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. 2011 Aug;152(8):1832-1837.
doi: 10.1016/j.pain.2011.03.034. Epub 2011 May 12.

Mitochondrial dependence of nerve growth factor-induced mechanical hyperalgesia

Carissa Chu  1 , Emma Levine, Robert W Gear, Oliver Bogen, Jon D Levine
Affiliations

Mitochondrial dependence of nerve growth factor-induced mechanical hyperalgesia

Carissa Chu et al. Pain. 2011 Aug.

Abstract

Mitochondria are present at high concentration at the site of sensory transduction in the peripheral terminals of nociceptors. Because nerve growth factor (NGF), which induces nociceptor sensitization by acting on the high-affinity tropomyosin receptor kinase A (TrkA) receptor, also produces local recruitment of mitochondria in DRG neurons, we evaluated the role of mitochondria in NGF-induced mechanical hyperalgesia. Inhibition of 3 major mitochondrial functions-oxidation of nutrients, adenosine triphosphate (ATP) production, and generation of reactive oxygen species--markedly attenuated NGF-induced mechanical hyperalgesia in the rat. Disruption of microtubules, which are required for the trafficking and subcellular localization of mitochondria, also attenuated NGF-induced hyperalgesia. Our results suggest a contribution of mitochondrial localization and function to NGF-dependent pain syndromes.

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Conflict of interest statement

The authors declare that no conflict of interest exists in connection with this study.

Figures

Figure 1
Figure 1
Effect of electron transport inhibitors on NGF hyperalgesia. A. Rotenone, a mETC complex I inhibitor, attenuated NGF hyperalgesia at all time points. B. Oligomycin, a mETC complex V (ATP synthase) inhibitor, attenuated NGF hyperalgesia at all time points. N = 6 for all groups. Data are plotted as mean ± SEM. Significant differences between the groups are indicated by asterisks (*) plotted above the time points where they apply. Abbreviation: PWT = paw-withdrawal threshold.
Figure 2
Figure 2
The effect of the anti-oxidants N-acetyl-L-cysteine (NAC) and glutathione on NGF-hyperalgesia. A. Various doses of both NAC and glutathione were administered thirty minutes after NGF in order to determine the doses to be used for testing. For NAC the highest dose (10 μg) was chosen because it attenuated NGF hyperalgesia significantly more than any of the lower doses. For glutathione the effect of the 10 μg dose was not significantly greater than that of the 5 μg dose, therefore the 5 μg dose was chosen for testing. B. NAC (10 μg) attenuated NGF hyperalgesia detectable at 1 hour and lasting up to 24 hours. C. Glutathione (5 μg) attenuated NGF hyperalgesia detectable at 30 minutes, but the effect was no longer significant by 24 hours. N = 6 for all groups. Data are plotted as mean ± SEM. Significant difference between the groups are indicated by asterisks (*) plotted above the time points where they apply. Abbreviation: PWT = paw-withdrawal threshold.
Figure 3
Figure 3
Effect of cytoskeletal inhibitors on NGF hyperalgesia. A. Latrunculin B, an actin disruptor had no significant effect on NGF hyperalgesia and any time point. B. Nocodazole, a microtubule disruptor, attenuated hyperalgesia up to 24 hours after NGF administration of hyperalgesic agent (n=6). C. Both Latrunculin B and nocodazole significantly attenuated epinephrine-induced hyperalgesia as demonstrated previously (Dina et al., 2003) (shown here as a positive control). Note that this experiment was not carried out to 24 hours because epinephrine-induced hyperalgesia lasts less than three hours. N = 6 for all groups. Data are plotted as mean ± SEM. Significant difference between the groups are indicated by asterisks (*) plotted above the time points where they apply. Abbreviations: PWT = paw-withdrawal threshold; EPI = epinephrine.
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