The Pathophysiology of Neuropathic Pain: A Review of Current Research and Hypotheses

Abstract

The treatment of neuropathic pain is often unsatisfactory. A better understanding of the underlying mechanisms is expected to improve treatment strategies and to develop new treatment options. Multiple animal models have been developed that allow the assessment of behavioral signs of neuropathic pain and the investigation of injury-induced changes in the peripheral and central nervous system. Much of our current knowledge has been generated from animal models that use traumatic nerve injuries to induce neuropathic pain. Behavioral signs in these models mimic symptoms seen in humans suffering from neuropathic pain, including signs of spontaneous pain, thermal and mechanical hyperalgesia. Electrophysiologic recordings in these models have shown that injured primary afferent neurons become hyperexcitable, that is, they show spontaneous activity and ectopic sensitivity to natural stimuli. Not surprisingly, injured neurons show an altered expression of ion channels involved in setting neuronal excitability. Recent research uncovered that uninjured neurons show similar changes, including spontaneous activity, an increased sensitivity to peripheral stimuli, and changes in protein expression. The changes in injured neurons are likely due to alterations in neurotrophic supply. These and processes related to Wallerian degeneration may account for the changes in uninjured neurons. Peripheral nerve injury also leads to changes in the central nervous system. Sensitization of central neurons is an important mechanism of neuropathic pain. Central disinhibition and activation of spinal microglia may contribute to this sensitization.