Jessop","year":"2010","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1006\/brbi.1994.1024","article-title":"Decreased \u03b2-Endorphin Content in Peripheral Blood Mononuclear Leukocytes from Patients with Crohn\u2032s Disease","volume":"8","author":"Wiedermann","year":"1994","journal-title":"Brain Behav. Immun."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1016\/0091-3057(95)02285-6","article-title":"Differential sensitivity of mice bred for stress-induced analgesia to morphine and ACEA-1011 in the formalin test","volume":"54","author":"Lutfy","year":"1996","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"901420","DOI":"10.1155\/2013\/901420","article-title":"Different Peripheral Tissue Injury Induces Differential Phenotypic Changes of Spinal Activated Microglia","volume":"2013","author":"Li","year":"2013","journal-title":"Clin. Dev. Immunol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.brainres.2008.05.004","article-title":"A comparison of spinal Iba1 and GFAP expression in rodent models of acute and chronic pain","volume":"1219","author":"Chai","year":"2008","journal-title":"Brain Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1744806919866529","DOI":"10.1177\/1744806919866529","article-title":"The preemptive analgesia of pre-electroacupuncture in rats with formalin-induced acute inflammatory pain","volume":"15","author":"Liu","year":"2019","journal-title":"Mol. Pain"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/S0304-3959(99)00033-0","article-title":"Physiological evidence that the \u2018interphase\u2019 in the formalin test is due to active inhibition","volume":"82","author":"Henry","year":"1999","journal-title":"Pain"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.neuropharm.2018.10.014","article-title":"Bidirectional selection for high and low stress-induced analgesia affects G-protein activity","volume":"144","author":"Lesniak","year":"2019","journal-title":"Neuropharmacology"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"R43","DOI":"10.1186\/ar2401","article-title":"Characterisation of the cannabinoid receptor system in synovial tissue and fluid in patients with osteoarthritis and rheumatoid arthritis","volume":"10","author":"Richardson","year":"2008","journal-title":"Arthritis Res. Ther."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2543","DOI":"10.1093\/brain\/awm160","article-title":"The endocannabinoid system is dysregulated in multiple sclerosis and in experimental autoimmune encephalomyelitis","volume":"130","author":"Centonze","year":"2007","journal-title":"Brain"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1002\/glia.20757","article-title":"CB1cannabinoid receptor-dependent and -independent inhibition of depolarization-induced calcium influx in oligodendrocytes","volume":"57","author":"Mato","year":"2009","journal-title":"Glia"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1016\/S0006-8993(03)02808-7","article-title":"Sodium channel inhibition by anandamide and synthetic cannabimimetics in brain","volume":"978","author":"Nicholson","year":"2003","journal-title":"Brain Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.ejphar.2004.06.011","article-title":"Anandamide transport inhibitor AM404 and structurally related compounds inhibit synaptic transmission between rat hippocampal neurons in culture independent of cannabinoid CB1 receptors","volume":"496","author":"Kelley","year":"2004","journal-title":"Eur. J. Pharmacol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1124\/mol.65.3.665","article-title":"Endocannabinoids Modulate N-Type Calcium Channels and G-Protein-Coupled Inwardly Rectifying Potassium Channels via CB1 Cannabinoid Receptors Heterologously Expressed in Mammalian Neurons","volume":"65","author":"Guo","year":"2004","journal-title":"Mol. Pharmacol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.brainres.2011.07.031","article-title":"Activation of spinal and supraspinal cannabinoid-1 receptors leads to antinociception in a rat model of neuropathic spinal cord injury pain","volume":"1412","author":"Hama","year":"2011","journal-title":"Brain Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.neulet.2010.12.052","article-title":"Antinociceptive effect of intrathecal cannabinoid receptor agonist WIN 55,212-2 in a rat bone tumor pain model","volume":"493","author":"Cui","year":"2011","journal-title":"Neurosci. Lett."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1097\/00000542-200309000-00027","article-title":"Pharmacologic Interaction between Cannabinoid and either Clonidine or Neostigmine in the Rat Formalin Test","volume":"99","author":"Yoon","year":"2003","journal-title":"Anesthesiology"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"3061","DOI":"10.1152\/jn.2001.86.6.3061","article-title":"Selective cannabinoid CB1 receptor activation inhibits spinal nociceptive transmission in vivo","volume":"86","author":"Kelly","year":"2001","journal-title":"J. Neurophysiol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2079","DOI":"10.1046\/j.1460-9568.2000.00101.x","article-title":"Activation of spinal cannabinoid1receptors inhibits C-fibre driven hyperexcitable neuronal responses and increases [35S]GTP\u03b3S binding in the dorsal horn of the spinal cord of noninflamed and inflamed rats","volume":"12","author":"Drew","year":"2000","journal-title":"Eur. J. Neurosci."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1523\/JNEUROSCI.18-01-00451.1998","article-title":"Hypoactivity of the Spinal Cannabinoid System Results in NMDA-Dependent Hyperalgesia","volume":"18","author":"Richardson","year":"1998","journal-title":"J. Neurosci."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1111\/j.1440-1681.2007.04592.x","article-title":"CB1 receptor activation in the basolateral amygdala produces antinociception in animal models of acute and tonic nociception","volume":"34","author":"Hasanein","year":"2007","journal-title":"Clin. Exp. Pharmacol. Physiol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1177\/0269881110379507","article-title":"Overexpression of CB2 cannabinoid receptors decreased vulnerability to anxiety and impaired anxiolytic action of alprazolam in mice","volume":"25","author":"Manzanares","year":"2011","journal-title":"J. Psychopharmacol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/j.neulet.2019.03.010","article-title":"Cannabinoid CB1 receptors mediate the anxiolytic effects induced by systemic alprazolam and intra-periaqueductal gray 5-HT1A receptor activation","volume":"703","author":"Batista","year":"2019","journal-title":"Neurosci. Lett."},{"key":"ref_52","first-page":"945","article-title":"A time-dependent contribution of hippocampal CB 1, CB 2 and PPAR\u03b3 receptors to cannabidiol-induced disruption of fear memory consolidation","volume":"177","author":"Raymundi","year":"2019","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.neuroscience.2019.08.041","article-title":"Involvement of Spinal Cannabinoid CB2 Receptors in Exercise-Induced Antinociception","volume":"418","author":"Sorgi","year":"2019","journal-title":"Neuroscience"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"12125","DOI":"10.1523\/JNEUROSCI.3400-08.2008","article-title":"Crucial Role of CB2 Cannabinoid Receptor in the Regulation of Central Immune Responses during Neuropathic Pain","volume":"28","author":"Racz","year":"2008","journal-title":"J. Neurosci."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"7468","DOI":"10.1038\/s41598-019-43858-4","article-title":"CB2 receptor deletion on myeloid cells enhanced mechanical allodynia in a mouse model of neuropathic pain","volume":"9","author":"Nent","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1016\/j.pain.2010.03.017","article-title":"A polymorphism in exon 2 of the \u03b4-opioid receptor affects nociception in response to specific agonists and antagonists in mice selectively bred for high and low analgesia","volume":"149","author":"Sacharczuk","year":"2010","journal-title":"Pain"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"4162","DOI":"10.1523\/JNEUROSCI.0274-19.2019","article-title":"Kappa Opioid Receptors Drive a Tonic Aversive Component of Chronic Pain","volume":"39","author":"Liu","year":"2019","journal-title":"J. Neurosci."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1038\/s41398-019-0565-8","article-title":"Role of the dorsal periaqueductal gray in posttraumatic stress disorder: Mediation by dopamine and neurokinin","volume":"9","author":"Lovick","year":"2019","journal-title":"Transl. Psychiatry"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/0006-8993(86)91380-6","article-title":"Differentiation of neurochemical basis of stress-induced analgesia in mice by selective breeding","volume":"397","author":"Panocka","year":"1986","journal-title":"Brain Res."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"891","DOI":"10.12688\/f1000research.18338.1","article-title":"A refinement to the formalin test in mice","volume":"8","author":"Lopes","year":"2019","journal-title":"F1000Res"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2\u2212\u0394\u0394CT Method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"814","DOI":"10.1002\/ejlt.201500115","article-title":"Optimized extraction of 2-arachidonyl glycerol and anandamide from aortic tissue and plasma for quantification by LC-MS\/MS","volume":"118","author":"Garst","year":"2016","journal-title":"Eur. 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