Keratinocytes and PDGF-B/PDGFRβ signaling modulate peripheral opioid tolerance

Peripheral opioids are safer than systemic opioids by avoiding central side effects. However, peripheral tolerance hampers their clinical use. We highlight an epithelial-neuronal communication mechanism for peripheral opioid tolerance. We discovered that both repeated intraplantar (i.pl.) morphine injections or repeated keratinocyte photostimulation in mice cause peripheral tolerance in a platelet-derived growth factor type B (PDGF-B) and PDGF receptor beta (PDGFRβ)-dependent manner. We also find that morphine i.pl. increases PDGF-B in mu-opioid receptor-expressing keratinocytes and alters the electrophysiological properties of keratinocytes. This underscores the importance of keratinocytes and the necessity for PDGF-B release for peripheral tolerance, though the source of PDGF-B remains undetermined. Nevertheless, we show that PDGFRβ inhibition completely blocks peripheral tolerance in peripheral chronic pain models, highlighting the translational relevance of our findings. Overall, we highlight that keratinocytes and PDGFRβ are promising targets to reduce peripheral tolerance, which could allow shifting from systemic to peripheral opioid delivery and increase opioid safety.