Various pain therapies have been developed on the basis of the gate control theory of pain, which postulates that nonpainful sensory inputs mediated by large-diameter afferent fibers (Aβ-fibers) can attenuate noxious signals relayed to the brain. To date, this theory has focused only on neuronal mechanisms. Here, we identified an unprecedented function of astrocytes in the gating of nociceptive signals transmitted by neurokinin 1 receptor–positive (NK1R+) projection neurons in the spinal cord. Electrical stimulation of peripheral Aβ-fibers in naïve mice activated spinal astrocytes, which in turn induced long-term depression (LTD) in NK1R+ neurons and antinociception through activation of endogenous adenosinergic mechanisms. Suppression of astrocyte activation by pharmacologic, chemogenetic, and optogenetic manipulations blocked the induction of LTD in NK1R+ neurons and pain inhibition by Aβ-fiber stimulation. Collectively, our study introduces astrocytes as an important component of pain gating by activation of Aβ-fibers, which thus exert nonneuronal control of pain.
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