Involvement of the Peripheral μ-Opioid Receptor in Tramadol-Induced Constipation in Rodents
Tramadol is a weak opioid that produces analgesic effect via both the μ-opioid receptor (MOR) and non-opioid targets. Constipation is the most common opioid-related side effect in patients with cancer and non-cancer pain. However, the contribution of MOR to tramadol-induced constipation is unclear....
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| Veröffentlicht in: | Biological & pharmaceutical bulletin 2021/11/01, Vol.44(11), pp.1746-1751 |
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| creator | Yasufuku, Kana Koike, Katsumi Kobayashi, Mika Chiba, Hiroki Kitaura, Motoji Takenouchi, Shino Hasegawa, Minoru Morioka, Yasuhide Mishima, Hirokazu Suzuki, Tsutomu Fujita, Masahide |
| description | Tramadol is a weak opioid that produces analgesic effect via both the μ-opioid receptor (MOR) and non-opioid targets. Constipation is the most common opioid-related side effect in patients with cancer and non-cancer pain. However, the contribution of MOR to tramadol-induced constipation is unclear. Therefore, we used naldemedine, a peripherally acting MOR antagonist, and MOR-knockout mice to investigate the involvement of peripheral MOR in tramadol-induced constipation using a small intestinal transit model. A single dose of tramadol (3–100 mg/kg, per os (p.o.)) inhibited small intestinal transit dose-dependently in rats. Naldemedine (0.01–10 mg/kg, p.o.) blocked the inhibition of small intestinal transit induced by tramadol (30 mg/kg, p.o.) in rats. The transition rate increased dose-dependently over the range of naldemedine 0.01–0.3 mg/kg, and complete recovery was observed at 0.3–10 m/kg. Additionally, tramadol (30 and 100 mg/kg, subcutaneously (s.c.)) inhibited small intestinal transit in wild-type mice but not in MOR-knockout mice. These results suggest that peripheral MOR participates in tramadol-induced constipation. |
| doi_str_mv | 10.1248/bpb.b21-00474 |
| format | Article |
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Constipation is the most common opioid-related side effect in patients with cancer and non-cancer pain. However, the contribution of MOR to tramadol-induced constipation is unclear. Therefore, we used naldemedine, a peripherally acting MOR antagonist, and MOR-knockout mice to investigate the involvement of peripheral MOR in tramadol-induced constipation using a small intestinal transit model. A single dose of tramadol (3–100 mg/kg, per os (p.o.)) inhibited small intestinal transit dose-dependently in rats. Naldemedine (0.01–10 mg/kg, p.o.) blocked the inhibition of small intestinal transit induced by tramadol (30 mg/kg, p.o.) in rats. The transition rate increased dose-dependently over the range of naldemedine 0.01–0.3 mg/kg, and complete recovery was observed at 0.3–10 m/kg. Additionally, tramadol (30 and 100 mg/kg, subcutaneously (s.c.)) inhibited small intestinal transit in wild-type mice but not in MOR-knockout mice. 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These results suggest that peripheral MOR participates in tramadol-induced constipation.</description><subject>Analgesics, Opioid - adverse effects</subject><subject>Analgesics, Opioid - blood</subject><subject>Analgesics, Opioid - pharmacokinetics</subject><subject>Animals</subject><subject>constipation</subject><subject>Intestine, Small - drug effects</subject><subject>Male</subject><subject>naldemedine</subject><subject>Naltrexone - adverse effects</subject><subject>Naltrexone - analogs & derivatives</subject><subject>Naltrexone - blood</subject><subject>Naltrexone - pharmacokinetics</subject><subject>Nociception - drug effects</subject><subject>Opioid-Induced Constipation - etiology</subject><subject>Opioid-Induced Constipation - metabolism</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Rats, Wistar</subject><subject>Receptors, Opioid, mu - drug effects</subject><subject>Receptors, Opioid, mu - metabolism</subject><subject>tramadol</subject><subject>Tramadol - adverse effects</subject><subject>Tramadol - blood</subject><subject>Tramadol - pharmacokinetics</subject><subject>μ-opioid receptor</subject><issn>0918-6158</issn><issn>1347-5215</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kE1v1DAQQC1ERbcfR64oRy4uHsd2kiNaCl2pUlFVbkiWY49ZV0kcbG8l_hu_gd_UbLfsZeYwT0-aR8h7YFfARfupn_urngNlTDTiDVlBLRoqOci3ZMU6aKkC2Z6Ss5wfGWMN4_U7crow0CnJVuTnZnqKwxOOOJUq-qpssfqOKcxbTGao_v2ld3OIwVX3aHEuMVVhqh6SGY2LA91MbmfRVes45RJmU0Kc9sB9dIsvX5ATb4aMl6_7nPz4ev2wvqG3d98268-31Iq2LrQFD70H0RtnPDdeGOlawzsPjVHoGahONXJ5w_bGcq68kKhq3oJ0Qsne1efk48E7p_h7h7noMWSLw2AmjLusueyAQ61Ut6D0gNoUc07o9ZzCaNIfDUzvg-olqF6C6pegC__hVb3rR3RH-n_BBfhyAB5zMb_wCJhUgh3wRSeEBtjPo_d4tluTNE71M32fiv4</recordid><startdate>20211101</startdate><enddate>20211101</enddate><creator>Yasufuku, Kana</creator><creator>Koike, Katsumi</creator><creator>Kobayashi, Mika</creator><creator>Chiba, Hiroki</creator><creator>Kitaura, Motoji</creator><creator>Takenouchi, Shino</creator><creator>Hasegawa, Minoru</creator><creator>Morioka, Yasuhide</creator><creator>Mishima, Hirokazu</creator><creator>Suzuki, Tsutomu</creator><creator>Fujita, Masahide</creator><general>The Pharmaceutical Society of Japan</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20211101</creationdate><title>Involvement of the Peripheral μ-Opioid Receptor in Tramadol-Induced Constipation in Rodents</title><author>Yasufuku, Kana ; Koike, Katsumi ; Kobayashi, Mika ; Chiba, Hiroki ; Kitaura, Motoji ; Takenouchi, Shino ; Hasegawa, Minoru ; Morioka, Yasuhide ; Mishima, Hirokazu ; Suzuki, Tsutomu ; Fujita, Masahide</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c483t-81f1bf14badaf2af4a5d8a29f17a6ef0169675158cbac226f45e632815d465bd3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Analgesics, Opioid - adverse effects</topic><topic>Analgesics, Opioid - blood</topic><topic>Analgesics, Opioid - pharmacokinetics</topic><topic>Animals</topic><topic>constipation</topic><topic>Intestine, Small - drug effects</topic><topic>Male</topic><topic>naldemedine</topic><topic>Naltrexone - adverse effects</topic><topic>Naltrexone - analogs & derivatives</topic><topic>Naltrexone - blood</topic><topic>Naltrexone - pharmacokinetics</topic><topic>Nociception - drug effects</topic><topic>Opioid-Induced Constipation - etiology</topic><topic>Opioid-Induced Constipation - metabolism</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Rats, Wistar</topic><topic>Receptors, Opioid, mu - drug effects</topic><topic>Receptors, Opioid, mu - metabolism</topic><topic>tramadol</topic><topic>Tramadol - adverse effects</topic><topic>Tramadol - blood</topic><topic>Tramadol - pharmacokinetics</topic><topic>μ-opioid receptor</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Yasufuku, Kana</creatorcontrib><creatorcontrib>Koike, Katsumi</creatorcontrib><creatorcontrib>Kobayashi, Mika</creatorcontrib><creatorcontrib>Chiba, Hiroki</creatorcontrib><creatorcontrib>Kitaura, Motoji</creatorcontrib><creatorcontrib>Takenouchi, Shino</creatorcontrib><creatorcontrib>Hasegawa, Minoru</creatorcontrib><creatorcontrib>Morioka, Yasuhide</creatorcontrib><creatorcontrib>Mishima, Hirokazu</creatorcontrib><creatorcontrib>Suzuki, Tsutomu</creatorcontrib><creatorcontrib>Fujita, Masahide</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Biological & pharmaceutical bulletin</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yasufuku, Kana</au><au>Koike, Katsumi</au><au>Kobayashi, Mika</au><au>Chiba, Hiroki</au><au>Kitaura, Motoji</au><au>Takenouchi, Shino</au><au>Hasegawa, Minoru</au><au>Morioka, Yasuhide</au><au>Mishima, Hirokazu</au><au>Suzuki, Tsutomu</au><au>Fujita, Masahide</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Involvement of the Peripheral μ-Opioid Receptor in Tramadol-Induced Constipation in Rodents</atitle><jtitle>Biological & pharmaceutical bulletin</jtitle><addtitle>Biol Pharm Bull</addtitle><date>2021-11-01</date><risdate>2021</risdate><volume>44</volume><issue>11</issue><spage>1746</spage><epage>1751</epage><pages>1746-1751</pages><artnum>b21-00474</artnum><issn>0918-6158</issn><eissn>1347-5215</eissn><abstract>Tramadol is a weak opioid that produces analgesic effect via both the μ-opioid receptor (MOR) and non-opioid targets. Constipation is the most common opioid-related side effect in patients with cancer and non-cancer pain. However, the contribution of MOR to tramadol-induced constipation is unclear. Therefore, we used naldemedine, a peripherally acting MOR antagonist, and MOR-knockout mice to investigate the involvement of peripheral MOR in tramadol-induced constipation using a small intestinal transit model. A single dose of tramadol (3–100 mg/kg, per os (p.o.)) inhibited small intestinal transit dose-dependently in rats. Naldemedine (0.01–10 mg/kg, p.o.) blocked the inhibition of small intestinal transit induced by tramadol (30 mg/kg, p.o.) in rats. The transition rate increased dose-dependently over the range of naldemedine 0.01–0.3 mg/kg, and complete recovery was observed at 0.3–10 m/kg. Additionally, tramadol (30 and 100 mg/kg, subcutaneously (s.c.)) inhibited small intestinal transit in wild-type mice but not in MOR-knockout mice. These results suggest that peripheral MOR participates in tramadol-induced constipation.</abstract><cop>Japan</cop><pub>The Pharmaceutical Society of Japan</pub><pmid>34719650</pmid><doi>10.1248/bpb.b21-00474</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 0918-6158 |
| ispartof | Biological and Pharmaceutical Bulletin, 2021/11/01, Vol.44(11), pp.1746-1751 |
| issn | 0918-6158 1347-5215 |
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| source | MEDLINE; J-STAGE (Japan Science & Technology Information Aggregator, Electronic) Freely Available Titles - Japanese; EZB-FREE-00999 freely available EZB journals; Free Full-Text Journals in Chemistry |
| subjects | Analgesics, Opioid - adverse effects Analgesics, Opioid - blood Analgesics, Opioid - pharmacokinetics Animals constipation Intestine, Small - drug effects Male naldemedine Naltrexone - adverse effects Naltrexone - analogs & derivatives Naltrexone - blood Naltrexone - pharmacokinetics Nociception - drug effects Opioid-Induced Constipation - etiology Opioid-Induced Constipation - metabolism Rats Rats, Sprague-Dawley Rats, Wistar Receptors, Opioid, mu - drug effects Receptors, Opioid, mu - metabolism tramadol Tramadol - adverse effects Tramadol - blood Tramadol - pharmacokinetics μ-opioid receptor |
| title | Involvement of the Peripheral μ-Opioid Receptor in Tramadol-Induced Constipation in Rodents |
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