Duloxetine deteriorates prefrontal noradrenergic pain facilitation, but reduces locus coeruleus activity to restore endogenous analgesia in chronic neuropathic pain state

Chronic neuropathic pain increases basal noradrenaline (NA) concentrations in the spinal cord and brain. Spinal NA further increased by duloxetine (DLX) alleviates neuropathic pain, however, the roles of basal and DLX induced NA in brain regions have not been well investigated. α2-adrenoceptor antagonist, atipamezole, to the medial prefrontal cortex (mPFC) produced anti-allodynia at 6 weeks following spinal nerve ligation (SNL6W) but produced no effects in the earlier phase of SNL animals (SNL2W). The anti-allodynia effect of intraperitoneal DLX is attenuated in SNL6W, and the combination of intraperitoneal DLX and atipamezole to the mPFC enhanced the anti-allodynia in SNL6W. Intrathecal atipamezole in SNL6W reduced DLX analgesia. Microdialysis experiments revealed that DLX increased NA in the mPFC and spinal cord in the same manner in both SNL6W and SNL2W. These results suggested that the basal mPFC NA maintains neuropathic pain in SNL6W. The spinal NA increased by DLX produces analgesia, but NA in mPFC may counteract the action of spinal NA. In the locus coeruleus (LC), DLX increased NA around LC and decreased the pERK immunoreactivity to restore noxious stimuli induced analgesia. These results suggest that reduced LC activity may lead to the restoration of stimulus responsive activity.