Mechanisms of neuropathic pain

Mechanical, metabolic or viral lesions of the peripheral or central nervous system may be followed by neuropathic pain. Lesions of peripheral nerves interrupt the communication from the target tissues (skin, deep somatic tissues) to the afferent (and efferent) neurons which occur via neurotrophins and other substances. The afferent (and efferent [autonomic, somatomotor]) neurons start to go through repair processes. The axons of the neurons sprout along the Schwann cell tubes. In case of no reinnervation of the target tissues irreversible peripheral and central changes do occur. The peripheral afferent neurons change neurochemically (increase or decrease of synthesis of transmitters, transduction molecules, channel molecules etc.), morphologically (shrinkage of neurons, death of afferent neurons with C fibers) and physiologically (development of spontaneous and evoked ectopic activity). The peripheral changes are followed by changes of the neurons and their synaptic connections in the central representations of nociception and pain in the dorsal horn of the spinal cord, brain stem, thalamus and cortex. This is macroscopically manifested in the reorganization and shrinkage of the central representations after lesions of large nerves. In the peripheral nervous system sympathetic (noradrenergic) neurons may be coupled to afferent neurons. This sympathetic-afferent coupling can occur via several mechanisms and is the peripheral substrate for sympathetically maintained pain. Unraveling the mechanisms of neuropathic pain will influence the classification of neuropathic pain and will lead to new concepts of therapy.