title: New Morphine Analogs Produce Peripheral Antinociception within a Certain Dose Range of Their Systemic Administration.
abstract: Growing data support peripheral opioid antinociceptive effects, particularly in inflammatory pain models. Here, we examined the antinociceptive effects of subcutaneously administered, recently synthesized 14-O-methylmorphine-6-O-sulfate (14-O-MeM6SU) compared with morphine-6-O-sulfate (M6SU) in a rat model of inflammatory pain induced by an injection of complete Freund's adjuvant and in a mouse model of visceral pain evoked by acetic acid. Subcutaneous doses of 14-O-MeM6SU and M6SU up to 126 and 547 nmol/kg, respectively, produced significant and subcutaneous or intraplantar naloxone methiodide (NAL-M)-reversible antinociception in inflamed paws compared with noninflamed paws. Neither of these doses significantly affected thiobutabarbital-induced sleeping time or rat pulmonary parameters. However, the antinociceptive effects of higher doses were only partially reversed by NAL-M, indicating contribution of the central nervous system. In the mouse writhing test, 14-O-MeM6SU was more potent than M6SU after subcutaneous or intracerebroventricular injections. Both displayed high subcutaneous/intracerebroventricular ED50 ratios. The antinociceptive effects of subcutaneous 14-O-MeM6SU and M6SU up to 136 and 3043 nmol/kg, respectively, were fully antagonized by subcutaneous NAL-M. In addition, the test compounds inhibited mouse gastrointestinal transit in antinociceptive doses. Taken together, these findings suggest that systemic administration of the novel compound 14-O-MeM6SU similar to M6SU in specific dose ranges shows peripheral antinociception in rat and mouse inflammatory pain models without central adverse effects. These findings apply to male animals and must be confirmed in female animals. Therefore, titration of systemic doses of opioid compounds with limited access to the brain might offer peripheral antinociception of clinical importance.
authors.affiliation: Departments of Pharmacology and Pharmacotherapy (E.L., P.R., Z.G., L.C., M.B., K.K., Z.S.Z., P.F., S.F., M.A.) and Pharmaceutical Chemistry (A.V., S.H.), Faculty of Medicine, Semmelweis University, Budapest, Hungary; Department of Anaesthesiology and Intensive Care Medicine, Charité University Berlin, Campus Virchow Klinikum and Campus Charité Mitte, Berlin, Germany (S.A.M., M.S.); Department of Pharmacology and Pharmacotherapy, Medical School, Szentágothai Research Centre (K.C., Z.H.), and MTA-PTE NAP B Chronic Pain Research Group, Faculty of Medicine (Z.H.), University of Pécs, Pécs, Hungary.
authors.forename: Erzsébet
authors.initials: E
authors.lastname: Lackó
authors.affiliation: Departments of Pharmacology and Pharmacotherapy (E.L., P.R., Z.G., L.C., M.B., K.K., Z.S.Z., P.F., S.F., M.A.) and Pharmaceutical Chemistry (A.V., S.H.), Faculty of Medicine, Semmelweis University, Budapest, Hungary; Department of Anaesthesiology and Intensive Care Medicine, Charité University Berlin, Campus Virchow Klinikum and Campus Charité Mitte, Berlin, Germany (S.A.M., M.S.); Department of Pharmacology and Pharmacotherapy, Medical School, Szentágothai Research Centre (K.C., Z.H.), and MTA-PTE NAP B Chronic Pain Research Group, Faculty of Medicine (Z.H.), University of Pécs, Pécs, Hungary.
authors.forename: Pál
authors.initials: P
authors.lastname: Riba
authors.affiliation: Departments of Pharmacology and Pharmacotherapy (E.L., P.R., Z.G., L.C., M.B., K.K., Z.S.Z., P.F., S.F., M.A.) and Pharmaceutical Chemistry (A.V., S.H.), Faculty of Medicine, Semmelweis University, Budapest, Hungary; Department of Anaesthesiology and Intensive Care Medicine, Charité University Berlin, Campus Virchow Klinikum and Campus Charité Mitte, Berlin, Germany (S.A.M., M.S.); Department of Pharmacology and Pharmacotherapy, Medical School, Szentágothai Research Centre (K.C., Z.H.), and MTA-PTE NAP B Chronic Pain Research Group, Faculty of Medicine (Z.H.), University of Pécs, Pécs, Hungary.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Giricz
authors.affiliation: Departments of Pharmacology and Pharmacotherapy (E.L., P.R., Z.G., L.C., M.B., K.K., Z.S.Z., P.F., S.F., M.A.) and Pharmaceutical Chemistry (A.V., S.H.), Faculty of Medicine, Semmelweis University, Budapest, Hungary; Department of Anaesthesiology and Intensive Care Medicine, Charité University Berlin, Campus Virchow Klinikum and Campus Charité Mitte, Berlin, Germany (S.A.M., M.S.); Department of Pharmacology and Pharmacotherapy, Medical School, Szentágothai Research Centre (K.C., Z.H.), and MTA-PTE NAP B Chronic Pain Research Group, Faculty of Medicine (Z.H.), University of Pécs, Pécs, Hungary.
authors.forename: András
authors.initials: A
authors.lastname: Váradi
authors.affiliation: Departments of Pharmacology and Pharmacotherapy (E.L., P.R., Z.G., L.C., M.B., K.K., Z.S.Z., P.F., S.F., M.A.) and Pharmaceutical Chemistry (A.V., S.H.), Faculty of Medicine, Semmelweis University, Budapest, Hungary; Department of Anaesthesiology and Intensive Care Medicine, Charité University Berlin, Campus Virchow Klinikum and Campus Charité Mitte, Berlin, Germany (S.A.M., M.S.); Department of Pharmacology and Pharmacotherapy, Medical School, Szentágothai Research Centre (K.C., Z.H.), and MTA-PTE NAP B Chronic Pain Research Group, Faculty of Medicine (Z.H.), University of Pécs, Pécs, Hungary.
authors.forename: Laura
authors.initials: L
authors.lastname: Cornic
authors.affiliation: Departments of Pharmacology and Pharmacotherapy (E.L., P.R., Z.G., L.C., M.B., K.K., Z.S.Z., P.F., S.F., M.A.) and Pharmaceutical Chemistry (A.V., S.H.), Faculty of Medicine, Semmelweis University, Budapest, Hungary; Department of Anaesthesiology and Intensive Care Medicine, Charité University Berlin, Campus Virchow Klinikum and Campus Charité Mitte, Berlin, Germany (S.A.M., M.S.); Department of Pharmacology and Pharmacotherapy, Medical School, Szentágothai Research Centre (K.C., Z.H.), and MTA-PTE NAP B Chronic Pain Research Group, Faculty of Medicine (Z.H.), University of Pécs, Pécs, Hungary.
authors.forename: Mihály
authors.initials: M
authors.lastname: Balogh
authors.affiliation: Departments of Pharmacology and Pharmacotherapy (E.L., P.R., Z.G., L.C., M.B., K.K., Z.S.Z., P.F., S.F., M.A.) and Pharmaceutical Chemistry (A.V., S.H.), Faculty of Medicine, Semmelweis University, Budapest, Hungary; Department of Anaesthesiology and Intensive Care Medicine, Charité University Berlin, Campus Virchow Klinikum and Campus Charité Mitte, Berlin, Germany (S.A.M., M.S.); Department of Pharmacology and Pharmacotherapy, Medical School, Szentágothai Research Centre (K.C., Z.H.), and MTA-PTE NAP B Chronic Pain Research Group, Faculty of Medicine (Z.H.), University of Pécs, Pécs, Hungary.
authors.forename: Kornél
authors.initials: K
authors.lastname: Király
authors.affiliation: Departments of Pharmacology and Pharmacotherapy (E.L., P.R., Z.G., L.C., M.B., K.K., Z.S.Z., P.F., S.F., M.A.) and Pharmaceutical Chemistry (A.V., S.H.), Faculty of Medicine, Semmelweis University, Budapest, Hungary; Department of Anaesthesiology and Intensive Care Medicine, Charité University Berlin, Campus Virchow Klinikum and Campus Charité Mitte, Berlin, Germany (S.A.M., M.S.); Department of Pharmacology and Pharmacotherapy, Medical School, Szentágothai Research Centre (K.C., Z.H.), and MTA-PTE NAP B Chronic Pain Research Group, Faculty of Medicine (Z.H.), University of Pécs, Pécs, Hungary.
authors.forename: Kata
authors.initials: K
authors.lastname: Csekő
authors.affiliation: Departments of Pharmacology and Pharmacotherapy (E.L., P.R., Z.G., L.C., M.B., K.K., Z.S.Z., P.F., S.F., M.A.) and Pharmaceutical Chemistry (A.V., S.H.), Faculty of Medicine, Semmelweis University, Budapest, Hungary; Department of Anaesthesiology and Intensive Care Medicine, Charité University Berlin, Campus Virchow Klinikum and Campus Charité Mitte, Berlin, Germany (S.A.M., M.S.); Department of Pharmacology and Pharmacotherapy, Medical School, Szentágothai Research Centre (K.C., Z.H.), and MTA-PTE NAP B Chronic Pain Research Group, Faculty of Medicine (Z.H.), University of Pécs, Pécs, Hungary.
authors.forename: Shaaban A
authors.initials: SA
authors.lastname: Mousa
authors.affiliation: Departments of Pharmacology and Pharmacotherapy (E.L., P.R., Z.G., L.C., M.B., K.K., Z.S.Z., P.F., S.F., M.A.) and Pharmaceutical Chemistry (A.V., S.H.), Faculty of Medicine, Semmelweis University, Budapest, Hungary; Department of Anaesthesiology and Intensive Care Medicine, Charité University Berlin, Campus Virchow Klinikum and Campus Charité Mitte, Berlin, Germany (S.A.M., M.S.); Department of Pharmacology and Pharmacotherapy, Medical School, Szentágothai Research Centre (K.C., Z.H.), and MTA-PTE NAP B Chronic Pain Research Group, Faculty of Medicine (Z.H.), University of Pécs, Pécs, Hungary.
authors.forename: Sándor
authors.initials: S
authors.lastname: Hosztafi
authors.affiliation: Departments of Pharmacology and Pharmacotherapy (E.L., P.R., Z.G., L.C., M.B., K.K., Z.S.Z., P.F., S.F., M.A.) and Pharmaceutical Chemistry (A.V., S.H.), Faculty of Medicine, Semmelweis University, Budapest, Hungary; Department of Anaesthesiology and Intensive Care Medicine, Charité University Berlin, Campus Virchow Klinikum and Campus Charité Mitte, Berlin, Germany (S.A.M., M.S.); Department of Pharmacology and Pharmacotherapy, Medical School, Szentágothai Research Centre (K.C., Z.H.), and MTA-PTE NAP B Chronic Pain Research Group, Faculty of Medicine (Z.H.), University of Pécs, Pécs, Hungary.
authors.forename: Michael
authors.initials: M
authors.lastname: Schäfer
authors.affiliation: Departments of Pharmacology and Pharmacotherapy (E.L., P.R., Z.G., L.C., M.B., K.K., Z.S.Z., P.F., S.F., M.A.) and Pharmaceutical Chemistry (A.V., S.H.), Faculty of Medicine, Semmelweis University, Budapest, Hungary; Department of Anaesthesiology and Intensive Care Medicine, Charité University Berlin, Campus Virchow Klinikum and Campus Charité Mitte, Berlin, Germany (S.A.M., M.S.); Department of Pharmacology and Pharmacotherapy, Medical School, Szentágothai Research Centre (K.C., Z.H.), and MTA-PTE NAP B Chronic Pain Research Group, Faculty of Medicine (Z.H.), University of Pécs, Pécs, Hungary.
authors.forename: Zoltán Sándor
authors.initials: ZS
authors.lastname: Zádori
authors.affiliation: Departments of Pharmacology and Pharmacotherapy (E.L., P.R., Z.G., L.C., M.B., K.K., Z.S.Z., P.F., S.F., M.A.) and Pharmaceutical Chemistry (A.V., S.H.), Faculty of Medicine, Semmelweis University, Budapest, Hungary; Department of Anaesthesiology and Intensive Care Medicine, Charité University Berlin, Campus Virchow Klinikum and Campus Charité Mitte, Berlin, Germany (S.A.M., M.S.); Department of Pharmacology and Pharmacotherapy, Medical School, Szentágothai Research Centre (K.C., Z.H.), and MTA-PTE NAP B Chronic Pain Research Group, Faculty of Medicine (Z.H.), University of Pécs, Pécs, Hungary.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Helyes
authors.affiliation: Departments of Pharmacology and Pharmacotherapy (E.L., P.R., Z.G., L.C., M.B., K.K., Z.S.Z., P.F., S.F., M.A.) and Pharmaceutical Chemistry (A.V., S.H.), Faculty of Medicine, Semmelweis University, Budapest, Hungary; Department of Anaesthesiology and Intensive Care Medicine, Charité University Berlin, Campus Virchow Klinikum and Campus Charité Mitte, Berlin, Germany (S.A.M., M.S.); Department of Pharmacology and Pharmacotherapy, Medical School, Szentágothai Research Centre (K.C., Z.H.), and MTA-PTE NAP B Chronic Pain Research Group, Faculty of Medicine (Z.H.), University of Pécs, Pécs, Hungary.
authors.forename: Péter
authors.initials: P
authors.lastname: Ferdinandy
authors.affiliation: Departments of Pharmacology and Pharmacotherapy (E.L., P.R., Z.G., L.C., M.B., K.K., Z.S.Z., P.F., S.F., M.A.) and Pharmaceutical Chemistry (A.V., S.H.), Faculty of Medicine, Semmelweis University, Budapest, Hungary; Department of Anaesthesiology and Intensive Care Medicine, Charité University Berlin, Campus Virchow Klinikum and Campus Charité Mitte, Berlin, Germany (S.A.M., M.S.); Department of Pharmacology and Pharmacotherapy, Medical School, Szentágothai Research Centre (K.C., Z.H.), and MTA-PTE NAP B Chronic Pain Research Group, Faculty of Medicine (Z.H.), University of Pécs, Pécs, Hungary.
authors.forename: Susanna
authors.initials: S
authors.lastname: Fürst
authors.affiliation: Departments of Pharmacology and Pharmacotherapy (E.L., P.R., Z.G., L.C., M.B., K.K., Z.S.Z., P.F., S.F., M.A.) and Pharmaceutical Chemistry (A.V., S.H.), Faculty of Medicine, Semmelweis University, Budapest, Hungary; Department of Anaesthesiology and Intensive Care Medicine, Charité University Berlin, Campus Virchow Klinikum and Campus Charité Mitte, Berlin, Germany (S.A.M., M.S.); Department of Pharmacology and Pharmacotherapy, Medical School, Szentágothai Research Centre (K.C., Z.H.), and MTA-PTE NAP B Chronic Pain Research Group, Faculty of Medicine (Z.H.), University of Pécs, Pécs, Hungary al-khrasani.mahmoud@med.semmelweis-univ.hu.
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Al-Khrasani
mesh_terms: D000700:Analgesics / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D041981:Gastrointestinal Tract / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D009020:Morphine / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D010146:Pain / Q000188:drug therapy; D051381:Rats; D017208:Rats, Wistar; D012119:Respiration / Q000187:drug effects; D013874:Thiopental / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D000700:Analgesics; C004316:thiobutabarbital; D009020:Morphine; D013874:Thiopental