Peripheral sensory neurons and non-neuronal cells express functional Piezo1 that is activated in peripheral nerve injury-induced neuropathic pain

Abstract

AbstractHere, we present evidence showing Piezo1 expression in the primary sensory neurons (PSNs) and non-neuronal cells of rat peripheral nervous system. Using a knockdown/knockout validated antibody, we detected Piezo1 immunoreactivity (IR) in ∼80% of PSNs of rat dorsal root ganglia (DRG) with higher IR density in the small- and medium-sized neurons, and within axons extending to both central presynaptic terminals innervating to the spinal dorsal horn and peripheral cutaneous sensory terminals in the skin. Piezo-IR was clearly identified in DRG perineuronal glia, including satellite glial cells (SGCs) and non-myelinating Schwann cells; in sciatic nerve Schwann cells surrounding the axons and cutaneous afferent endings; and in skin epidermal Merkel cells and melanocytes. Neuronal and non-neuronal Piezo1 channels were functional, since various cells (dissociated PSNs and SGCs from DRGs, isolated Schwann cells, and primary human melanocytes) exhibited a robust response to Piezo1 agonist Yoda1 by an increase of intracellular Ca2+ concentration ([Ca2+]i). These responses were abolished by Piezo1 antagonist GsMTx4. Immunoblots showed elevated Piezo1 protein in DRG proximal to peripheral nerve injury-induced painful neuropathy, while PSNs and SGCs from rats with neuropathic pain showed greater Yuda1-evoked elevation of [Ca2+]i and an increased frequency of cells responding to Yoda1, compared to controls. Ipsilateral sciatic nerve application of GsMTx4 alleviated mechanical hypersensitivity following nerve injury. Overall, our data show that Piezo1 is widely expressed by the neuronal and non-neuronal cells in the peripheral sensory pathways and that painful nerve injury is associated with activation of Piezo1 in PSNs and peripheral glia cells.