Peripherally restricted PICK1 inhibitor mPD5 ameliorates pain behaviors in murine inflammatory and neuropathic pain models
Chronic pain is a complex, debilitating, and escalating health problem worldwide, impacting one in five adults. Current treatment is compromised by dose-limiting side effects including high abuse liability, loss of ability to function socially and professionally, fatigue, drowsiness, and apathy. PIC...
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| Published in: | JCI insight Vol. 9; no. 20 |
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American Society for Clinical Investigation
17-09-2024
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| Abstract | Chronic pain is a complex, debilitating, and escalating health problem worldwide, impacting one in five adults. Current treatment is compromised by dose-limiting side effects including high abuse liability, loss of ability to function socially and professionally, fatigue, drowsiness, and apathy. PICK1 has emerged as a promising target for the treatment of chronic pain conditions. Here, we developed and characterized a cell-permeable fatty acid conjugated bivalent peptide inhibitor of PICK1 and assessed its effects on acute and chronic pain. The myristoylated myr-NPEG4-(HWLKV)2 (mPD5), self-assembled into core-shell micelles that provided favourable pharmacodynamic properties and relieved evoked mechanical and thermal hypersensitivity, as well as ongoing hypersensitivity, and anxio-depressive symptoms in mouse models of neuropathic and inflammatory pain following subcutaneous administration. No overt side effects were associated with mPD5 administration, and it had no effect on acute nociception. Finally, neuropathic pain was relieved far into the chronic phase (18 weeks post SNI surgery) and while the effect of a single injection ceased after a few hours, repeated administration provided pain relief lasting up to 20 hours after the last injection. |
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| AbstractList | Chronic pain is a complex, debilitating, and escalating health problem worldwide, impacting 1 in 5 adults. Current treatment is compromised by dose-limiting side effects, including high abuse liability, loss of ability to function socially and professionally, fatigue, drowsiness, and apathy. PICK1 has emerged as a promising target for the treatment of chronic pain conditions. Here, we developed and characterized a cell-permeable fatty acid–conjugated bivalent peptide inhibitor of PICK1 and assessed its effects on acute and chronic pain. The myristoylated PICK1 inhibitor, myr-NPEG
4
-(HWLKV)
2
(mPD5), self-assembled into core-shell micelles that provided favorable pharmacodynamic properties and relieved evoked mechanical and thermal hypersensitivity as well as ongoing hypersensitivity and anxiodepressive symptoms in mouse models of neuropathic and inflammatory pain following subcutaneous administration. No overt side effects were associated with mPD5 administration, and it had no effect on acute nociception. Finally, neuropathic pain was relieved far into the chronic phase (18 weeks after spared nerve injury surgery) and while the effect of a single injection ceased after a few hours, repeated administration provided pain relief lasting up to 20 hours after the last injection.
mPD5 is a peripherally restricted peptide drug that relieves both ongoing and evoked hypersensitivity in multiple mouse models of pain in female and male mice. Chronic pain is a complex, debilitating, and escalating health problem worldwide, impacting 1 in 5 adults. Current treatment is compromised by dose-limiting side effects, including high abuse liability, loss of ability to function socially and professionally, fatigue, drowsiness, and apathy. PICK1 has emerged as a promising target for the treatment of chronic pain conditions. Here, we developed and characterized a cell-permeable fatty acid-conjugated bivalent peptide inhibitor of PICK1 and assessed its effects on acute and chronic pain. The myristoylated PICK1 inhibitor, myr-NPEG4-(HWLKV)2 (mPD5), self-assembled into core-shell micelles that provided favorable pharmacodynamic properties and relieved evoked mechanical and thermal hypersensitivity as well as ongoing hypersensitivity and anxiodepressive symptoms in mouse models of neuropathic and inflammatory pain following subcutaneous administration. No overt side effects were associated with mPD5 administration, and it had no effect on acute nociception. Finally, neuropathic pain was relieved far into the chronic phase (18 weeks after spared nerve injury surgery) and while the effect of a single injection ceased after a few hours, repeated administration provided pain relief lasting up to 20 hours after the last injection.Chronic pain is a complex, debilitating, and escalating health problem worldwide, impacting 1 in 5 adults. Current treatment is compromised by dose-limiting side effects, including high abuse liability, loss of ability to function socially and professionally, fatigue, drowsiness, and apathy. PICK1 has emerged as a promising target for the treatment of chronic pain conditions. Here, we developed and characterized a cell-permeable fatty acid-conjugated bivalent peptide inhibitor of PICK1 and assessed its effects on acute and chronic pain. The myristoylated PICK1 inhibitor, myr-NPEG4-(HWLKV)2 (mPD5), self-assembled into core-shell micelles that provided favorable pharmacodynamic properties and relieved evoked mechanical and thermal hypersensitivity as well as ongoing hypersensitivity and anxiodepressive symptoms in mouse models of neuropathic and inflammatory pain following subcutaneous administration. No overt side effects were associated with mPD5 administration, and it had no effect on acute nociception. Finally, neuropathic pain was relieved far into the chronic phase (18 weeks after spared nerve injury surgery) and while the effect of a single injection ceased after a few hours, repeated administration provided pain relief lasting up to 20 hours after the last injection. Chronic pain is a complex, debilitating, and escalating health problem worldwide, impacting one in five adults. Current treatment is compromised by dose-limiting side effects including high abuse liability, loss of ability to function socially and professionally, fatigue, drowsiness, and apathy. PICK1 has emerged as a promising target for the treatment of chronic pain conditions. Here, we developed and characterized a cell-permeable fatty acid conjugated bivalent peptide inhibitor of PICK1 and assessed its effects on acute and chronic pain. The myristoylated myr-NPEG4-(HWLKV)2 (mPD5), self-assembled into core-shell micelles that provided favourable pharmacodynamic properties and relieved evoked mechanical and thermal hypersensitivity, as well as ongoing hypersensitivity, and anxio-depressive symptoms in mouse models of neuropathic and inflammatory pain following subcutaneous administration. No overt side effects were associated with mPD5 administration, and it had no effect on acute nociception. Finally, neuropathic pain was relieved far into the chronic phase (18 weeks post SNI surgery) and while the effect of a single injection ceased after a few hours, repeated administration provided pain relief lasting up to 20 hours after the last injection. |
| Author | Topp, Marie Løth Noes-Holt, Gith Houser, Grace Anne Jensen, Kathrine Louise Thomsen, Cecilie Dubgaard Heegaard, Anne-Marie Ibrahim Soltan, Ahmed Barakat Mayer, Felix Paul Tidenmand, Federik Grønbæk Madsen, Kenneth Lindegaard Christensen, Nikolaj Riis Goddard, Carolyn Marie Sivertsen, Line Sørensen, Andreas Toft Jakobsen, Alexander Comaposada-Baro, Raquel Peck, Emily G Diaz-delCastillo, Marta Hopkins, Chelsea Jager, Sara Elgaard Jiménez-Fernández, Lucía Arleth, Lise Kanneworff, Ida Buur |
| AuthorAffiliation | 5 X-ray and Neutron Science, Niels Bohr Institute, Faculty of Science, University of Copenhagen, Copenhagen, Denmark 2 Center for Biopharmaceuticals, Department of Drug Design and Pharmacology, and 3 Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark 4 Department of Translational Neuroscience, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA 1 Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience |
| AuthorAffiliation_xml | – name: 4 Department of Translational Neuroscience, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA – name: 5 X-ray and Neutron Science, Niels Bohr Institute, Faculty of Science, University of Copenhagen, Copenhagen, Denmark – name: 3 Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark – name: 2 Center for Biopharmaceuticals, Department of Drug Design and Pharmacology, and – name: 1 Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience |
| Author_xml | – sequence: 1 givenname: Kathrine Louise surname: Jensen fullname: Jensen, Kathrine Louise organization: Molecular Neuropharmacology and Genetics Laboratory, Department of Neurosci, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark – sequence: 2 givenname: Nikolaj Riis surname: Christensen fullname: Christensen, Nikolaj Riis organization: Molecular Neuropharmacology and Genetics Laboratory, Department of Neurosci, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark – sequence: 3 givenname: Carolyn Marie surname: Goddard fullname: Goddard, Carolyn Marie organization: Molecular Neuropharmacology and Genetics Laboratory, Department of Neurosci, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark – sequence: 4 givenname: Sara Elgaard surname: Jager fullname: Jager, Sara Elgaard organization: Molecular Neuropharmacology and Genetics Laboratory, Department of Neurosci, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark – sequence: 5 givenname: Gith surname: Noes-Holt fullname: Noes-Holt, Gith organization: Molecular Neuropharmacology and Genetics Laboratory, Department of Neurosci, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark – sequence: 6 givenname: Ida Buur surname: Kanneworff fullname: Kanneworff, Ida Buur organization: Molecular Neuropharmacology and Genetics Laboratory, Department of Neurosci, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark – sequence: 7 givenname: Alexander surname: Jakobsen fullname: Jakobsen, Alexander organization: Molecular Neuropharmacology and Genetics Laboratory, Department of Neurosci, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark – sequence: 8 givenname: Lucía surname: Jiménez-Fernández fullname: Jiménez-Fernández, Lucía organization: Molecular Neuropharmacology and Genetics Laboratory, Department of Neurosci, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark – sequence: 9 givenname: Emily G surname: Peck fullname: Peck, Emily G organization: Molecular Neuropharmacology and Genetics Laboratory, Department of Neurosci, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark – sequence: 10 givenname: Line surname: Sivertsen fullname: Sivertsen, Line organization: Molecular Neuropharmacology and Genetics Laboratory, Department of Neurosci, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark – sequence: 11 givenname: Raquel surname: Comaposada-Baro fullname: Comaposada-Baro, Raquel organization: Molecular Neuropharmacology and Genetics Laboratory, Department of Neurosci, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark – sequence: 12 givenname: Grace Anne surname: Houser fullname: Houser, Grace Anne organization: Molecular Neuropharmacology and Genetics Laboratory, Department of Neurosci, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark – sequence: 13 givenname: Felix Paul surname: Mayer fullname: Mayer, Felix Paul organization: Molecular Neuropharmacology and Genetics Laboratory, Department of Neurosci, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark – sequence: 14 givenname: Marta surname: Diaz-delCastillo fullname: Diaz-delCastillo, Marta organization: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark – sequence: 15 givenname: Marie Løth surname: Topp fullname: Topp, Marie Løth organization: Molecular Neuropharmacology and Genetics Laboratory, Department of Neurosci, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark – sequence: 16 givenname: Chelsea surname: Hopkins fullname: Hopkins, Chelsea organization: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark – sequence: 17 givenname: Cecilie Dubgaard surname: Thomsen fullname: Thomsen, Cecilie Dubgaard organization: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark – sequence: 18 givenname: Ahmed Barakat surname: Ibrahim Soltan fullname: Ibrahim Soltan, Ahmed Barakat organization: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark – sequence: 19 givenname: Federik Grønbæk surname: Tidenmand fullname: Tidenmand, Federik Grønbæk organization: X-ray and Neutron Science, Niels Bohr Institute, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark – sequence: 20 givenname: Lise surname: Arleth fullname: Arleth, Lise organization: X-ray and Neutron Science, Niels Bohr Institute, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark – sequence: 21 givenname: Anne-Marie surname: Heegaard fullname: Heegaard, Anne-Marie organization: Department of Pharmacology and Pharmacotherapy, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark – sequence: 22 givenname: Andreas Toft surname: Sørensen fullname: Sørensen, Andreas Toft organization: Molecular Neuropharmacology and Genetics Laboratory, Department of Neurosci, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark – sequence: 23 givenname: Kenneth Lindegaard surname: Madsen fullname: Madsen, Kenneth Lindegaard organization: Molecular Neuropharmacology and Genetics Laboratory, Department of Neurosci, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/39287978$$D View this record in MEDLINE/PubMed |
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| Keywords | Neuroscience Pharmacology Pain Peptides |
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| Snippet | Chronic pain is a complex, debilitating, and escalating health problem worldwide, impacting one in five adults. Current treatment is compromised by... Chronic pain is a complex, debilitating, and escalating health problem worldwide, impacting 1 in 5 adults. Current treatment is compromised by dose-limiting... |
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| Title | Peripherally restricted PICK1 inhibitor mPD5 ameliorates pain behaviors in murine inflammatory and neuropathic pain models |
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