Peripheral opioid tolerance involves skin keratinocytes and platelet-derived growth factor type B signaling

Opioid analgesic tolerance is a deleterious side-effect that requires escalation of dose to overcome reduced analgesia overtime. Dose-escalation dramatically reduces opioid safety due to centrally-mediated life-threatening side-effects, including respiratory depression or addiction. Peripheral opioid delivery is a safer alternative as it provides effective local analgesia with limited central penetration. However, tolerance also occurs peripherally, via mechanisms that remain unknown. Centrally, activation of the mu-opioid receptor (MOPr) by opioids induces release of platelet-derived growth factor-B (PDGF-B); and inhibition of PDGF receptor beta (PDGFRβ) prevents opioid tolerance. In the periphery, MOPr and PDGF-B are expressed in skin keratinocytes, and PDGFRβ is expressed in peripheral sensory neurons (PSNs), known to convey tolerance. Previous studies also showed that optogenetic stimulation of keratinocytes modulates PSNs via release of keratinocytes-derived factors. Thus, we hypothesized that mechanisms of peripheral opioid tolerance could involve keratinocytes and PDGFRβ signaling. Using behavioral pharmacology, optogenetics and in situ hybridization in mice, we found that selective inhibition of PDGFRβ at the periphery, prevents peripheral morphine tolerance caused by repeated intraplantar (i.pl.) morphine injections. In addition, we show that PDGF-B is necessary and sufficient to cause peripheral morphine tolerance and repeated peripheral morphine injections lead to an increase in PDGF-B mRNA in MOPr-expressing keratinocytes. In parallel, we discovered that repeated optogenetic activation of keratinocytes is sufficient to induce peripheral morphine tolerance in a PDGF-B/PDGFRβ-dependent manner. Together, these data show that keratinocytes and PDGF-B/PDGFRβ signaling are essential components in the mechanisms of peripheral opioid tolerance. ### Competing Interest Statement The authors have declared no competing interest.