Strategies to Treat Chronic Pain and Strengthen Impaired Descending Noradrenergic Inhibitory System

Gabapentinoids (gabapentin and pregabalin) and antidepressants (tricyclic antidepressants and serotonin noradrenaline reuptake inhibitors) are often used to treat chronic pain. The descending noradrenergic inhibitory system from the locus coeruleus (LC) to the dorsal horn of the spinal cord plays an important role in the analgesic mechanisms of these drugs. Gabapentinoids activate the LC by inhibiting the release of γ-aminobutyric acid (GABA) and inducing the release of glutamate, thereby increasing noradrenaline levels in the spinal cord. Antidepressants increase noradrenaline levels in the spinal cord by inhibiting reuptake, and accumulating noradrenaline inhibits chronic pain through α₂-adrenergic receptors in the spinal cord. Recent animal studies, however, revealed that the function of the descending noradrenergic inhibitory system is impaired in chronic pain states. Other recent studies found that histone deacetylase inhibitors and antidepressants restore the impaired noradrenergic descending inhibitory system acting on noradrenergic neurons in the LC.