Sunday, May 11, 2025
5/11/2025
Targeting PDGFRβ to treat peripheral opioid tolerance - PROJECT SUMMARY/ABSTRACT Chronic systemic opioid use leads to misuse, addiction and overdoses. Topical and peripheral application of low doses of opioids are safer alternatives, as they provide efficient local analgesia with limited penetration in the central nervous system (CNS). Unfortunately, tolerance decreases peripheral opioid analgesia and the mechanisms of this phenomenon remain unknown. We propose the innovative hypothesis that peripheral tolerance could develop because of opioid action on skin keratinocytes and activation of peripheral PDGFRβ signaling. CNS-tolerance involves activation of the platelet-derived growth factor receptor beta (PDGFRβ) by the platelet-derived growth factor B (PDGF-B) ligand, which is released in response to activation of the µ-opioid receptor (MOR) by opioids. Accordingly, intrathecal injections of imatinib, a PDGFRβ inhibitor, prevented opioid tolerance. Previous reports have hypothesized that central and peripheral tolerance occur by different mechanisms. However, we found that imatinib can also prevent tolerance to peripherally administered morphine, suggesting a shared mechanism that involves PDGFRβ signaling. In separate studies, using mice that express channelrhodopsin (ChR2) in keratinocytes (Krt14-ChR2), we found that optogenetic stimulation of keratinocytes activates a subpopulation of peripheral sensory neurons (PSNs), likely through release of neuroactivators from activated keratinocytes. Since PDGF-B is expressed in keratinocytes, these findings led to the idea that keratinocytes are a component of peripheral tolerance. In exciting preliminary studies, we discovered that repeated optogenetic stimulation of keratinocytes generated peripheral tolerance that could be blocked by imatinib, providing evidence that peripheral tolerance involves keratinocyte and PDGFRβ signaling. We now hypothesize that peripheral tolerance is mediated by the release of PDGF-B from MOR-activated keratinocytes with opioids. We will test this hypothesis by first, evaluating the role of PDGF-B signaling from keratinocytes in the development of peripheral tolerance, using behavioral pharmacology, optogenetics, proteomics and mRNA/protein imaging methods. Second, we will determine if MORs on keratinocytes mediate peripheral tolerance, by generating mice in which MOR will be specifically deleted either from keratinocytes or PSNs. We will also determine if keratinocytes are essential for peripheral tolerance, by evaluating if their selective optogenetic inhibition alters the development of tolerance. This project explores new cellular and molecular substrates for peripheral tolerance that involve epithelial- neural communication. Outcomes from this study could lead to new therapeutic strategies to treat chronic pain by repurposing PDGFRβ inhibitors to prevent peripheral opioid tolerance. This approach has the potential to significantly increase opioid safety in chronic pain treatment by minimizing undesirable central side effects.
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