{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T14:51:16Z","timestamp":1780671076516,"version":"3.54.1"},"reference-count":74,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2023,10,17]],"date-time":"2023-10-17T00:00:00Z","timestamp":1697500800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the National Science Center, Poland","award":["2020\/04\/X\/NZ7\/01338"],"award-info":[{"award-number":["2020\/04\/X\/NZ7\/01338"]}]},{"name":"the National Science Center, Poland","award":["2020\/36\/C\/NZ7\/00284"],"award-info":[{"award-number":["2020\/36\/C\/NZ7\/00284"]}]},{"name":"the National Science Center, Poland","award":["N42\/DBS\/000242"],"award-info":[{"award-number":["N42\/DBS\/000242"]}]},{"name":"the Faculty of Pharmacy Jagiellonian University Medical College, Krakow, Poland","award":["2020\/04\/X\/NZ7\/01338"],"award-info":[{"award-number":["2020\/04\/X\/NZ7\/01338"]}]},{"name":"the Faculty of Pharmacy Jagiellonian University Medical College, Krakow, Poland","award":["2020\/36\/C\/NZ7\/00284"],"award-info":[{"award-number":["2020\/36\/C\/NZ7\/00284"]}]},{"name":"the Faculty of Pharmacy Jagiellonian University Medical College, Krakow, Poland","award":["N42\/DBS\/000242"],"award-info":[{"award-number":["N42\/DBS\/000242"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Itch and pain are closely related but distinct sensations that share largely overlapping mediators and receptors. We hypothesized that the novel, multi-target compound E153 has the potential to attenuate pain and pruritus of different origins. After the evaluation of sigma receptor affinity and pharmacokinetic studies, we tested the compound using different procedures and models of pain and pruritus. Additionally, we used pharmacological tools, such as PRE-084, RAMH, JNJ 5207852, and S1RA, to precisely determine the role of histamine H3 and sigma 1 receptors in the analgesic and antipruritic effects of the compound. In vitro studies revealed that the test compound had potent affinity for sigma 1 and sigma 2 receptors, moderate affinity for opioid kappa receptors, and no affinity for delta or \u03bc receptors. Pharmacokinetic studies showed that after intraperitoneal administration, the compound was present at high concentrations in both the peripheral tissues and the central nervous system. The blood\u2013brain barrier-penetrating properties indicate its ability to act centrally at the levels of the brain and spinal cord. Furthermore, the test compound attenuated different types of pain, including acute, inflammatory, and neuropathic. It also showed a broad spectrum of antipruritic activity, attenuating histamine-dependent and histamine-independent itching. Finally, we proved that antagonism of both sigma 1 and histamine H3 receptors is involved in the analgesic activity of the compound, while the antipruritic effect to a greater extent depends on sigma 1 antagonism.<\/jats:p>","DOI":"10.3390\/ph16101481","type":"journal-article","created":{"date-parts":[[2023,10,17]],"date-time":"2023-10-17T08:08:33Z","timestamp":1697530113000},"page":"1481","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Efficacy of the Multi-Target Compound E153 in Relieving Pain and Pruritus of Different Origins"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3072-8890","authenticated-orcid":false,"given":"Szczepan","family":"Mogilski","sequence":"first","affiliation":[{"name":"Department of Pharmacodynamics, Jagiellonian University Medical College, Medyczna 9, 30-688 Krak\u00f3w, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4878-0723","authenticated-orcid":false,"given":"Monika","family":"Kubacka","sequence":"additional","affiliation":[{"name":"Department of Pharmacodynamics, Jagiellonian University Medical College, Medyczna 9, 30-688 Krak\u00f3w, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2476-9709","authenticated-orcid":false,"given":"Artur","family":"\u015awierczek","sequence":"additional","affiliation":[{"name":"Department of Pharmacokinetics and Physical Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krak\u00f3w, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"El\u017cbieta","family":"Wyska","sequence":"additional","affiliation":[{"name":"Department of Pharmacokinetics and Physical Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krak\u00f3w, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katarzyna","family":"Szczepa\u0144ska","sequence":"additional","affiliation":[{"name":"Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9, 30-688 Krak\u00f3w, Poland"},{"name":"Department of Medicinal Chemistry, Maj Institute of Pharmacology, Polish Academy of Sciences, Sm\u0119tna 12, 31-343 Krak\u00f3w, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacek","family":"Sapa","sequence":"additional","affiliation":[{"name":"Department of Pharmacodynamics, Jagiellonian University Medical College, Medyczna 9, 30-688 Krak\u00f3w, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katarzyna","family":"Kie\u0107-Kononowicz","sequence":"additional","affiliation":[{"name":"Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9, 30-688 Krak\u00f3w, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8454-4440","authenticated-orcid":false,"given":"Dorota","family":"\u0141a\u017cewska","sequence":"additional","affiliation":[{"name":"Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9, 30-688 Krak\u00f3w, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,10,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1007\/s40122-017-0091-4","article-title":"Pharmacotherapy for Neuropathic Pain: A Review","volume":"6","author":"Fornasari","year":"2017","journal-title":"Pain Ther."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1671","DOI":"10.1007\/s00424-013-1284-2","article-title":"New insights into the mechanisms of itch: Are pain and itch controlled by distinct mechanisms?","volume":"465","author":"Liu","year":"2013","journal-title":"Pflug. Arch-Eur. J. Physiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1554","DOI":"10.1080\/09546634.2020.1840502","article-title":"Antihistamines-refractory chronic pruritus in psoriatic patients undergoing biologics: Aprepitant vs antihistamine double dosage, a real-world data","volume":"33","author":"Damiani","year":"2022","journal-title":"J. Dermatol. Treat."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1016\/j.neuron.2018.03.023","article-title":"Peripheral and Central Mechanisms of Itch","volume":"98","author":"Dong","year":"2018","journal-title":"Neuron"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1007\/s12264-017-0129-y","article-title":"Modulation of Pain and Itch by Spinal Glia","volume":"34","author":"Tsuda","year":"2018","journal-title":"Neurosci. Bull."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1038\/nn.3289","article-title":"A subpopulation of nociceptors specifically linked to itch","volume":"16","author":"Han","year":"2013","journal-title":"Nat. Neurosci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1016\/j.biocel.2006.11.016","article-title":"Pain signalling pathways: From cytokines to ion channels","volume":"39","author":"Okuse","year":"2007","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/978-3-540-33823-9_1","article-title":"Peripheral and central mechanisms of pain generation","volume":"177","author":"Schaible","year":"2007","journal-title":"Analgesia"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.brainresrev.2008.12.017","article-title":"Peripheral mechanisms of pain and analgesia","volume":"60","author":"Stein","year":"2009","journal-title":"Brain Res. Rev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/j.tins.2020.03.004","article-title":"Getting in Touch with Mechanical Pain Mechanisms","volume":"43","author":"Hill","year":"2020","journal-title":"Trends Neurosci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1610","DOI":"10.1016\/S0140-6736(99)01313-6","article-title":"The neurobiology of pain","volume":"353","author":"Besson","year":"1999","journal-title":"Lancet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1007\/s00424-010-0784-6","article-title":"Understanding inflammatory pain: Ion channels contributing to acute and chronicnociception","volume":"459","author":"Linley","year":"2010","journal-title":"Pflug. Arch-Eur. J. Physiol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1711","DOI":"10.2174\/138161209788186272","article-title":"Neuropathic Pain: Models and Mechanisms","volume":"15","author":"Jarvis","year":"2009","journal-title":"Curr. Pharm. Des."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3651","DOI":"10.1113\/JP273795","article-title":"Mechanisms of pruritogen-induced activation of itch nerves in isolated mouse skin","volume":"595","author":"Ru","year":"2017","journal-title":"J. Physiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"10525","DOI":"10.1073\/pnas.1903316116","article-title":"MRGPRX4 is a G protein-coupled receptor activated by bile acids that may contribute to cholestatic pruritus","volume":"116","author":"Meixiong","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_16","unstructured":"Wu, G.Y., and Tang, Z.X. (2018). Mrgprs: An Essential Role in Itch. Biomed. J., 2."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3052","DOI":"10.1038\/s41467-020-16859-5","article-title":"Central circuit mechanisms of itch","volume":"11","author":"Chen","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1146\/annurev-neuro-083019-024537","article-title":"Neural Mechanisms of Itch","volume":"43","author":"Lay","year":"2020","journal-title":"Annu. Rev. Neurosci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1146\/annurev-physiol-022516-034303","article-title":"Spinal Circuits for Touch, Pain, and Itch","volume":"80","author":"Koch","year":"2018","journal-title":"Annu. Rev. Physiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1038\/s41583-019-0218-1","article-title":"Astrocytes in chronic pain and itch","volume":"20","author":"Ji","year":"2019","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Nelson, T.S., and Taylor, B.K. (2020). Targeting spinal neuropeptide Y1 receptor-expressing interneurons to alleviate chronic pain and itch. Prog. Neurobiol., 196.","DOI":"10.1016\/j.pneurobio.2020.101894"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1111\/ijd.14678","article-title":"Pain and Pruritus: A study of their similarities and differences","volume":"59","author":"Anzelc","year":"2020","journal-title":"Int. J. Dermatol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"5341","DOI":"10.1016\/j.bmc.2017.07.058","article-title":"Biphenyloxy-alkyl-piperidine and azepane derivatives as histamine H3 receptor ligands","volume":"25","author":"Kaleta","year":"2017","journal-title":"Bioorg. Med. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"\u0141a\u017cewska, D., Zar\u0119ba, P., Gody\u0144, J., Doroz-P\u0142onka, A., Frank, A., Reiner-Link, D., Bajda, M., Stary, D., Mogilski, S., and Olejarz-Maciej, A. (2021). Biphenylalkoxyamine Derivatives-Histamine H3 Receptor Ligands with Butyrylcholinesterase Inhibitory Activity. Molecules, 26.","DOI":"10.3390\/molecules26123580"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1016\/j.neuropharm.2018.10.028","article-title":"Drug-receptor kinetics and sigma-1 receptor affinity differentiate clinically evaluated histamine H3 receptor antagonists","volume":"144","author":"Riddy","year":"2019","journal-title":"Neuropharmacology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1111\/cns.12486","article-title":"Preclinical Assessment of Inflammatory Pain","volume":"22","author":"Muley","year":"2015","journal-title":"CNS Neurosci. Ther."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"37835","DOI":"10.1038\/srep37835","article-title":"Sigma-1 Receptor Agonism Promotes Mechanical Allodynia After Priming the Nociceptive System with Capsaicin","volume":"6","author":"Entrena","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"709","DOI":"10.3389\/fphar.2017.00709","article-title":"The Histamine H3 Receptor Antagonist E159 Reverses Memory Deficits Induced by Dizocilpine in Passive Avoidance and Novel Object Recognition Paradigm in Rats","volume":"8","author":"Alachkar","year":"2017","journal-title":"Front. Pharmacol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.neuropharm.2016.04.007","article-title":"Histamine receptors","volume":"106","author":"Haas","year":"2016","journal-title":"Neuropharmacology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.tins.2014.01.001","article-title":"Developmental roles of brain histamine","volume":"37","author":"Panula","year":"2014","journal-title":"Trends Neurosci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1111\/bph.14524","article-title":"Histamine pharmacology: From Sir Henry Dale to the 21st century","volume":"177","author":"Tiligada","year":"2020","journal-title":"Br. J. Pharmacol."},{"key":"ref_32","first-page":"S17","article-title":"Histamine, histamine receptors, and neuropathic pain relief","volume":"174","author":"Obara","year":"2019","journal-title":"Br. J. Pharmacol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1016\/j.pharep.2014.12.019","article-title":"Effects of microinjection of histamine into the anterior cingulate cortex on pain-related behaviors induced by formalin in rats","volume":"67","author":"Tamaddonfard","year":"2015","journal-title":"Pharmacol. Rep."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"S53","DOI":"10.1016\/S0091-6749(03)01877-3","article-title":"Histamine: A mediator of inflammation","volume":"112","author":"MacGlashan","year":"2003","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1016\/j.jdermsci.2017.04.004","article-title":"Combined treatment with H1 and H4 receptor antagonists reduces inflammation in a mouse model of atopic dermatitis","volume":"87","author":"Schaper","year":"2017","journal-title":"J. Dermatol. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.neuroscience.2011.06.002","article-title":"Histamine H1, H3 and H4 receptors are involved in pruritus","volume":"190","author":"Rossbach","year":"2011","journal-title":"Neuroscience"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2203","DOI":"10.1056\/NEJMra033121","article-title":"Advances in H 1-Antihistamines","volume":"351","author":"Simons","year":"2004","journal-title":"N. Engl. J. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1016\/j.neuroscience.2009.12.001","article-title":"Histamine potentiates acid-induced responses mediating transient receptor potential V1 in mouse primary sensory neurons","volume":"166","author":"Kajihara","year":"2010","journal-title":"Neuroscience"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.pbb.2015.03.019","article-title":"Antinociceptive, anti-inflammatory and smooth muscle relaxant activities of the pyrrolo [3,4-d]pyridazinone derivatives: Possible mechanisms of action","volume":"133","author":"Mogilski","year":"2015","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1002\/ejp.1097","article-title":"Effects of S 38093, an antagonist\/inverse agonist of histamine H3 receptors, in models of neuropathic pain in rats","volume":"22","author":"Chaumette","year":"2017","journal-title":"Eur. J. Pain"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.phrs.2014.09.007","article-title":"Histamine in the locus coeruleus promotes descending noradrenergic inhibition of neuropathic hypersensitivity","volume":"90","author":"Wei","year":"2014","journal-title":"Pharmacol. Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1124\/jpet.110.171264","article-title":"H3 Receptors and Pain Modulation: Peripheral, Spinal, and Brain Interactions","volume":"336","author":"Hough","year":"2010","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"33","DOI":"10.3389\/fnsys.2012.00033","article-title":"Histamine neurons in the tuberomamillary nucleus: A whole center or distinct subpopulations?","volume":"6","author":"Blandina","year":"2012","journal-title":"Front. Syst. Neurosci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.neuropharm.2013.01.021","article-title":"Selective brain region activation by histamine H3 receptor antagonist\/inverse agonist ABT-239 enhances acetylcholine and histamine release and increases c-Fos expression","volume":"70","author":"Munari","year":"2013","journal-title":"Neuropharmacology"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/j.jpain.2004.12.003","article-title":"Inhibition of chemical and low-intensity mechanical nociception by activation of histamine H3 receptors","volume":"6","author":"Cannon","year":"2005","journal-title":"J. Pain"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1016\/j.neuropharm.2011.01.004","article-title":"Effects of histamine H3 receptors on chemical hyperalgesia in diabetic rats","volume":"60","author":"Hasanein","year":"2011","journal-title":"Neuropharmacology"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.taap.2017.01.017","article-title":"Ciproxifan, a histamine H3 receptor antagonist and inverse agonist, presynaptically inhibits glutamate release in rat hippocampus","volume":"319","author":"Lu","year":"2017","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1182","DOI":"10.1016\/j.bcp.2007.01.007","article-title":"Structurally novel histamine H3 receptor antagonists GSK207040 and GSK334429 improve scopolamine-induced memory impairment and capsaicin-induced secondary allodynia in rats","volume":"73","author":"Medhurst","year":"2007","journal-title":"Biochem. Pharmacol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2897","DOI":"10.1111\/bph.14185","article-title":"Antinociceptive effects of novel histamine H3 and H4 receptor antagonists and their influence on morphine analgesia of neuropathic pain in the mouse","volume":"175","author":"Latacz","year":"2018","journal-title":"Br. J. Pharmacol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1032","DOI":"10.1124\/jpet.107.120311","article-title":"GSK189254, a Novel H3 Receptor Antagonist That Binds to Histamine H3 Receptors in Alzheimer\u2019s Disease Brain and Improves Cognitive Performance in Preclinical Models","volume":"321","author":"Medhurst","year":"2007","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.ejphar.2007.11.042","article-title":"Antinociceptive effect of novel trihalomethyl-substituted pyrazoline methyl esters in formalin and hot-plate tests in mice","volume":"581","author":"Milano","year":"2008","journal-title":"Eur. J. Pharmacol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.ejphar.2017.01.018","article-title":"Formalin injection produces long-lasting hypersensitivity with characteristics of neuropathic pain","volume":"797","year":"2017","journal-title":"Eur. J. Pharmacol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1016\/j.jpain.2008.12.003","article-title":"Comparison of Oxaliplatin- and Cisplatin-Induced Painful Peripheral Neuropathy in the Rat","volume":"10","author":"Joseph","year":"2009","journal-title":"J. Pain"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/j.ejphar.2005.02.004","article-title":"Anti-exudative effects of opioid receptor agonists in a rat model of carrageenan-induced acute inflammation of the paw","volume":"511","author":"Romero","year":"2005","journal-title":"Eur. J. Pharmacol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.1016\/j.neuropharm.2009.03.011","article-title":"JNJ-10181457, a selective non-imidazole histamine H3 receptor antagonist, normalizes acetylcholine neurotransmission and has efficacy in translational rat models of cognition","volume":"56","author":"Galici","year":"2009","journal-title":"Neuropharmacology"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.physbeh.2016.11.011","article-title":"Cholinergic activation affects the acute and chronic antinociceptive effects of morphine","volume":"169","author":"Gawel","year":"2017","journal-title":"Physiol. Behav."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1046\/j.1365-2133.2003.05341.x","article-title":"Involvement of histamine H3 receptors in scratching behaviour in mast cell-deficient mice","volume":"149","author":"Hossen","year":"2003","journal-title":"Br. J. Dermatol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1124\/jpet.112.194761","article-title":"Antagonism of Supraspinal Histamine H3 Receptors Modulates Spinal Neuronal Activity in Neuropathic Rats","volume":"343","author":"McGaraughty","year":"2012","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1801","DOI":"10.1021\/acschemneuro.7b00200","article-title":"Sigma 2 Receptor\/Tmem97 Agonists Produce Long Lasting Antineuropathic Pain Effects in Mice","volume":"8","author":"Sahn","year":"2017","journal-title":"ACS Chem. Neurosci."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"613","DOI":"10.3389\/fphar.2019.00613","article-title":"Sigma-1 Receptor Inhibition Reduces Neuropathic Pain Induced by Partial Sciatic Nerve Transection in Mice by Opioid-Dependent and -Independent Mechanisms","volume":"10","author":"Perazzoli","year":"2019","journal-title":"Front. Pharmacol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"105339","DOI":"10.1016\/j.phrs.2020.105339","article-title":"Sigma-1 receptor: A drug target for the modulation of neuroimmune and neuroglial interactions during chronic pain","volume":"163","author":"Tejada","year":"2021","journal-title":"Pharmacol. Res."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"136","DOI":"10.3389\/fphar.2019.00136","article-title":"Modulation by Sigma-1 Receptor of Morphine Analgesia and Tolerance: Nociceptive Pain, Tactile Allodynia and Grip Strength Deficits During Joint Inflammation","volume":"10","author":"Tejada","year":"2019","journal-title":"Front. Pharmacol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"634","DOI":"10.3389\/fphar.2019.00634","article-title":"Ligands Exert Biased Activity to Regulate Sigma 1 Receptor Interactions with Cationic TRPA1, TRPV1, and TRPM8 Channels","volume":"10","author":"Onetti","year":"2019","journal-title":"Front. Pharmacol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1097\/FBP.0000000000000038","article-title":"S1RA, a selective sigma-1 receptor antagonist, inhibits inflammatory pain in the carrageenan and complete Freund\u2019s adjuvant models in mice","volume":"25","author":"Gris","year":"2014","journal-title":"Behav. Pharmacol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"422","DOI":"10.3389\/fphar.2019.00422","article-title":"Supraspinal and Peripheral, but Not Intrathecal, \u03c31R Blockade by S1RA Enhances Morphine Antinociception","volume":"10","author":"Carceller","year":"2019","journal-title":"Front. Pharmacol."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Motawe, Z.Y., Abdelmaboud, S.S., Cuevas, J., and Breslin, J.W. (2020). PRE-084 as a tool to uncover potential therapeutic applications for selective sigma-1 receptor activation. Int. J. Biochem. Cell Biol., 126.","DOI":"10.1016\/j.biocel.2020.105803"},{"key":"ref_67","first-page":"E1657","article-title":"TRPV1 channels and the progesterone receptor Sig-1R interact to regulate pain","volume":"115","author":"Islas","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1002\/0471142301.ns0809s41","article-title":"Models of nociception: Hot-plate, tail-flick, and formalin tests in rodents","volume":"41","author":"Bannon","year":"2007","journal-title":"Curr. Protoc. Neurosci."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"2119","DOI":"10.1111\/epi.16669","article-title":"KA-104, a new multitargeted anticonvulsant with potent antinociceptive activity in preclinical models","volume":"61","author":"Mogilski","year":"2020","journal-title":"Epilepsia"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1007\/s00011-016-0997-z","article-title":"Aryl-1,3,5-triazine ligands of histamine H4 receptor attenuate inflammatory and nociceptive response to carrageen, zymosan and lipopolysaccharide","volume":"66","author":"Mogilski","year":"2017","journal-title":"Inflamm. Res."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/j.neuropharm.2017.07.022","article-title":"Antinociceptive, antiallodynic and antihyperalgesic effects of the 5-HT1A receptor selective agonist, NLX-112 in mouse models of pain","volume":"125","author":"Rojek","year":"2017","journal-title":"Neuropharmacology"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1038\/sj.bjp.0705754","article-title":"Involvement of histamine H 4and H 1receptors in scratching induced by histamine receptor agonists in BalbC mice","volume":"142","author":"Bell","year":"2004","journal-title":"Br. J. Pharmacol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1007\/s12264-016-0076-z","article-title":"Antioxidants Attenuate Acute and Chronic Itch: Peripheral and Central Mechanisms of Oxidative Stress in Pruritus","volume":"33","author":"Zhou","year":"2016","journal-title":"Neurosci. Bull."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1016\/j.phrs.2016.09.030","article-title":"Hydrogen sulfide donors alleviate itch secondary to the activation of type-2 protease activated receptors (PAR-2) in mice","volume":"113","author":"Rodrigues","year":"2016","journal-title":"Pharmacol. Res."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/16\/10\/1481\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:08:18Z","timestamp":1760130498000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/16\/10\/1481"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,17]]},"references-count":74,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2023,10]]}},"alternative-id":["ph16101481"],"URL":"https:\/\/doi.org\/10.3390\/ph16101481","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10,17]]}}}