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Mitochondria likely play a role in chronic pain. Universally known as being the power production center of the cell, the mitochondria do more than merely supply ATP. They are also involved in the creation of reactive oxygen species, mitochondrial permeability transition pore—which may lead to mitochondrial death in reperfusion injury73—apoptotic pathways, and intracellular calcium mobilization.74 Each of these may play a role in neuropathic pain.75 Mitochondrial division appears to play an important role in the creation and sustaining of some types of neuropathic pain. By inhibiting mitochondrial division in sensory neurons, mechanical hyperalgesia, normally brought on by anti-HIV drug 2,3-dideoxycytidine or the cancer drug oxaliplatin, was decreased. There was less hypersensitivity created by reactive oxygen species. In addition, inhibiting mitochondrial division also showed a treatment effect by reversing mechanical hyperalgesia secondary to the inflammatory mediators TNF-a, glial-derived neurotrophic factor, and the nitric oxide donor NOR-3 76

While the inhibition of mitochondrial division appears to play an important role in the treatment and protection of neuropathic pain, the loss of mitochondrial function in Schwann cells can also lead to the development of progressive neuropathy. By creating mitochondrial dysfunction in peripheral nerve Schwann cells (by deleting mitochondrial transcription factor-A gene), it was shown that a progressive peripheral neuropathy developed with age. These were associated with nerve conduction abnormalities as well as muscle denervation.77 Clinically, Schwann cell mitochondrial abnormalities have been identified in some neuropathies.78-79

Calcium modulation and the creation of reactive oxygen species are other important mitochondrial elements in the chronic pain state. We know that, during central sensitization, NMDA receptors lead to increased Ca2+ concentrations in the dorsal horn. By blocking mitochondrial uptake of Ca2+, NMDA receptor activation did not lead to central sensitization.80 Mitochondrial oxidative phosphorylation is a major source of superoxide ions found in excited neurons and is typically controlled by superoxide dismutase.81 Scavenging superoxide significantly reduces mechanical hyperalgesia.82 This provides a strong mechanistic explanation for the role of the mitochondria in central sensitization.

Leptin and Ghrelin

Leptin is typically considered to play a role in metabolism, being produced by adipocytes in a fed state. However, leptin levels have been noted to increase during acute infection, and acute and chronic inflammatory processes. Leptin also appears to be a potent immunomodulatory hormone and may play a role in several autoimmune pathways.83 Leptin increases phagocytic activity and cytokine secretion. It can stimulate neutrophil chemotaxis and oxidative burst. It can increase the activity of natural killer cells.8 Leptin promotes the switch toward Thl activity.84 Leptin promotes pro-inflammatory cytokine secretion and may play a role in enhancing autoimmune disorders.85 It is interesting to note that women show increased serum leptin levels compared to age- and BMI- matched men.86

On the other hand, ghrelin is produced primarily in the stomach during non-fed states and serves not only as an orexigen controlling energy expenditure, but also as a GH secretagogue receptor. Ghrelin and GH secretagogue receptor are also found on immune cells such as lymphocytes, monocytes, and dendritic cells. Ghrelin has anti-inflammatory effects on the immune system.5


In the chronic pain patient, there are multiple pathways that are disrupted or altered. A more comprehensive approach to unwinding this situation is likely to be more effective than our current strategies. Chronic opioid therapy falls short in many respects. The following chapter will discuss this further.


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