The Scaffold Protein PICK1 as a Target in Chronic Pain
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The Scaffold Protein PICK1 as a Target in Chronic Pain. / Sørensen, Andreas Toft; Rombach, Joscha; Gether, Ulrik; Madsen, Kenneth Lindegaard.
In: Cells, Vol. 11, No. 8, 1255, 2022.Research output: Contribution to journal › Review › Research › peer-review
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TY - JOUR
T1 - The Scaffold Protein PICK1 as a Target in Chronic Pain
AU - Sørensen, Andreas Toft
AU - Rombach, Joscha
AU - Gether, Ulrik
AU - Madsen, Kenneth Lindegaard
N1 - Publisher Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2022
Y1 - 2022
N2 - 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.
AB - 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.
KW - calcium permeable AMPAR
KW - drug development
KW - inflammatory pain
KW - maladap-tive plasticity
KW - neuropathic pain
KW - therapeutic peptides
U2 - 10.3390/cells11081255
DO - 10.3390/cells11081255
M3 - Review
C2 - 35455935
AN - SCOPUS:85127862236
VL - 11
JO - Cells
JF - Cells
SN - 2073-4409
IS - 8
M1 - 1255
ER -
ID: 303802139