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
Main Authors:	Jensen, Kathrine Louise, Christensen, Nikolaj Riis, Goddard, Carolyn Marie, Jager, Sara Elgaard, Noes-Holt, Gith, Kanneworff, Ida Buur, Jakobsen, Alexander, Jiménez-Fernández, Lucía, Peck, Emily G, Sivertsen, Line, Comaposada-Baro, Raquel, Houser, Grace Anne, Mayer, Felix Paul, Diaz-delCastillo, Marta, Topp, Marie Løth, Hopkins, Chelsea, Thomsen, Cecilie Dubgaard, Ibrahim Soltan, Ahmed Barakat, Tidenmand, Federik Grønbæk, Arleth, Lise, Heegaard, Anne-Marie, Sørensen, Andreas Toft, Madsen, Kenneth Lindegaard
Format:	Journal Article
Language:	English
Published:	United States American Society for Clinical Investigation 17-09-2024
Subjects:	Neuroscience Pharmacology Pain Peptides
Online Access:	Get full text
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2379-3708 2379-3708
DOI:	10.1172/jci.insight.170976