Nerve injury increases basal extracellular glutamate (Glu) concentration in the locus coeruleus (LC) by down-regulating glutamate transporter-1 (GLT-1), and this inhibits evoked glutamate release by enhanced presynaptic inhibition via presynaptic metabotropic glutamate receptors (mGluRs). The increased basal extracellular glutamate concentration results in increased tonic activity of noradrenergic (NA) neurons and the reduced evoked glutamate release that diminishes α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated NA neuronal activation important to noxious stimulation–induced analgesia (NSIA).