RT Journal Article SR Electronic T1 Paroxetine Increases δ Opioid Responsiveness in Sensory Neurons JF eneuro JO eNeuro FD Society for Neuroscience SP ENEURO.0063-22.2022 DO 10.1523/ENEURO.0063-22.2022 VO 9 IS 4 A1 Allison Doyle Brackley A1 Nathaniel A. Jeske YR 2022 UL http://www.eneuro.org/content/9/4/ENEURO.0063-22.2022.abstract AB There are currently no Food and Drug Administration (FDA)-approved δ-opioid receptor (DOR)-selective agonists, despite having fewer side effects in rodents and nonhuman primates compared with traditional μ-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 noninflammatory pain patients (Stein et al., 1989). It was recently identified that G-protein-coupled receptor kinase 2 (GRK2) maintains DOR incompetence in noninflamed nociceptors (Brackley et al., 2016, 2017). Here, we report that paroxetine, a selective serotonin reuptake inhibitor (SSRI) 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 noninflamed 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 noninflammatory pain conditions.