{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T01:41:13Z","timestamp":1780537273205,"version":"3.54.1"},"reference-count":27,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2024,8,7]],"date-time":"2024-08-07T00:00:00Z","timestamp":1722988800000},"content-version":"vor","delay-in-days":6,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Addiction Biology"],"published-print":{"date-parts":[[2024,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The endocannabinoid system interacts with the reward system to modulate responsiveness to natural reinforcers, as well as drugs of abuse. Previous preclinical studies suggested that direct blockade of CB1 cannabinoid receptors (CB1R) could be leveraged as a potential pharmacological approach to treat substance use disorder, but this strategy failed during clinical trials due to severe psychiatric side effects. Alternative strategies have emerged to circumvent the side effects of direct CB1 binding through the development of allosteric modulators. We hypothesized that negative allosteric modulation of CB1R signalling would reduce the reinforcing properties of morphine and decrease behaviours associated with opioid misuse. By employing intravenous self\u2010administration in mice, we studied the effects of GAT358, a functionally\u2010biased CB1R negative allosteric modulator (NAM), on morphine intake, relapse\u2010like behaviour and motivation to work for morphine infusions. GAT358 reduced morphine infusion intake during the maintenance phase of morphine self\u2010administration under a fixed ratio 1 schedule of reinforcement. GAT358 also decreased morphine\u2010seeking behaviour after forced abstinence. Moreover, GAT358 dose dependently decreased the motivation to obtain morphine infusions under a progressive ratio schedule of reinforcement. Strikingly, GAT358 did not affect the motivation to work for food rewards in an identical progressive ratio task, suggesting that the effect of GAT358 in decreasing opioid self\u2010administration was reward specific. Furthermore, GAT58 did not produce motor ataxia in the rotarod test. Our results suggest that CB1R NAMs reduced the reinforcing properties of morphine and could represent a viable therapeutic route to safely decrease misuse of opioids.<\/jats:p>","DOI":"10.1111\/adb.13429","type":"journal-article","created":{"date-parts":[[2024,8,7]],"date-time":"2024-08-07T12:25:27Z","timestamp":1723033527000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Negative allosteric modulation of CB1 cannabinoid receptor signalling decreases intravenous morphine self\u2010administration and relapse in mice"],"prefix":"10.1111","volume":"29","author":[{"given":"Idaira","family":"Oliva","sequence":"first","affiliation":[{"name":"Department of Psychological and Brain Sciences Indiana University Bloomington  Bloomington Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fezaan","family":"Kazi","sequence":"additional","affiliation":[{"name":"Department of Psychological and Brain Sciences Indiana University Bloomington  Bloomington Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucas N.","family":"Cantwell","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences Northeastern University  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ganesh A.","family":"Thakur","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences Northeastern University  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathon D.","family":"Crystal","sequence":"additional","affiliation":[{"name":"Department of Psychological and Brain Sciences Indiana University Bloomington  Bloomington Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0941-6435","authenticated-orcid":false,"given":"Andrea G.","family":"Hohmann","sequence":"additional","affiliation":[{"name":"Department of Psychological and Brain Sciences Indiana University Bloomington  Bloomington Indiana USA"},{"name":"Gill Institute for Neuroscience Indiana University Bloomington  Bloomington Indiana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,8,7]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12916\u2010018\u20101058\u2010y"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1097\/00006205\u2010900000000\u201099727"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2016.00294"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2015.00006"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2006.01.008"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drugalcdep.2014.08.004"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.7b00707"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.coph.2020.08.014"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0707347"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.112.080879"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.12329"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2015.07.017"},{"key":"e_1_2_12_14_1","unstructured":"ThakurGA TichkuleRB KulkarniPM KulkarniAR.Allosteric modulators of the cannabinoid 1 receptor. 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