Traumatic neuroma caused the post-amputation neuropathic pain: epidemiology, mechanisms and factors involved in pain generation

Abstract

Loss of the integrity of the peripheral nerves as a result of the traumatic injury or due to lower limb amputations in case of advanced ischemic disease is leading to serious complications and impaired tissue regeneration. Patients who experiencedamputation procedure do not only suffer from physical limitations and psychological problems, but also from chronic neuropathic pain, referred to as post-amputation pain (PAP), which significant decrease their quality of life. One of the main reason of PAP is post-traumatic neuromas, which are form chaotic structures consisting of regenerative axons and connective tissue, as a results of excessive regeneration of axons. The process of peripheral nerve regeneration starts with Wallerian degeneration and its main role is to degenerate damaged axons in the distal end of the injured nerve and initiate repair processes. In the process of nerves regeneration are involved Schwann cells, which attract immunocompetent cells (mainly macrophages, neutrophils and T lymphocytes) and activate inflammation process, necessary to remove damaged tissues and cells. However, the coordination of the production of pro- and anti-inflammatory cytokines and the activity of neurotrophic factors is of key importance. During regeneration of peripheral nerves, in the microenvironment of the damaged tissues increase the activity of neurotrophic factors including: nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF), and ciliary neurotrophic factor (CNTF) - proteins promoting survival and regeneration of axons. The activity of neurotrophic factors supports axonal regeneration from the proximal part into the distal direction and the final re-innervation of the tissue. In the case of amputation of the limb, the lack of distal stump of the nerve disturb proper regeneration of axons, and excessive activity of neurotrophic factors at the site of injury leads to uncontrolled axonal proliferation and neuroma formation. In addition, the increased activity of NGF enhances the expression of the protein associated with the calcitonin gene related protein (CGRP), which is one of the factors involved in the genesis of neuropathic pain. The protection of the proximal end of the damaged nerve from the regenerative signals coming from the microenvironment of damaged nerve can prevent excessive growth of axons and may inhibit the post-traumatic neuroma formation.