Objective

Chronic pain affects daily quality of life in people. Current analgesics are partially effective and cause severe side effects. Over the last years we have pioneered the concept that immune cell infiltration and activation into the PNS and CNS are important processes that contribute to the establishment of chronic pain mechanisms. Recently we were intrigued by the possibility that non-soluble determinants could enable the cross-talk between neurons and macrophages within the PNS. We have identified a fundamental role for sensory neuron-derived exosomes cargoed with a specific micro-RNA (miR-21) in the development of allodynia following peripheral nerve injury. We report a novel function of dorsal root ganglia (DRG) neuron cell bodies, which release exosomes and miR-21 upon noxious-like activation. Neuron-derived exosomes are readily phagocytosed by macrophages in which an increase of miR-21 expression promotes a pro-inflammatory phenotype. After nerve injury miR-21 is up-regulated in DRG neurons and both intrathecal delivery of a miR-21-5p antagomir and conditional deletion of miR-21 in sensory neurons reduce neuropathic hypersensitivity and as well as the extent of inflammatory macrophage recruitment in the DRG. The delivery of exosomes containing miR-21 antagomir in a macrophage-specific manner may prove to be an innovating analgesic therapy.