Paroxetine increases delta opioid responsiveness in sensory neurons

Allison Doyle Brackley; Nathaniel A Jeske

doi:10.1523/ENEURO.0063-22.2022

Paroxetine increases delta opioid responsiveness in sensory neurons

eNeuro. 2022 Jul 25;9(4):ENEURO.0063-22.2022. doi: 10.1523/ENEURO.0063-22.2022. Online ahead of print.

Authors

Allison Doyle Brackley¹, Nathaniel A Jeske^{2

3

4}

Affiliations

¹ Departments of Physiology, University of Texas Health San Antonio, TX, USA.
² Departments of Physiology, University of Texas Health San Antonio, TX, USA jeske@uthscsa.edu.
³ Oral and Maxillofacial Surgery, University of Texas Health San Antonio, TX, USA.
⁴ Pharmacology, University of Texas Health San Antonio, TX, USA.

Abstract

There are currently no Food and Drug Administration (FDA)-approved delta opioid receptor (DOR)-selective agonists, despite having fewer side effects in rodents and non-human primates compared to traditional mu opioid receptor (MOR) therapeutics (Vanderah, 2010). Targeting peripheral receptors is an attractive strategy to reduce abuse potential. However, peripheral opioid receptors do not readily respond to agonists unless primed by inflammation, which would limit their efficacy in non-inflammatory pain patients (Stein et al., 1989). It was recently identified that G protein-coupled receptor kinase 2 (GRK2) maintains DOR incompetence in non-inflamed nociceptors (Brackley et al., 2016; Brackley et al., 2017). Here, we report that paroxetine, a selective serotonin reuptake inhibitor and potent GRK2 inhibitor (Thal et al., 2012), reduces chronic GRK2 association with membrane DOR, thereby enhancing peripheral DOR-mediated analgesic competence in the absence of inflammation. Interestingly, paroxetine's effects on GRK2 in vivo are limited to peripheral tissues in the male rat. The effects of paroxetine on DOR competence are notably antagonized by GRK2 overexpression. This is the first study to suggest that paroxetine induces peripheral DOR analgesic competence through a GRK2-dependent mechanism, improving analgesic efficacy in non-inflamed tissue. Because paroxetine targets the protein that governs peripheral opioid receptor responsiveness, and does so in the absence of inflammation, we propose that paroxetine may be suitable as a co-therapy with peripherally-restrictive doses of opioids to improve analgesic efficacy in non-inflammatory pain conditions.Significance StatementOpioids that target MOR represent the gold-standard for analgesic healthcare, despite widespread abuse potential and the ongoing opioid-epidemic. Work herein uncovers the therapeutic potential of targeting peripheral DOR for analgesic utility with an FDA-approved GRK2 inhibitor paroxetine to boost efficacy and reduce side effect profiles. Analgesic pain management targeting DOR with increased efficacy through adjuvant paroxetine treatment could reduce over-reliance on MOR agonist opioids for pain relief and usher in new options for analgesia.

Keywords: GRK2; opioid; pain; paroxetine.

Abstract

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