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We have previously confirmed that novel endomorphin analogues CEMR\u20101 and CEMR\u20102 behaved as potent <jats:italic>\u03bc<\/jats:italic> agonists and displayed potent antinociceptive activities at the supraspinal and peripheral levels. The present study was undertaken to evaluate the antinociceptive properties of CEMR\u20101 and CEMR\u20102 following intrathecal (i.t.) administration. Furthermore, their antinociceptive tolerance and opioid\u2010like side effects were also determined.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>The spinal antinociceptive effects of CEMR\u20101 and CEMR\u20102 were determined in a series of pain models, including acute radiant heat paw withdrawal test, spared nerve injury\u2010induced neuropathic pain, complete Freund's adjuvant\u2010induced inflammatory pain, visceral pain and formalin pain. Antinociceptive tolerance was evaluated in radiant heat paw withdrawal test.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Spinal administration of CEMR\u20101 and CEMR\u20102 produced potent and prolonged antinociceptive effects in acute pain. CEMR\u20101 and CEMR\u20102 may produce their antinociception through distinct <jats:italic>\u03bc<\/jats:italic> receptor subtypes. These two analogues also exhibited significant analgesic activities in neuropathic, inflammatory, visceral and formalin pain at the spinal level. It is noteworthy that CEMR\u20101 showed non\u2010tolerance\u2010forming analgesic properties, while CEMR\u20102 exhibited substantially reduced antinociceptive tolerance. Furthermore, both analogues displayed no or reduced side effects on conditioned place preference response, physical dependence, locomotor activity and gastrointestinal transit.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>The present investigation demonstrated that CEMR\u20101 and CEMR\u20102 displayed potent and long\u2010lasting antinociception with a favourable side effect profile at the spinal level. Therefore, CEMR\u20101 and CEMR\u20102 might serve as promising analgesic compounds with minimal opioid\u2010like side effects.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.16287","type":"journal-article","created":{"date-parts":[[2023,11,22]],"date-time":"2023-11-22T13:47:43Z","timestamp":1700660863000},"page":"1268-1289","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Novel endomorphin analogues CEMR\u20101 and CEMR\u20102 produce potent and long\u2010lasting antinociception with a favourable side effect profile at the spinal level"],"prefix":"10.1111","volume":"181","author":[{"given":"Yu\u2010zhe","family":"Zhang","sequence":"first","affiliation":[{"name":"School of Life Science and Technology Harbin Institute of Technology  Harbin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Si\u2010yu","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Life Science and Technology Harbin Institute of Technology  Harbin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue\u2010ci","family":"Guo","sequence":"additional","affiliation":[{"name":"School of Life Science and Technology Harbin Institute of Technology  Harbin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao\u2010han","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Life Science and Technology Harbin Institute of Technology  Harbin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao\u2010fang","family":"Wang","sequence":"additional","affiliation":[{"name":"Jiangxi University of Chinese Medicine  Nanchang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng\u2010meng","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Life Science and Technology Harbin Institute of Technology  Harbin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting\u2010ting","family":"Qiu","sequence":"additional","affiliation":[{"name":"School of Life Science and Technology Harbin Institute of Technology  Harbin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng\u2010tong","family":"Han","sequence":"additional","affiliation":[{"name":"School of Life Science and Technology Harbin Institute of Technology  Harbin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Life Science and Technology Harbin Institute of Technology  Harbin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7604-3515","authenticated-orcid":false,"given":"Chang\u2010lin","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Life Science and Technology Harbin Institute of Technology  Harbin China"},{"name":"State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources Guangxi Normal University  Guilin China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,1,10]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ddtec.2011.07.007"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15538"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainresbull.2007.07.008"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1097\/j.pain.0000000000001362"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2019.00347"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainresbull.2019.12.001"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1159\/000484207"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpain.2019.03.002"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/35047086"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm300836n"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pain.2005.10.036"},{"issue":"2","key":"e_1_2_12_13_1","first-page":"223","article-title":"Refinement of pain evaluation techniques. 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