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The Scaffold Protein PICK1 as a Target in Chronic Pain

Well-tolerated and effective drugs for treating chronic pain conditions are urgently needed. Most chronic pain patients are not effectively relieved from their pain and suffer from debilitating drug side effects. This has not only drastic negative consequences for the patients’ quality of life, but...

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Autores principales: Sørensen, Andreas Toft, Rombach, Joscha, Gether, Ulrik, Madsen, Kenneth Lindegaard
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9031029/
https://www.ncbi.nlm.nih.gov/pubmed/35455935
http://dx.doi.org/10.3390/cells11081255
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author Sørensen, Andreas Toft
Rombach, Joscha
Gether, Ulrik
Madsen, Kenneth Lindegaard
author_facet Sørensen, Andreas Toft
Rombach, Joscha
Gether, Ulrik
Madsen, Kenneth Lindegaard
author_sort Sørensen, Andreas Toft
collection PubMed
description Well-tolerated and effective drugs for treating chronic pain conditions are urgently needed. Most chronic pain patients are not effectively relieved from their pain and suffer from debilitating drug side effects. This has not only drastic negative consequences for the patients’ quality of life, but also constitute an enormous burden on society. It is therefore of great interest to explore new potent targets for effective pain treatment with fewer side effects and without addiction liability. A critical component of chronic pain conditions is central sensitization, which involves the reorganization and strengthening of synaptic transmission within nociceptive pathways. Such changes are considered as maladaptive and depend on changes in the surface expression and signaling of AMPA-type glutamate receptors (AMPARs). The PDZ-domain scaffold protein PICK1 binds the AMPARs and has been suggested to play a key role in these maladaptive changes. In the present paper, we review the regulation of AMPARs by PICK1 and its relation to pain pathology. Moreover, we highlight other pain-relevant PICK1 interactions, and we evaluate various compounds that target PICK1 and have been successfully tested in pain models. Finally, we evaluate the potential on-target side effects of interfering with the action of PICK1 action in CNS and beyond. We conclude that PICK1 constitutes a valid drug target for the treatment of inflammatory and neuropathic pain conditions without the side effects and abuse liability associated with current pain medication.
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spelling pubmed-90310292022-04-23 The Scaffold Protein PICK1 as a Target in Chronic Pain Sørensen, Andreas Toft Rombach, Joscha Gether, Ulrik Madsen, Kenneth Lindegaard Cells Review Well-tolerated and effective drugs for treating chronic pain conditions are urgently needed. Most chronic pain patients are not effectively relieved from their pain and suffer from debilitating drug side effects. This has not only drastic negative consequences for the patients’ quality of life, but also constitute an enormous burden on society. It is therefore of great interest to explore new potent targets for effective pain treatment with fewer side effects and without addiction liability. A critical component of chronic pain conditions is central sensitization, which involves the reorganization and strengthening of synaptic transmission within nociceptive pathways. Such changes are considered as maladaptive and depend on changes in the surface expression and signaling of AMPA-type glutamate receptors (AMPARs). The PDZ-domain scaffold protein PICK1 binds the AMPARs and has been suggested to play a key role in these maladaptive changes. In the present paper, we review the regulation of AMPARs by PICK1 and its relation to pain pathology. Moreover, we highlight other pain-relevant PICK1 interactions, and we evaluate various compounds that target PICK1 and have been successfully tested in pain models. Finally, we evaluate the potential on-target side effects of interfering with the action of PICK1 action in CNS and beyond. We conclude that PICK1 constitutes a valid drug target for the treatment of inflammatory and neuropathic pain conditions without the side effects and abuse liability associated with current pain medication. MDPI 2022-04-07 /pmc/articles/PMC9031029/ /pubmed/35455935 http://dx.doi.org/10.3390/cells11081255 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Sørensen, Andreas Toft
Rombach, Joscha
Gether, Ulrik
Madsen, Kenneth Lindegaard
The Scaffold Protein PICK1 as a Target in Chronic Pain
title The Scaffold Protein PICK1 as a Target in Chronic Pain
title_full The Scaffold Protein PICK1 as a Target in Chronic Pain
title_fullStr The Scaffold Protein PICK1 as a Target in Chronic Pain
title_full_unstemmed The Scaffold Protein PICK1 as a Target in Chronic Pain
title_short The Scaffold Protein PICK1 as a Target in Chronic Pain
title_sort scaffold protein pick1 as a target in chronic pain
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9031029/
https://www.ncbi.nlm.nih.gov/pubmed/35455935
http://dx.doi.org/10.3390/cells11081255
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