Impaired Pain-evoked Analgesia after Nerve Injury in Rats Reflects Altered Glutamate Regulation in the Locus Coeruleus.

BACKGROUND Patients with neuropathic pain show reduced endogenous analgesia induced by a conditioned noxious stimulus. Here, the authors tested whether peripheral nerve injury impairs descending noradrenergic inhibition from the locus coeruleus (LC) after L5-L6 spinal nerve ligation (SNL) in rats. METHODS A subdermal injection of capsaicin was used to examine noxious stimulation-induced analgesia (NSIA), evoked LC glutamate and spinal noradrenaline release, and evoked LC neuronal activity in normal and SNL rats. The authors also examined the role of presynaptic metabotropic glutamate receptors or the astroglial glutamate transporter-1 (GLT-1). RESULTS SNL increased basal extracellular glutamate concentration in the LC (170.1%; 95% CI, 44.7 to 295.5; n = 15) and basal spinal cord noradrenaline release (252.1%; 95% CI, 113.6 to 391.3; n = 15), which was associated with an increased tonic LC neuronal activity and a down-regulation of GLT-1 in the LC. SNL reduced NSIA (-77.6%; 95% CI, -116.4 to -38.8; n = 14) and capsaicin evoked release of glutamate in the LC (-36.2%; 95% CI, -49.3 to -23.2; n = 8) and noradrenaline in the spinal cord (-38.8%; 95% CI, -45.1 to -32.5; n = 8). Capsaicin-evoked LC neuronal activation was masked in SNL rats. Removing autoinhibition of glutamatergic terminals by metabotropic glutamate receptor blockade or increasing GLT-1 expression by histone deacetylase inhibition restored NSIA in SNL rats. SNL-induced impairment of NSIA was mimicked in normal rats by knockdown of GLT-1 in the LC. CONCLUSIONS These results suggest that increased extracellular glutamate in the LC consequent to down-regulation of GLT-1 contributes to LC dysfunction and impaired pain-evoked endogenous analgesia after nerve injury.