Modulation of G-protein activation, calcium currents and opioid receptor phosphorylation by the pH-dependent antinociceptive agonist NFEPP
N-(3-fluoro-1-phenethylpiperidine-4-yl)-N-phenyl propionamide is a newly-designed pain killer selectively activating G-protein-coupled mu-opioid receptors (MOR) in acidic injured tissues, and therefore devoid of central side effects which are typically elicited at normal pH values in healthy tissues...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2023-05-01
|
| Series: | Frontiers in Molecular Neuroscience |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fnmol.2023.1171855/full |
| _version_ | 1797829035122753536 |
|---|---|
| author | Melih Özgür Celik Viola Seitz Fatih Yergöz Sandeep Dembla Nina Kathleen Blum Stefan Schulz Christoph Stein |
| author_facet | Melih Özgür Celik Viola Seitz Fatih Yergöz Sandeep Dembla Nina Kathleen Blum Stefan Schulz Christoph Stein |
| author_sort | Melih Özgür Celik |
| collection | DOAJ |
| description | N-(3-fluoro-1-phenethylpiperidine-4-yl)-N-phenyl propionamide is a newly-designed pain killer selectively activating G-protein-coupled mu-opioid receptors (MOR) in acidic injured tissues, and therefore devoid of central side effects which are typically elicited at normal pH values in healthy tissues. However, the neuronal mechanisms underlying NFEPP’s antinociceptive effects were not examined in detail so far. Voltage-dependent Ca2+ channels (VDCCs) in nociceptive neurons play a major role in the generation and inhibition of pain. In this study, we focused on the effects of NFEPP on calcium currents in rat dorsal root ganglion (DRG) neurons. The inhibitory role of the G-protein subunits Gi/o and Gβγ on VDCCs was investigated using the blockers pertussis toxin and gallein, respectively. GTPγS binding, calcium signals and MOR phosphorylation were also investigated. All experiments were performed at acidic and normal pH values using NFEPP in comparison to the conventional opioid agonist fentanyl. At low pH, NFEPP produced more efficient G-protein activation in transfected HEK293 cells and significantly reduced VDCCs in depolarized DRG neurons. The latter effect was mediated by Gβγ subunits, and NFEPP-mediated MOR phosphorylation was pH-dependent. Fentanyl’s responses were not affected by pH changes. Our data indicate that NFEPP-induced MOR signaling is more effective at low pH and that the inhibition of calcium channels in DRG neurons underlies NFEPP’s antinociceptive actions. |
| first_indexed | 2024-04-09T13:13:56Z |
| format | Article |
| id | doaj.art-d24edb3270114fefa997af4d5bc07964 |
| institution | Directory Open Access Journal |
| issn | 1662-5099 |
| language | English |
| last_indexed | 2024-04-09T13:13:56Z |
| publishDate | 2023-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Neuroscience |
| spelling | doaj.art-d24edb3270114fefa997af4d5bc079642023-05-12T05:51:46ZengFrontiers Media S.A.Frontiers in Molecular Neuroscience1662-50992023-05-011610.3389/fnmol.2023.11718551171855Modulation of G-protein activation, calcium currents and opioid receptor phosphorylation by the pH-dependent antinociceptive agonist NFEPPMelih Özgür Celik0Viola Seitz1Fatih Yergöz2Sandeep Dembla3Nina Kathleen Blum4Stefan Schulz5Christoph Stein6Department of Experimental Anesthesiology, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, GermanyDepartment of Experimental Anesthesiology, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, GermanyDepartment of Experimental Anesthesiology, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, GermanyDepartment of Experimental Anesthesiology, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, GermanyDepartment of Pharmacology, Universitätsklinikum Jena, Jena, GermanyDepartment of Pharmacology, Universitätsklinikum Jena, Jena, GermanyDepartment of Experimental Anesthesiology, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, GermanyN-(3-fluoro-1-phenethylpiperidine-4-yl)-N-phenyl propionamide is a newly-designed pain killer selectively activating G-protein-coupled mu-opioid receptors (MOR) in acidic injured tissues, and therefore devoid of central side effects which are typically elicited at normal pH values in healthy tissues. However, the neuronal mechanisms underlying NFEPP’s antinociceptive effects were not examined in detail so far. Voltage-dependent Ca2+ channels (VDCCs) in nociceptive neurons play a major role in the generation and inhibition of pain. In this study, we focused on the effects of NFEPP on calcium currents in rat dorsal root ganglion (DRG) neurons. The inhibitory role of the G-protein subunits Gi/o and Gβγ on VDCCs was investigated using the blockers pertussis toxin and gallein, respectively. GTPγS binding, calcium signals and MOR phosphorylation were also investigated. All experiments were performed at acidic and normal pH values using NFEPP in comparison to the conventional opioid agonist fentanyl. At low pH, NFEPP produced more efficient G-protein activation in transfected HEK293 cells and significantly reduced VDCCs in depolarized DRG neurons. The latter effect was mediated by Gβγ subunits, and NFEPP-mediated MOR phosphorylation was pH-dependent. Fentanyl’s responses were not affected by pH changes. Our data indicate that NFEPP-induced MOR signaling is more effective at low pH and that the inhibition of calcium channels in DRG neurons underlies NFEPP’s antinociceptive actions.https://www.frontiersin.org/articles/10.3389/fnmol.2023.1171855/fullNFEPPmu opioid receptor (MOR)VDCCfentanylpain |
| spellingShingle | Melih Özgür Celik Viola Seitz Fatih Yergöz Sandeep Dembla Nina Kathleen Blum Stefan Schulz Christoph Stein Modulation of G-protein activation, calcium currents and opioid receptor phosphorylation by the pH-dependent antinociceptive agonist NFEPP Frontiers in Molecular Neuroscience NFEPP mu opioid receptor (MOR) VDCC fentanyl pain |
| title | Modulation of G-protein activation, calcium currents and opioid receptor phosphorylation by the pH-dependent antinociceptive agonist NFEPP |
| title_full | Modulation of G-protein activation, calcium currents and opioid receptor phosphorylation by the pH-dependent antinociceptive agonist NFEPP |
| title_fullStr | Modulation of G-protein activation, calcium currents and opioid receptor phosphorylation by the pH-dependent antinociceptive agonist NFEPP |
| title_full_unstemmed | Modulation of G-protein activation, calcium currents and opioid receptor phosphorylation by the pH-dependent antinociceptive agonist NFEPP |
| title_short | Modulation of G-protein activation, calcium currents and opioid receptor phosphorylation by the pH-dependent antinociceptive agonist NFEPP |
| title_sort | modulation of g protein activation calcium currents and opioid receptor phosphorylation by the ph dependent antinociceptive agonist nfepp |
| topic | NFEPP mu opioid receptor (MOR) VDCC fentanyl pain |
| url | https://www.frontiersin.org/articles/10.3389/fnmol.2023.1171855/full |
| work_keys_str_mv | AT melihozgurcelik modulationofgproteinactivationcalciumcurrentsandopioidreceptorphosphorylationbythephdependentantinociceptiveagonistnfepp AT violaseitz modulationofgproteinactivationcalciumcurrentsandopioidreceptorphosphorylationbythephdependentantinociceptiveagonistnfepp AT fatihyergoz modulationofgproteinactivationcalciumcurrentsandopioidreceptorphosphorylationbythephdependentantinociceptiveagonistnfepp AT sandeepdembla modulationofgproteinactivationcalciumcurrentsandopioidreceptorphosphorylationbythephdependentantinociceptiveagonistnfepp AT ninakathleenblum modulationofgproteinactivationcalciumcurrentsandopioidreceptorphosphorylationbythephdependentantinociceptiveagonistnfepp AT stefanschulz modulationofgproteinactivationcalciumcurrentsandopioidreceptorphosphorylationbythephdependentantinociceptiveagonistnfepp AT christophstein modulationofgproteinactivationcalciumcurrentsandopioidreceptorphosphorylationbythephdependentantinociceptiveagonistnfepp |