oligomycins and Neuralgia

Mitochondria critically regulate cytoplasmic Ca(2+) concentration ([Ca(2+)]c), but the effects of sensory neuron injury have not been examined. Using FCCP (1µM) to eliminate mitochondrial Ca(2+) uptake combined with oligomycin (10µM) to prevent ATP depletion, we first identified features of depolarization-induced neuronal [Ca(2+)]c transients that are sensitive to blockade of mitochondrial Ca(2+) buffering in order to assess mitochondrial contributions to [Ca(2+)]c regulation. This established the loss of a shoulder during the recovery of the depolarization (K(+))-induced transient, increased transient peak and area, and elevated shoulder level as evidence of diminished mitochondrial Ca(2+) buffering. We then examined transients in Control neurons and neurons from the 4th lumbar (L4) and 5th lumbar (L5) dorsal root ganglia after L5 spinal nerve ligation (SNL). The SNL L4 neurons showed decreased transient peak and area compared to control neurons, while the SNL L5 neurons showed increased shoulder level. Additionally, SNL L4 neurons developed shoulders following transients with lower peaks than Control neurons. Application of FCCP plus oligomycin elevated resting [Ca(2+)]c in SNL L4 neurons more than in Control neurons. Whereas application of FCCP plus oligomycin 2s after neuronal depolarization initiated mitochondrial Ca(2+) release in most Control and SNL L4 neurons, this usually failed to release mitochondrial Ca(2+) from SNL L5 neurons. For comparable cytoplasmic Ca(2+) loads, the releasable mitochondrial Ca(2+) in SNL L5 neurons was less than Control while it was increased in SNL L4 neurons. These findings show diminished mitochondrial Ca(2+) buffering in axotomized SNL L5 neurons but enhanced Ca(2+) buffering by neurons in adjacent SNL L4 neurons.

Topics: Animals; Axotomy; Calcium; Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; Ganglia, Spinal; Male; Mitochondria; Neuralgia; Nociceptors; Oligomycins; Peripheral Nerve Injuries; Rats, Sprague-Dawley

The dose-limiting side effect of taxane, platinum-complex, and other kinds of anticancer drugs is a chronic, distal, bilaterally symmetrical, sensory peripheral neuropathy that is often accompanied by neuropathic pain. Work with animal models of these conditions suggests that the neuropathy is a consequence of toxic effects on mitochondria in primary afferent sensory neurons. If this is true, then additional mitochondrial insult ought to make the neuropathic pain worse. This prediction was tested in rats with painful peripheral neuropathy due to the taxane agent, paclitaxel, and the platinum-complex agent, oxaliplatin. Rats with established neuropathy were given 1 of 3 mitochondrial poisons: rotenone (an inhibitor of respiratory Complex I), oligomycin (an inhibitor of adenosine triphosphate synthase), and auranofin (an inhibitor of the thioredoxin-thioredoxin reductase mitochondrial antioxidant defense system). All 3 toxins significantly increased the severity of paclitaxel-evoked and oxaliplatin-evoked mechano-allodynia and mechano-hyperalgesia while having no effect on the mechano-sensitivity of chemotherapy-naïve rats. Chemotherapy-evoked painful peripheral neuropathy is associated with an abnormal spontaneous discharge in primary afferent A fibers and C fibers. Oligomycin, at the same dose that exacerbated allodynia and hyperalgesia, significantly increased the discharge frequency of spontaneously discharging A fibers and C fibers in both paclitaxel-treated and oxaliplatin-treated rats, but did not evoke any discharge in naïve control rats. These results implicate mitochondrial dysfunction in the production of chemotherapy-evoked neuropathic pain and suggest that drugs that have positive effects on mitochondrial function may be of use in its treatment and prevention.

Topics: Animals; Antineoplastic Agents; Antirheumatic Agents; Auranofin; Behavior, Animal; Drug Interactions; Hyperalgesia; Male; Mitochondria; Nerve Fibers; Neuralgia; Oligomycins; Organoplatinum Compounds; Oxaliplatin; Paclitaxel; Pain Measurement; Pain Threshold; Rats; Rats, Sprague-Dawley; Rotenone; Time Factors; Uncoupling Agents