Effects of the novel, selective and low-efficacy mu opioid receptor ligand NAQ on intracranial self-stimulation in rats
Rationale Low-efficacy mu opioid receptor agonists may be useful for some clinical indications, but clinically available low-efficacy mu agonists also have low selectivity for mu vs. kappa opioid receptors. NAQ (17-cyclopropylmethyl-3,14ß-dihydroxy-4,5α-epoxy-6α-[(3′-isoquinolyl)acetamido]morphinan)...
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| Veröffentlicht in: | Psychopharmacology 2015-02, Vol.232 (4), p.815-824 |
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| creator | Altarifi, Ahmad A. Yuan, Yunyun Zhang, Yan Selley, Dana E. Negus, S. Stevens |
| description | Rationale
Low-efficacy mu opioid receptor agonists may be useful for some clinical indications, but clinically available low-efficacy mu agonists also have low selectivity for mu vs. kappa opioid receptors. NAQ (17-cyclopropylmethyl-3,14ß-dihydroxy-4,5α-epoxy-6α-[(3′-isoquinolyl)acetamido]morphinan) is a novel opioid receptor ligand with low-efficacy at mu receptors and greater mu-receptor selectivity than existing low-efficacy agonists.
Objectives
This study examined behavioral effects of NAQ in rats using an intracranial self-stimulation (ICSS) procedure that has been used previously to examine other opioids. NAQ effects were examined before, during, and after chronic morphine treatment, and effects of NAQ were compared to effects of nalbuphine and naltrexone.
Methods
Adult male Sprague–Dawley rats were trained to respond for electrical brain stimulation delivered via electrodes implanted in the medial forebrain bundle. A range of brain stimulation frequencies maintained a wide range of baseline ICSS rates. Effects of NAQ (0.32–10 mg/kg), nalbuphine (1.0 mg/kg), and naltrexone (0.1 mg/kg) were determined before morphine treatment and during treatment with 3.2 and 18 mg/kg/day morphine. NAQ effects were also redetermined beginning 2 weeks after termination of morphine treatment.
Results
NAQ produced weak ICSS facilitation in morphine-naïve rats but more robust ICSS facilitation during and after morphine treatment and also reversed morphine withdrawal-associated depression of ICSS. These effects were similar to effects of nalbuphine.
Conclusions
These results agree with the in vitro characterization of NAQ as a low-efficacy mu agonist. Opioid exposure may enhance abuse-related effects of NAQ, but NAQ may also serve as a low-efficacy and relatively safe option for treatment of opioid withdrawal or dependence. |
| doi_str_mv | 10.1007/s00213-014-3719-7 |
| format | Article |
| fullrecord | <record><control><sourceid>gale_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4310756</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A408916469</galeid><sourcerecordid>A408916469</sourcerecordid><originalsourceid>FETCH-LOGICAL-c665t-2f0ef5136f6735f9cb54613a962a20fa5ece12eb7480207441021a0a317089b83</originalsourceid><addsrcrecordid>eNqNkl1rFDEUhgdR7Fr9Ad5IwBsvnJqTr5m5EZZSP6Aogl6HbPZkm5JN1mRmS_-9GbfWVhRMLgI5z3k55-VtmudAT4DS7k2hlAFvKYiWdzC03YNmAYKzltGOPWwWlHLecpD9UfOklEtaj-jF4-aISej6HsSiuTpzDu1YSHJkvEAS0x7Da1Iw1F-_R2LimoR01aJz3hp7TbYTSTuf_JpktLgbUybBb2bs0_ILSZH4OGZjs4nehFnItWX02ymY0f-skmzG8rR55Ewo-OzmPW6-vTv7evqhPf_8_uPp8ry1SsmxZY6ik8CVUx2XbrArKRRwMyhmGHVG1hGA4aoTPa1LCwHVEUMNh472w6rnx83bg-5uWm1xbXEeLuhd9luTr3UyXt-vRH-hN2mvBQfaSVUFXt0I5PR9wjLqrS8WQzAR01Q0KEUF43Lo_gOVTAAfGKvoyz_QyzTlWJ2olOglKFD9b2pjAmofXZqdnUX1UtT9KqqGSp38hap3jVtvU0Tn6_-9Bjg02JxKyehu7QCq52DpQ7B0DZaeg6Xn3V7c9fG241eSKsAOQKmluMF8Z6N_qv4AYaHWzA</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1648516168</pqid></control><display><type>article</type><title>Effects of the novel, selective and low-efficacy mu opioid receptor ligand NAQ on intracranial self-stimulation in rats</title><source>MEDLINE</source><source>SpringerLink Journals - AutoHoldings</source><creator>Altarifi, Ahmad A. ; Yuan, Yunyun ; Zhang, Yan ; Selley, Dana E. ; Negus, S. Stevens</creator><creatorcontrib>Altarifi, Ahmad A. ; Yuan, Yunyun ; Zhang, Yan ; Selley, Dana E. ; Negus, S. Stevens</creatorcontrib><description>Rationale
Low-efficacy mu opioid receptor agonists may be useful for some clinical indications, but clinically available low-efficacy mu agonists also have low selectivity for mu vs. kappa opioid receptors. NAQ (17-cyclopropylmethyl-3,14ß-dihydroxy-4,5α-epoxy-6α-[(3′-isoquinolyl)acetamido]morphinan) is a novel opioid receptor ligand with low-efficacy at mu receptors and greater mu-receptor selectivity than existing low-efficacy agonists.
Objectives
This study examined behavioral effects of NAQ in rats using an intracranial self-stimulation (ICSS) procedure that has been used previously to examine other opioids. NAQ effects were examined before, during, and after chronic morphine treatment, and effects of NAQ were compared to effects of nalbuphine and naltrexone.
Methods
Adult male Sprague–Dawley rats were trained to respond for electrical brain stimulation delivered via electrodes implanted in the medial forebrain bundle. A range of brain stimulation frequencies maintained a wide range of baseline ICSS rates. Effects of NAQ (0.32–10 mg/kg), nalbuphine (1.0 mg/kg), and naltrexone (0.1 mg/kg) were determined before morphine treatment and during treatment with 3.2 and 18 mg/kg/day morphine. NAQ effects were also redetermined beginning 2 weeks after termination of morphine treatment.
Results
NAQ produced weak ICSS facilitation in morphine-naïve rats but more robust ICSS facilitation during and after morphine treatment and also reversed morphine withdrawal-associated depression of ICSS. These effects were similar to effects of nalbuphine.
Conclusions
These results agree with the in vitro characterization of NAQ as a low-efficacy mu agonist. Opioid exposure may enhance abuse-related effects of NAQ, but NAQ may also serve as a low-efficacy and relatively safe option for treatment of opioid withdrawal or dependence.</description><identifier>ISSN: 0033-3158</identifier><identifier>EISSN: 1432-2072</identifier><identifier>DOI: 10.1007/s00213-014-3719-7</identifier><identifier>PMID: 25178814</identifier><language>eng</language><publisher>Berlin/Heidelberg: Springer Berlin Heidelberg</publisher><subject>Animal behavior ; Animals ; Biomedical and Life Sciences ; Biomedicine ; Brain - drug effects ; Brain - metabolism ; Brain - physiology ; Complications and side effects ; Dosage and administration ; Electrodes, Implanted ; Genetic aspects ; Ligands ; Male ; Medial Forebrain Bundle - drug effects ; Morphinans - pharmacology ; Morphine ; Narcotics ; Neurosciences ; Opioid receptors ; Original Investigation ; Pharmacology/Toxicology ; Physiological aspects ; Psychiatry ; Psychopharmacology ; Rats ; Rats, Sprague-Dawley ; Receptors, Opioid, kappa - agonists ; Receptors, Opioid, kappa - metabolism ; Receptors, Opioid, mu - agonists ; Receptors, Opioid, mu - metabolism ; Rodents ; Self Stimulation - drug effects ; Substrate Specificity</subject><ispartof>Psychopharmacology, 2015-02, Vol.232 (4), p.815-824</ispartof><rights>Springer-Verlag Berlin Heidelberg 2014</rights><rights>COPYRIGHT 2015 Springer</rights><rights>Springer-Verlag Berlin Heidelberg 2015</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c665t-2f0ef5136f6735f9cb54613a962a20fa5ece12eb7480207441021a0a317089b83</citedby><cites>FETCH-LOGICAL-c665t-2f0ef5136f6735f9cb54613a962a20fa5ece12eb7480207441021a0a317089b83</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s00213-014-3719-7$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s00213-014-3719-7$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>230,314,780,784,885,27922,27923,41486,42555,51317</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25178814$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Altarifi, Ahmad A.</creatorcontrib><creatorcontrib>Yuan, Yunyun</creatorcontrib><creatorcontrib>Zhang, Yan</creatorcontrib><creatorcontrib>Selley, Dana E.</creatorcontrib><creatorcontrib>Negus, S. Stevens</creatorcontrib><title>Effects of the novel, selective and low-efficacy mu opioid receptor ligand NAQ on intracranial self-stimulation in rats</title><title>Psychopharmacology</title><addtitle>Psychopharmacology</addtitle><addtitle>Psychopharmacology (Berl)</addtitle><description>Rationale
Low-efficacy mu opioid receptor agonists may be useful for some clinical indications, but clinically available low-efficacy mu agonists also have low selectivity for mu vs. kappa opioid receptors. NAQ (17-cyclopropylmethyl-3,14ß-dihydroxy-4,5α-epoxy-6α-[(3′-isoquinolyl)acetamido]morphinan) is a novel opioid receptor ligand with low-efficacy at mu receptors and greater mu-receptor selectivity than existing low-efficacy agonists.
Objectives
This study examined behavioral effects of NAQ in rats using an intracranial self-stimulation (ICSS) procedure that has been used previously to examine other opioids. NAQ effects were examined before, during, and after chronic morphine treatment, and effects of NAQ were compared to effects of nalbuphine and naltrexone.
Methods
Adult male Sprague–Dawley rats were trained to respond for electrical brain stimulation delivered via electrodes implanted in the medial forebrain bundle. A range of brain stimulation frequencies maintained a wide range of baseline ICSS rates. Effects of NAQ (0.32–10 mg/kg), nalbuphine (1.0 mg/kg), and naltrexone (0.1 mg/kg) were determined before morphine treatment and during treatment with 3.2 and 18 mg/kg/day morphine. NAQ effects were also redetermined beginning 2 weeks after termination of morphine treatment.
Results
NAQ produced weak ICSS facilitation in morphine-naïve rats but more robust ICSS facilitation during and after morphine treatment and also reversed morphine withdrawal-associated depression of ICSS. These effects were similar to effects of nalbuphine.
Conclusions
These results agree with the in vitro characterization of NAQ as a low-efficacy mu agonist. Opioid exposure may enhance abuse-related effects of NAQ, but NAQ may also serve as a low-efficacy and relatively safe option for treatment of opioid withdrawal or dependence.</description><subject>Animal behavior</subject><subject>Animals</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Brain - drug effects</subject><subject>Brain - metabolism</subject><subject>Brain - physiology</subject><subject>Complications and side effects</subject><subject>Dosage and administration</subject><subject>Electrodes, Implanted</subject><subject>Genetic aspects</subject><subject>Ligands</subject><subject>Male</subject><subject>Medial Forebrain Bundle - drug effects</subject><subject>Morphinans - pharmacology</subject><subject>Morphine</subject><subject>Narcotics</subject><subject>Neurosciences</subject><subject>Opioid receptors</subject><subject>Original Investigation</subject><subject>Pharmacology/Toxicology</subject><subject>Physiological aspects</subject><subject>Psychiatry</subject><subject>Psychopharmacology</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Receptors, Opioid, kappa - agonists</subject><subject>Receptors, Opioid, kappa - metabolism</subject><subject>Receptors, Opioid, mu - agonists</subject><subject>Receptors, Opioid, mu - metabolism</subject><subject>Rodents</subject><subject>Self Stimulation - drug effects</subject><subject>Substrate Specificity</subject><issn>0033-3158</issn><issn>1432-2072</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNqNkl1rFDEUhgdR7Fr9Ad5IwBsvnJqTr5m5EZZSP6Aogl6HbPZkm5JN1mRmS_-9GbfWVhRMLgI5z3k55-VtmudAT4DS7k2hlAFvKYiWdzC03YNmAYKzltGOPWwWlHLecpD9UfOklEtaj-jF4-aISej6HsSiuTpzDu1YSHJkvEAS0x7Da1Iw1F-_R2LimoR01aJz3hp7TbYTSTuf_JpktLgbUybBb2bs0_ILSZH4OGZjs4nehFnItWX02ymY0f-skmzG8rR55Ewo-OzmPW6-vTv7evqhPf_8_uPp8ry1SsmxZY6ik8CVUx2XbrArKRRwMyhmGHVG1hGA4aoTPa1LCwHVEUMNh472w6rnx83bg-5uWm1xbXEeLuhd9luTr3UyXt-vRH-hN2mvBQfaSVUFXt0I5PR9wjLqrS8WQzAR01Q0KEUF43Lo_gOVTAAfGKvoyz_QyzTlWJ2olOglKFD9b2pjAmofXZqdnUX1UtT9KqqGSp38hap3jVtvU0Tn6_-9Bjg02JxKyehu7QCq52DpQ7B0DZaeg6Xn3V7c9fG241eSKsAOQKmluMF8Z6N_qv4AYaHWzA</recordid><startdate>20150201</startdate><enddate>20150201</enddate><creator>Altarifi, Ahmad A.</creator><creator>Yuan, Yunyun</creator><creator>Zhang, Yan</creator><creator>Selley, Dana E.</creator><creator>Negus, S. Stevens</creator><general>Springer Berlin Heidelberg</general><general>Springer</general><general>Springer Nature B.V</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>3V.</scope><scope>7QG</scope><scope>7QR</scope><scope>7RV</scope><scope>7TK</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>88G</scope><scope>8AO</scope><scope>8FD</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>K9.</scope><scope>KB0</scope><scope>M0S</scope><scope>M1P</scope><scope>M2M</scope><scope>NAPCQ</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PSYQQ</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20150201</creationdate><title>Effects of the novel, selective and low-efficacy mu opioid receptor ligand NAQ on intracranial self-stimulation in rats</title><author>Altarifi, Ahmad A. ; Yuan, Yunyun ; Zhang, Yan ; Selley, Dana E. ; Negus, S. Stevens</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c665t-2f0ef5136f6735f9cb54613a962a20fa5ece12eb7480207441021a0a317089b83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Animal behavior</topic><topic>Animals</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Brain - drug effects</topic><topic>Brain - metabolism</topic><topic>Brain - physiology</topic><topic>Complications and side effects</topic><topic>Dosage and administration</topic><topic>Electrodes, Implanted</topic><topic>Genetic aspects</topic><topic>Ligands</topic><topic>Male</topic><topic>Medial Forebrain Bundle - drug effects</topic><topic>Morphinans - pharmacology</topic><topic>Morphine</topic><topic>Narcotics</topic><topic>Neurosciences</topic><topic>Opioid receptors</topic><topic>Original Investigation</topic><topic>Pharmacology/Toxicology</topic><topic>Physiological aspects</topic><topic>Psychiatry</topic><topic>Psychopharmacology</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Receptors, Opioid, kappa - agonists</topic><topic>Receptors, Opioid, kappa - metabolism</topic><topic>Receptors, Opioid, mu - agonists</topic><topic>Receptors, Opioid, mu - metabolism</topic><topic>Rodents</topic><topic>Self Stimulation - drug effects</topic><topic>Substrate Specificity</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Altarifi, Ahmad A.</creatorcontrib><creatorcontrib>Yuan, Yunyun</creatorcontrib><creatorcontrib>Zhang, Yan</creatorcontrib><creatorcontrib>Selley, Dana E.</creatorcontrib><creatorcontrib>Negus, S. Stevens</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Neurosciences Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Psychology Database (Alumni)</collection><collection>ProQuest Pharma Collection</collection><collection>Technology Research Database</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Psychology Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest One Psychology</collection><collection>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Psychopharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Altarifi, Ahmad A.</au><au>Yuan, Yunyun</au><au>Zhang, Yan</au><au>Selley, Dana E.</au><au>Negus, S. Stevens</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Effects of the novel, selective and low-efficacy mu opioid receptor ligand NAQ on intracranial self-stimulation in rats</atitle><jtitle>Psychopharmacology</jtitle><stitle>Psychopharmacology</stitle><addtitle>Psychopharmacology (Berl)</addtitle><date>2015-02-01</date><risdate>2015</risdate><volume>232</volume><issue>4</issue><spage>815</spage><epage>824</epage><pages>815-824</pages><issn>0033-3158</issn><eissn>1432-2072</eissn><abstract>Rationale
Low-efficacy mu opioid receptor agonists may be useful for some clinical indications, but clinically available low-efficacy mu agonists also have low selectivity for mu vs. kappa opioid receptors. NAQ (17-cyclopropylmethyl-3,14ß-dihydroxy-4,5α-epoxy-6α-[(3′-isoquinolyl)acetamido]morphinan) is a novel opioid receptor ligand with low-efficacy at mu receptors and greater mu-receptor selectivity than existing low-efficacy agonists.
Objectives
This study examined behavioral effects of NAQ in rats using an intracranial self-stimulation (ICSS) procedure that has been used previously to examine other opioids. NAQ effects were examined before, during, and after chronic morphine treatment, and effects of NAQ were compared to effects of nalbuphine and naltrexone.
Methods
Adult male Sprague–Dawley rats were trained to respond for electrical brain stimulation delivered via electrodes implanted in the medial forebrain bundle. A range of brain stimulation frequencies maintained a wide range of baseline ICSS rates. Effects of NAQ (0.32–10 mg/kg), nalbuphine (1.0 mg/kg), and naltrexone (0.1 mg/kg) were determined before morphine treatment and during treatment with 3.2 and 18 mg/kg/day morphine. NAQ effects were also redetermined beginning 2 weeks after termination of morphine treatment.
Results
NAQ produced weak ICSS facilitation in morphine-naïve rats but more robust ICSS facilitation during and after morphine treatment and also reversed morphine withdrawal-associated depression of ICSS. These effects were similar to effects of nalbuphine.
Conclusions
These results agree with the in vitro characterization of NAQ as a low-efficacy mu agonist. Opioid exposure may enhance abuse-related effects of NAQ, but NAQ may also serve as a low-efficacy and relatively safe option for treatment of opioid withdrawal or dependence.</abstract><cop>Berlin/Heidelberg</cop><pub>Springer Berlin Heidelberg</pub><pmid>25178814</pmid><doi>10.1007/s00213-014-3719-7</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animal behavior Animals Biomedical and Life Sciences Biomedicine Brain - drug effects Brain - metabolism Brain - physiology Complications and side effects Dosage and administration Electrodes, Implanted Genetic aspects Ligands Male Medial Forebrain Bundle - drug effects Morphinans - pharmacology Morphine Narcotics Neurosciences Opioid receptors Original Investigation Pharmacology/Toxicology Physiological aspects Psychiatry Psychopharmacology Rats Rats, Sprague-Dawley Receptors, Opioid, kappa - agonists Receptors, Opioid, kappa - metabolism Receptors, Opioid, mu - agonists Receptors, Opioid, mu - metabolism Rodents Self Stimulation - drug effects Substrate Specificity |
| title | Effects of the novel, selective and low-efficacy mu opioid receptor ligand NAQ on intracranial self-stimulation in rats |
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