A Novel Peripheral Action of PICK1 Inhibition in Inflammatory Pain
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A Novel Peripheral Action of PICK1 Inhibition in Inflammatory Pain. / Jensen, Kathrine Louise; Noes-Holt, Gith; Sørensen, Andreas Toft; Madsen, Kenneth Lindegaard.
In: Frontiers in Cellular Neuroscience, Vol. 15, 750902, 2021.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - A Novel Peripheral Action of PICK1 Inhibition in Inflammatory Pain
AU - Jensen, Kathrine Louise
AU - Noes-Holt, Gith
AU - Sørensen, Andreas Toft
AU - Madsen, Kenneth Lindegaard
N1 - Publisher Copyright: Copyright © 2021 Jensen, Noes-Holt, Sørensen and Madsen.
PY - 2021
Y1 - 2021
N2 - Chronic pain is a major healthcare problem that impacts one in five adults across the globe. Current treatment is compromised by dose-limiting side effects including drowsiness, apathy, fatigue, loss of ability to function socially and professionally as well as a high abuse liability. Most of these side effects result from broad suppression of excitatory neurotransmission. Chronic pain states are associated with specific changes in the efficacy of synaptic transmission in the pain pathways leading to amplification of non-noxious stimuli and spontaneous pain. Consequently, a reversal of these specific changes may pave the way for the development of efficacious pain treatment with fewer side effects. We have recently described a high-affinity, bivalent peptide TAT-P4-(C5)2, enabling efficient targeting of the neuronal scaffold protein, PICK1, a key protein in mediating chronic pain sensitization. In the present study, we demonstrate that in an inflammatory pain model, the peptide does not only relieve mechanical allodynia by targeting PICK1 involved in central sensitization, but also by peripheral actions in the inflamed paw. Further, we assess the effects of the peptide on novelty-induced locomotor activity, abuse liability, and memory performance without identifying significant side effects.
AB - Chronic pain is a major healthcare problem that impacts one in five adults across the globe. Current treatment is compromised by dose-limiting side effects including drowsiness, apathy, fatigue, loss of ability to function socially and professionally as well as a high abuse liability. Most of these side effects result from broad suppression of excitatory neurotransmission. Chronic pain states are associated with specific changes in the efficacy of synaptic transmission in the pain pathways leading to amplification of non-noxious stimuli and spontaneous pain. Consequently, a reversal of these specific changes may pave the way for the development of efficacious pain treatment with fewer side effects. We have recently described a high-affinity, bivalent peptide TAT-P4-(C5)2, enabling efficient targeting of the neuronal scaffold protein, PICK1, a key protein in mediating chronic pain sensitization. In the present study, we demonstrate that in an inflammatory pain model, the peptide does not only relieve mechanical allodynia by targeting PICK1 involved in central sensitization, but also by peripheral actions in the inflamed paw. Further, we assess the effects of the peptide on novelty-induced locomotor activity, abuse liability, and memory performance without identifying significant side effects.
KW - avidity
KW - bivalent peptide
KW - neuropathic pain
KW - PDZ inhibitor
KW - peptide inhibitor
KW - PICK1 inhibitor
U2 - 10.3389/fncel.2021.750902
DO - 10.3389/fncel.2021.750902
M3 - Journal article
C2 - 34975407
AN - SCOPUS:85121983822
VL - 15
JO - Frontiers in Cellular Neuroscience
JF - Frontiers in Cellular Neuroscience
SN - 1662-5102
M1 - 750902
ER -
ID: 289156060