Many forms of nerve injury can also produce death of sensory neurons.96 Apoptosis may be a result of mito-chondrial dysfunction97 and has been associated with a number of neuropathies.96,9899 Mitochondria-dependent apoptosis is activated by a number of factors including reactive oxygen species, ceramide, and nitric oxide,100 which have been implicated in the pathophysiology of neuropathies. These factors cause the release of cyto-chrome C from mitochondria leading to the formation of the apoptosome complex and subsequent activation of effector caspases. Alternatively, apoptotic pathways can be activated via stimulation of death receptors, such as TNFR1100 which can act via the JNK (c-Jun-N-terminal kinase) pathway to activate effector caspases. In support of this, TNFa is released in response to chemotherapeutic agents that produce painful peripheral neuropathy,101 following direct nerve injury,102 and in response to HIV-gp120 in vitro103 and caspases have been shown to be important in neuropathic responses in various models of neuropathy.20,96,104,105 It is thought that the activation of these pathways may be involved in neuropathic pain even though there may be a prolonged latent phase of apoptosis, before cell death.
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