{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T12:46:34Z","timestamp":1792154794037,"version":"4.4.0"},"reference-count":117,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2018,10,11]],"date-time":"2018-10-11T00:00:00Z","timestamp":1539216000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01DA01851"],"award-info":[{"award-number":["R01DA01851"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001505","name":"Health Research Council of New Zealand","doi-asserted-by":"publisher","award":["16\/646"],"award-info":[{"award-number":["16\/646"]}],"id":[{"id":"10.13039\/501100001505","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>The acute activation of kappa opioid receptors (KOPr) produces antinociceptive and anti-cocaine effects, however, their side-effects have limited further clinical development. Mesyl Sal B is a potent and selective KOPr analogue of Salvinorin A (Sal A), a psychoactive natural product isolated from the plant Salvia divinorum. We assessed the antinociceptive, anti-cocaine, and side-effects of Mesyl Sal B. The anti-cocaine effects are evaluated in cocaine-induced hyperactivity and behavioral sensitization to cocaine in male Sprague Dawley rats. Mesyl Sal B was assessed for anhedonia (conditioned taste aversion), aversion (conditioned place aversion), pro-depressive effects (forced swim test), anxiety (elevated plus maze) and learning and memory deficits (novel object recognition). In male B6.SJL mice, the antinociceptive effects were evaluated in warm-water (50 \u00b0C) tail withdrawal and intraplantar formaldehyde (2%) assays and the sedative effects measured with the rotarod performance task. Mesyl Sal B (0.3 mg\/kg) attenuated cocaine-induced hyperactivity and behavioral sensitization to cocaine without modulating sucrose self-administration and without producing aversion, sedation, anxiety, or learning and memory impairment in rats. However, increased immobility was observed in the forced swim test indicating pro-depressive effects. Mesyl Sal B was not as potent as Sal A at reducing pain in the antinociceptive assays. In conclusion, Mesyl Sal B possesses anti-cocaine effects, is longer acting in vivo and has fewer side-effects when compared to Sal A, however, the antinociceptive effects are limited.<\/jats:p>","DOI":"10.3390\/molecules23102602","type":"journal-article","created":{"date-parts":[[2018,10,12]],"date-time":"2018-10-12T02:58:04Z","timestamp":1539313084000},"page":"2602","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["Kappa Opioid Receptor Agonist Mesyl Sal B Attenuates Behavioral Sensitization to Cocaine with Fewer Aversive Side-Effects than Salvinorin A in Rodents"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9699-553X","authenticated-orcid":false,"given":"Bronwyn M.","family":"Kivell","sequence":"first","affiliation":[{"name":"School of Biological Science, Centre for Biodiscovery, Victoria University of Wellington, P.O. Box 600, Wellington, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5334-5497","authenticated-orcid":false,"given":"Kelly F.","family":"Paton","sequence":"additional","affiliation":[{"name":"School of Biological Science, Centre for Biodiscovery, Victoria University of Wellington, P.O. Box 600, Wellington, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nitin","family":"Kumar","sequence":"additional","affiliation":[{"name":"School of Biological Science, Centre for Biodiscovery, Victoria University of Wellington, P.O. Box 600, Wellington, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aashish S.","family":"Morani","sequence":"additional","affiliation":[{"name":"School of Biological Science, Centre for Biodiscovery, Victoria University of Wellington, P.O. Box 600, Wellington, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aimee","family":"Culverhouse","sequence":"additional","affiliation":[{"name":"School of Biological Science, Centre for Biodiscovery, Victoria University of Wellington, P.O. Box 600, Wellington, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy","family":"Shepherd","sequence":"additional","affiliation":[{"name":"School of Biological Science, Centre for Biodiscovery, Victoria University of Wellington, P.O. Box 600, Wellington, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan A.","family":"Welsh","sequence":"additional","affiliation":[{"name":"School of Biological Science, Centre for Biodiscovery, Victoria University of Wellington, P.O. Box 600, Wellington, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Biggerstaff","sequence":"additional","affiliation":[{"name":"School of Biological Science, Centre for Biodiscovery, Victoria University of Wellington, P.O. Box 600, Wellington, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6366-5577","authenticated-orcid":false,"given":"Rachel S.","family":"Crowley","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, University of Kansas, Lawrence, KS 6604, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0649-8052","authenticated-orcid":false,"given":"Thomas E.","family":"Prisinzano","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, University of Kansas, Lawrence, KS 6604, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,10,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1038\/npp.2009.110","article-title":"Neurocircuitry of addiction","volume":"35","author":"Koob","year":"2010","journal-title":"Neuropsychopharmacology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3113","DOI":"10.1098\/rstb.2008.0094","article-title":"Neurobiological mechanisms for opponent motivational processes in addiction","volume":"363","author":"Koob","year":"2008","journal-title":"Philos. Trans. R. Soc. Lond. B Biol. Sci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/S0014-2999(96)00961-2","article-title":"Kappa-opioid receptor agonist U50,488H modulates cocaine and morphine self-administration in drug-naive rats and mice","volume":"321","author":"Kuzmin","year":"1997","journal-title":"Eur. J. Pharmacol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/0006-8993(95)00306-B","article-title":"Kappa opioid inhibition of morphine and cocaine self-administration in rats","volume":"681","author":"Glick","year":"1995","journal-title":"Brain Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1007\/s002130000424","article-title":"Dissociable effects of the \u03ba-opioid receptor agonists bremazocine, U69593, and U50488H on locomotor activity and long-term behavioral sensitization induced by amphetamine and cocaine","volume":"150","author":"Vanderschuren","year":"2000","journal-title":"Psychopharmacology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1097\/00008877-200107000-00002","article-title":"Kappa opioid agonists alter dopamine markers and cocaine-stimulated locomotor activity","volume":"12","author":"Collins","year":"2001","journal-title":"Behav. Pharmacol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1016\/S0022-3565(25)12305-7","article-title":"kappa-Opioid receptor agonists prevent sensitization to the conditioned rewarding effects of cocaine","volume":"276","author":"Shippenberg","year":"1996","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1016\/S0022-3565(25)12030-2","article-title":"Development of behavioral sensitization to cocaine: Influence of kappa opioid receptor agonists","volume":"275","author":"Heidbreder","year":"1995","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1007\/s002130051016","article-title":"U69593, a kappa-opioid agonist, decreases cocaine self-administration and decreases cocaine-produced drug-seeking","volume":"144","author":"Schenk","year":"1999","journal-title":"Psychopharmacology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1007\/s002130000476","article-title":"Reinstatement of extinguished drug-taking behavior in rats: Effect of the kappa-opioid receptor agonist, U69593","volume":"151","author":"Schenk","year":"2000","journal-title":"Psychopharmacology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1797","DOI":"10.1097\/00001756-199409080-00028","article-title":"U-69593 prevents cocaine sensitization by normalizing basal accumbens dopamine","volume":"5","author":"Heidbreder","year":"1994","journal-title":"Neuroreport"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"9333","DOI":"10.1523\/JNEUROSCI.20-24-09333.2000","article-title":"Kappa-opioid receptor activation modifies dopamine uptake in the nucleus accumbens and opposes the effects of cocaine","volume":"20","author":"Thompson","year":"2000","journal-title":"J. Neurosci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"5029","DOI":"10.1523\/JNEUROSCI.0854-05.2005","article-title":"Endogenous kappa-opioid receptor systems regulate mesoaccumbal dopamine dynamics and vulnerability to cocaine","volume":"25","author":"Chefer","year":"2005","journal-title":"J. Neurosci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1016\/j.neuropharm.2014.07.016","article-title":"Salvinorin A regulates dopamine transporter function via a kappa opioid receptor and ERK1\/2-dependent mechanism","volume":"86","author":"Kivell","year":"2014","journal-title":"Neuropharmacology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2938","DOI":"10.1073\/pnas.0511159103","article-title":"Kappa opioids selectively control dopaminergic neurons projecting to the prefrontal cortex","volume":"103","author":"Margolis","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1007\/s00213-003-1680-y","article-title":"Effects of kappa-opioid receptor ligands on intracranial self-stimulation in rats","volume":"172","author":"Todtenkopf","year":"2004","journal-title":"Psychopharmacology"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1126\/science.3016896","article-title":"Psychotomimesis mediated by kappa opiate receptors","volume":"233","author":"Pfeiffer","year":"1986","journal-title":"Science"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1007\/s002130100788","article-title":"Enadoline, a selective kappa opioid agonist: Comparison with butorphanol and hydromorphone in humans","volume":"157","author":"Walsh","year":"2001","journal-title":"Psychopharmacology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1111\/j.1749-6632.2000.tb06678.x","article-title":"Interactions between kappa opioid agonists and cocaine. Preclinical studies","volume":"909","author":"Mello","year":"2000","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/0024-3205(86)90309-7","article-title":"Preference conditioning produced by opioid active and inactive isomers of levorphanol and morphine in rat","volume":"38","author":"Mucha","year":"1986","journal-title":"Life Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1016\/S0022-3565(25)10296-6","article-title":"Neuroanatomical sites mediating the motivational effects of opioids as mapped by the conditioned place preference paradigm in rats","volume":"264","author":"Ableitner","year":"1993","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1124\/jpet.114.216820","article-title":"The G protein-biased kappa-opioid receptor agonist RB-64 is analgesic with a unique spectrum of activities in vivo","volume":"352","author":"White","year":"2015","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"ra117","DOI":"10.1126\/scisignal.aai8441","article-title":"Biased agonists of the kappa opioid receptor suppress pain and itch without causing sedation or dysphoria","volume":"9","author":"Brust","year":"2016","journal-title":"Sci. Signal."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1111\/bph.12692","article-title":"Pharmacology and anti-addiction effects of the novel kappa opioid receptor agonist Mesyl Sal B, a potent and long-acting analogue of salvinorin A","volume":"172","author":"Simonson","year":"2015","journal-title":"Br. J. Pharmacol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1124\/jpet.115.225896","article-title":"Functional selectivity of kappa opioid receptor agonists in peripheral sensory neurons","volume":"355","author":"Jamshidi","year":"2015","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1111\/jcpt.12404","article-title":"Will peripherally restricted kappa-opioid receptor agonists (pKORAs) relieve pain with less opioid adverse effects and abuse potential?","volume":"41","author":"Boyd","year":"2016","journal-title":"J. Clin. Pharm. Ther."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1016\/j.bmcl.2004.12.018","article-title":"Synthesis and evaluation of novel peripherally restricted kappa-opioid receptor agonists","volume":"15","author":"Kumar","year":"2005","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"11934","DOI":"10.1073\/pnas.182234399","article-title":"Salvinorin A: A potent naturally occurring nonnitrogenous kappa opioid selective agonist","volume":"99","author":"Roth","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1124\/jpet.103.059394","article-title":"Salvinorin A, an active component of the hallucinogenic sage salvia divinorum is a highly efficacious kappa-opioid receptor agonist: Structural and functional considerations","volume":"308","author":"Chavkin","year":"2004","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1124\/jpet.105.092304","article-title":"Depressive-like effects of the kappa-opioid receptor agonist salvinorin A on behavior and neurochemistry in rats","volume":"316","author":"Carlezon","year":"2006","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1007\/s00213-008-1458-3","article-title":"Comparison of the discriminative stimulus effects of salvinorin A and its derivatives to U69,593 and U50,488 in rats","volume":"203","author":"Baker","year":"2009","journal-title":"Psychopharmacology"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1124\/jpet.107.132142","article-title":"2-Methoxymethyl-salvinorin B is a potent kappa opioid receptor agonist with longer lasting action in vivo than salvinorin A","volume":"324","author":"Wang","year":"2008","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1016\/j.pbb.2009.09.002","article-title":"Effect of kappa-opioid receptor agonists U69593, U50488H, spiradoline and salvinorin A on cocaine-induced drug-seeking in rats","volume":"94","author":"Morani","year":"2009","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2499","DOI":"10.1007\/s00213-017-4637-2","article-title":"The C-2 derivatives of salvinorin A, ethoxymethyl ether Sal B and beta-tetrahydropyran Sal B, have anti-cocaine properties with minimal side effects","volume":"234","author":"Ewald","year":"2017","journal-title":"Psychopharmacology"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1002\/syn.20191","article-title":"Pharmacokinetics of the plant-derived kappa-opioid hallucinogen salvinorin A in nonhuman primates","volume":"58","author":"Schmidt","year":"2005","journal-title":"Synapse"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"588","DOI":"10.1124\/jpet.108.145342","article-title":"Unconditioned behavioral effects of the powerful kappa-opioid hallucinogen salvinorin A in nonhuman primates: Fast onset and entry into cerebrospinal fluid","volume":"328","author":"Butelman","year":"2009","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1016\/j.lfs.2005.09.008","article-title":"Psychopharmacology of the hallucinogenic sage Salvia divinorum","volume":"78","author":"Prisinzano","year":"2005","journal-title":"Life Sci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1124\/jpet.112.193227","article-title":"Behavioral effects and central nervous system levels of the broadly available kappa-agonist hallucinogen salvinorin A are affected by P-glycoprotein modulation in vivo","volume":"341","author":"Butelman","year":"2012","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1966","DOI":"10.1111\/j.1742-4658.2006.05212.x","article-title":"A unique binding epitope for salvinorin A, a non-nitrogenous kappa opioid receptor agonist","volume":"273","author":"Kane","year":"2006","journal-title":"FEBS J."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1824","DOI":"10.1021\/jm701040v","article-title":"Toward a structure-based model of salvinorin A recognition of the kappa-opioid receptor","volume":"51","author":"Kane","year":"2008","journal-title":"J. Med. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"4765","DOI":"10.1021\/jm048963m","article-title":"Neoclerodane diterpenes as a novel scaffold for mu opioid receptor ligands","volume":"48","author":"Harding","year":"2005","journal-title":"J. Med. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1021\/jm049438q","article-title":"Studies toward the pharmacophore of salvinorin A, a potent kappa opioid receptor agonist","volume":"48","author":"Munro","year":"2005","journal-title":"J. Med. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1279","DOI":"10.1016\/j.bmc.2007.10.067","article-title":"Standard protecting groups create potent and selective kappa opioids: Salvinorin B alkoxymethyl ethers","volume":"16","author":"Munro","year":"2008","journal-title":"Bioorg. Med. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"4679","DOI":"10.1016\/j.bmcl.2006.05.093","article-title":"Synthesis and in vitro evaluation of salvinorin A analogues: Effect of configuration at C(2) and substitution at C(18)","volume":"16","author":"Beguin","year":"2006","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1732","DOI":"10.1021\/cr0782269","article-title":"Salvinorin A analogs as probes in opioid pharmacology","volume":"108","author":"Prisinzano","year":"2008","journal-title":"Chem. Rev."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1039\/B912196J","article-title":"New therapeutic potential for psychoactive natural products","volume":"27","author":"Prisinzano","year":"2010","journal-title":"Nat. Prod. Rep."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.ejphar.2013.10.050","article-title":"The 2-methoxy methyl analogue of salvinorin A attenuates cocaine-induced drug seeking and sucrose reinforcements in rats","volume":"720","author":"Morani","year":"2013","journal-title":"Eur. J. Pharmacol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1217","DOI":"10.1039\/c1md00192b","article-title":"Potential Drug Abuse Therapeutics Derived from the Hallucinogenic Natural Product Salvinorin A","volume":"2","author":"Lovell","year":"2011","journal-title":"MedChemComm"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"914","DOI":"10.1021\/np060094b","article-title":"Synthesis of salvinorin A analogues as opioid receptor probes","volume":"69","author":"Tidgewell","year":"2006","journal-title":"J. Nat. Prod."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.brainres.2017.02.027","article-title":"Synergistic blockade of alcohol escalation drinking in mice by a combination of novel kappa opioid receptor agonist Mesyl Salvinorin B and naltrexone","volume":"1662","author":"Zhou","year":"2017","journal-title":"Brain Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2833","DOI":"10.1111\/j.1460-9568.2004.03712.x","article-title":"A single high dose of cocaine induces behavioral sensitization and modifies mRNA encoding GluR1 and GAP-43 in rats","volume":"20","author":"Grignaschi","year":"2004","journal-title":"Eur. J. Neurosci."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/0165-0173(91)90007-U","article-title":"Dopamine transmission in the initiation and expression of drug- and stress-induced sensitization of motor activity","volume":"16","author":"Kalivas","year":"1991","journal-title":"Brain Res. Brain Res. Rev."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1016\/S0022-3565(25)20628-0","article-title":"Role of extracellular dopamine in the initiation and long-term expression of behavioral sensitization to cocaine","volume":"278","author":"Heidbreder","year":"1996","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1177\/026988119801200107","article-title":"A role for sensitization in craving and relapse in cocaine addiction","volume":"12","author":"Kalivas","year":"1998","journal-title":"J. Psychopharmacol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1016\/S0022-3565(25)24578-5","article-title":"Opposite effects of mu and kappa opiate agonists on dopamine release in the nucleus accumbens and in the dorsal caudate of freely moving rats","volume":"244","author":"Imperato","year":"1988","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1002\/syn.890050104","article-title":"Effect of acute and daily cocaine treatment on extracellular dopamine in the nucleus accumbens","volume":"5","author":"Kalivas","year":"1990","journal-title":"Synapse"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1523\/JNEUROSCI.13-01-00266.1993","article-title":"Time course of extracellular dopamine and behavioral sensitization to cocaine. I. Dopamine axon terminals","volume":"13","author":"Kalivas","year":"1993","journal-title":"J. Neurosci."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1007\/s002130050454","article-title":"Extracellular dopamine, norepinephrine, and serotonin in the ventral tegmental area and nucleus accumbens of freely moving rats during intracerebral dialysis following systemic administration of cocaine and other uptake blockers","volume":"134","author":"Reith","year":"1997","journal-title":"Psychopharmacology"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/S0014-2999(99)00824-9","article-title":"Psychostimulant sensitization: Differential changes in accumbal shell and core dopamine","volume":"388","author":"Cadoni","year":"2000","journal-title":"Eur. J. Pharmacol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/0165-0173(93)90013-P","article-title":"The neural basis of drug craving: An incentive-sensitization theory of addiction","volume":"18","author":"Robinson","year":"1993","journal-title":"Brain Res. Rev."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1046\/j.1360-0443.2001.9611038.x","article-title":"Incentive-sensitization and addiction","volume":"96","author":"Robinson","year":"2001","journal-title":"Addiction"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1146\/annurev.psych.54.101601.145237","article-title":"Addiction","volume":"54","author":"Robinson","year":"2003","journal-title":"Annu. Rev. Psychol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1007\/s00213-004-2087-0","article-title":"Effects of the plant-derived hallucinogen salvinorin A on basal dopamine levels in the caudate putamen and in a conditioned place aversion assay in mice: Agonist actions at kappa opioid receptors","volume":"179","author":"Zhang","year":"2005","journal-title":"Psychopharmacology"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1097\/00008877-200512000-00005","article-title":"Kappa-opioid receptor-mediated effects of the plant-derived hallucinogen, salvinorin A, on inverted screen performance in the mouse","volume":"16","author":"Fantegrossi","year":"2005","journal-title":"Behav. Pharmacol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1007\/s00213-009-1771-5","article-title":"The discriminative effects of the \u03ba-opioid hallucinogen salvinorin A in nonhuman primates: Dissociation from classic hallucinogen effects","volume":"210","author":"Butelman","year":"2010","journal-title":"Psychopharmacology"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1007\/s00213-010-1836-5","article-title":"Depressive-like effects of the kappa opioid receptor agonist salvinorin A are associated with decreased phasic dopamine release in the nucleus accumbens","volume":"210","author":"Ebner","year":"2010","journal-title":"Psychopharmacology"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"4309","DOI":"10.1007\/s00213-014-3571-9","article-title":"Effects of systemic opioid receptor ligands on ethanol- and sucrose seeking and drinking in alcohol-preferring (P) and Long Evans rats","volume":"231","author":"Czachowski","year":"2014","journal-title":"Psychopharmacology"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"4293","DOI":"10.1523\/JNEUROSCI.6146-08.2009","article-title":"Endogenous kappa opioid activation mediates stress-induced deficits in learning and memory","volume":"29","author":"Carey","year":"2009","journal-title":"J. Neurosci."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/0165-0270(85)90031-7","article-title":"Validation of open:closed arm entries in an elevated plus-maze as a measure of anxiety in the rat","volume":"14","author":"Pellow","year":"1985","journal-title":"J. Neurosci. Methods"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1016\/0378-8741(83)90004-1","article-title":"Ethnopharmacology of ska Maria Pastora (Salvia divinorum, Epling and Jativa-M.)","volume":"7","author":"Valdes","year":"1983","journal-title":"J. Ethnopharmacol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"4716","DOI":"10.1021\/jo00198a026","article-title":"Divinorin A, a psychotropic terpenoid, and divinorin B from the hallucinogenic Mexican mint, Salvia divinorum","volume":"49","author":"Valdes","year":"1984","journal-title":"J. Org. Chem."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1097\/FBP.0b013e3283512c1e","article-title":"A single injection of a novel kappa opioid receptor agonist salvinorin A attenuates the expression of cocaine-induced behavioral sensitization in rats","volume":"23","author":"Morani","year":"2012","journal-title":"Behav. Pharmacol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1137","DOI":"10.1002\/ibd.21873","article-title":"Salvinorin A has antiinflammatory and antinociceptive effects in experimental models of colitis in mice mediated by KOR and CB1 receptors","volume":"18","author":"Fichna","year":"2012","journal-title":"Inflamm. Bowel Dis."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1186\/1744-8069-8-60","article-title":"Salvinorin A reduces mechanical allodynia and spinal neuronal hyperexcitability induced by peripheral formalin injection","volume":"8","author":"Guida","year":"2012","journal-title":"Mol. Pain"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.ejphar.2006.06.077","article-title":"The antinociceptive effect of salvinorin A in mice","volume":"545","author":"John","year":"2006","journal-title":"Eur. J. Pharmacol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.pbb.2005.12.011","article-title":"Antinociceptive profile of salvinorin A, a structurally unique kappa opioid receptor agonist","volume":"83","author":"McCurdy","year":"2006","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1002\/ejp.1002","article-title":"The analgesic and anti-inflammatory effects of Salvinorin A analogue beta-tetrahydropyran Salvinorin B in mice","volume":"21","author":"Paton","year":"2017","journal-title":"Eur. J. Pain"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1177\/1091581811418538","article-title":"Learning and memory impairment induced by salvinorin A, the principal ingredient of Salvia divinorum, in wistar rats","volume":"30","author":"Braida","year":"2011","journal-title":"Int. J. Toxicol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"11027","DOI":"10.1021\/acs.jmedchem.6b01235","article-title":"Synthetic studies of neoclerodane diterpenes from Salvia divinorum: Identification of a potent and centrally acting mu opioid analgesic with reduced abuse liability","volume":"59","author":"Crowley","year":"2016","journal-title":"J. Med. Chem."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"10464","DOI":"10.1021\/jm501521d","article-title":"Synthesis and kappa-opioid receptor activity of furan-substituted salvinorin A analogues","volume":"57","author":"Riley","year":"2014","journal-title":"J. Med. Chem."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"3866","DOI":"10.1021\/acs.jmedchem.7b00148","article-title":"Addressing structural flexibility at the A-ring on Salvinorin A: Discovery of a potent kappa opioid agonist with enhanced metabolic stability","volume":"60","author":"Sherwood","year":"2017","journal-title":"J. Med. Chem."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1016\/j.ejphar.2015.07.018","article-title":"Biased agonism at kappa opioid receptors: Implication in pain and mood disorders","volume":"763","author":"Dogra","year":"2015","journal-title":"Eur. J. Pharmacol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.cellsig.2017.01.016","article-title":"Nalfurafine is a G-protein biased agonist having significantly greater bias at the human than rodent form of the kappa opioid receptor","volume":"32","author":"Schattauer","year":"2017","journal-title":"Cell Signal."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/j.ejphar.2015.05.054","article-title":"Intrinsic relative activities of kappa opioid agonists in activating Galpha proteins and internalizing receptor: Differences between human and mouse receptors","volume":"761","author":"DiMattio","year":"2015","journal-title":"Eur. J. Pharmacol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1007\/s00109-011-0752-4","article-title":"Ultrapotent effects of salvinorin A, a hallucinogenic compound from Salvia divinorum, on LPS-stimulated murine macrophages and its anti-inflammatory action in vivo","volume":"89","author":"Aviello","year":"2011","journal-title":"J. Mol. Med. (Berl)"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1016\/j.neuropharm.2015.08.032","article-title":"Noribogaine is a G-protein biased kappa-opioid receptor agonist","volume":"99","author":"Maillet","year":"2015","journal-title":"Neuropharmacology"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.brainres.2009.08.062","article-title":"The dynorphin\/kappa opioid system as a modulator of stress-induced and pro-addictive behaviors","volume":"1314","author":"Bruchas","year":"2010","journal-title":"Brain Res."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1016\/0006-8993(92)91327-B","article-title":"Basal extracellular dopamine levels in the nucleus accumbens are decreased during cocaine withdrawal after unlimited-access self-administration","volume":"593","author":"Weiss","year":"1992","journal-title":"Brain Res."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/S0022-3565(24)36769-2","article-title":"Effects of kappa opioids on cocaine self-administration by rhesus monkeys","volume":"282","author":"Negus","year":"1997","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1016\/S0022-3565(24)37657-8","article-title":"Effects of kappa opioid agonists on cocaine- and food-maintained responding by rhesus monkeys","volume":"286","author":"Mello","year":"1998","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"2761","DOI":"10.1016\/j.bmcl.2005.03.113","article-title":"Synthesis and in vitro pharmacological evaluation of salvinorin A analogues modified at C(2)","volume":"15","author":"Beguin","year":"2005","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"2181","DOI":"10.1016\/S0196-9781(02)00246-2","article-title":"Intraventricular insulin decreases kappa opioid-mediated sucrose intake in rats","volume":"23","author":"Sipols","year":"2002","journal-title":"Peptides"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/S0006-8993(01)02624-5","article-title":"The kappa-opioid antagonist GNTI reduces U50,488-, DAMGO-, and deprivation-induced feeding, but not butorphanol- and neuropeptide Y-induced feeding in rats","volume":"909","author":"Jewett","year":"2001","journal-title":"Brain Res."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1016\/S0306-4522(97)00605-2","article-title":"Hippocampal dynorphin B injections impair spatial learning in rats: A kappa-opioid receptor-mediated effect","volume":"85","author":"Sandin","year":"1998","journal-title":"Neuroscience"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/0166-4328(88)90168-4","article-title":"The amygdala mediates the impairing effect of the selective kappa-opioid receptor agonist U-50,488 on memory in CD1 mice","volume":"30","author":"Castellano","year":"1988","journal-title":"Behav. Brain Res."},{"key":"ref_96","unstructured":"Paris, J.J., Reilley, K.J., and McLaughlin, J.P. (2011). Kappa Opioid Receptor-Mediated Disruption of Novel Object Recognition: Relevance for Psychostimulant Treatment. J. Addict. Res. Ther., S4."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1932","DOI":"10.1038\/npp.2010.67","article-title":"Behavioral stress may increase the rewarding valence of cocaine-associated cues through a dynorphin\/kappa-opioid receptor-mediated mechanism without affecting associative learning or memory retrieval mechanisms","volume":"35","author":"Schindler","year":"2010","journal-title":"Neuropsychopharmacology"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1016\/S0959-4388(96)80082-1","article-title":"CREB and the formation of long-term memory","volume":"6","author":"Yin","year":"1996","journal-title":"Curr. Opin. Neurobiol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1007\/s00213-010-1806-y","article-title":"Kinase cascades and ligand-directed signaling at the kappa opioid receptor","volume":"210","author":"Bruchas","year":"2010","journal-title":"Psychopharmacology"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/0014-2999(88)90094-5","article-title":"Mu-, delta- and kappa-opioid receptor-mediated inhibition of neurotransmitter release and adenylate cyclase activity in rat brain slices: Studies with fentanyl isothiocyanate","volume":"154","author":"Schoffelmeer","year":"1988","journal-title":"Eur. J. Pharmacol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/0006-8993(87)91571-X","article-title":"Place preference conditioning reveals the involvement of D1-dopamine receptors in the motivational properties of mu- and kappa-opioid agonists","volume":"436","author":"Shippenberg","year":"1987","journal-title":"Brain Res."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/S0022-3565(25)38109-7","article-title":"Examination of the neurochemical substrates mediating the motivational effects of opioids: Role of the mesolimbic dopamine system and D-1 vs. D-2 dopamine receptors","volume":"265","author":"Shippenberg","year":"1993","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1770","DOI":"10.1038\/npp.2013.76","article-title":"Prefrontal cortical kappa-opioid receptor modulation of local neurotransmission and conditioned place aversion","volume":"38","author":"Tejeda","year":"2013","journal-title":"Neuropsychopharmacology"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1016\/j.bbr.2017.06.015","article-title":"The long-term effects of stress and kappa opioid receptor activation on conditioned place aversion in male and female California mice","volume":"332","author":"Copeland","year":"2017","journal-title":"Behav. Brain Res."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1016\/j.jep.2013.10.059","article-title":"The effect of Salvia divinorum and Mitragyna speciosa extracts, fraction and major constituents on place aversion and place preference in rats","volume":"151","author":"Sufka","year":"2014","journal-title":"J. Ethnopharmacol."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1016\/j.biopsych.2007.07.020","article-title":"Involvement of kappa-opioid and endocannabinoid system on Salvinorin A-induced reward","volume":"63","author":"Braida","year":"2008","journal-title":"Biol. Psychiatry"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"844","DOI":"10.1111\/j.1476-5381.2009.00230.x","article-title":"Potential anxiolytic- and antidepressant-like effects of salvinorin A, the main active ingredient of Salvia divinorum, in rodents","volume":"157","author":"Braida","year":"2009","journal-title":"Br. J. Pharmacol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1007\/BF02245592","article-title":"Active behaviors in the rat forced swimming test differentially produced by serotonergic and noradrenergic antidepressants","volume":"121","author":"Detke","year":"1995","journal-title":"Psychopharmacology"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1097\/FBP.0b013e3283586189","article-title":"Antidepressive effects of the kappa-opioid receptor agonist salvinorin A in a rat model of anhedonia","volume":"23","author":"Harden","year":"2012","journal-title":"Behav. Pharmacol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"1251","DOI":"10.1093\/ndt\/gfp588","article-title":"Effect of a novel kappa-receptor agonist, nalfurafine hydrochloride, on severe itch in 337 haemodialysis patients: A Phase III, randomized, double-blind, placebo-controlled study","volume":"25","author":"Kumagai","year":"2010","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/S0014-2999(99)00369-6","article-title":"Pharmacological properties of TRK-820 on cloned mu-, delta- and kappa-opioid receptors and nociceptin receptor","volume":"376","author":"Seki","year":"1999","journal-title":"Eur. J. Pharmacol."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"823","DOI":"10.5414\/CP201852","article-title":"One year long-term study on abuse liability of nalfurafine in hemodialysis patients","volume":"51","author":"Ueno","year":"2013","journal-title":"Int. J. Clin. Pharmacol. Ther."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.jphs.2015.11.008","article-title":"Nalfurafine hydrochloride, a selective kappa opioid receptor agonist, has no reinforcing effect on intravenous self-administration in rhesus monkeys","volume":"130","author":"Nakao","year":"2016","journal-title":"J. Pharmacol. Sci."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1124\/jpet.106.112417","article-title":"Effects of salvinorin A, a kappa-opioid hallucinogen, on a neuroendocrine biomarker assay in nonhuman primates with high kappa-receptor homology to humans","volume":"320","author":"Butelman","year":"2007","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_115","doi-asserted-by":"crossref","unstructured":"Munro, T.A., Huang, X.P., Inglese, C., Perrone, M.G., Van\u2019t Veer, A., Carroll, F.I., Beguin, C., Carlezon, W.A., Colabufo, N.A., and Cohen, B.M. (2013). Selective kappa opioid antagonists nor-BNI, GNTI and JDTic have low affinities for non-opioid receptors and transporters. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0070701"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/0304-3959(77)90130-0","article-title":"The formalin test: A quantitative study of the analgesic effects of morphine, meperidine, and brain stem stimulation in rats and cats","volume":"4","author":"Dubuisson","year":"1977","journal-title":"Pain"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1038\/nprot.2007.44","article-title":"The use of the elevated plus maze as an assay of anxiety-related behavior in rodents","volume":"2","author":"Walf","year":"2007","journal-title":"Nat. Protoc."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/23\/10\/2602\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,3]],"date-time":"2026-04-03T19:38:26Z","timestamp":1775245106000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/23\/10\/2602"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,10,11]]},"references-count":117,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2018,10]]}},"alternative-id":["molecules23102602"],"URL":"https:\/\/doi.org\/10.3390\/molecules23102602","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,10,11]]}}}