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Altered Mitochondrial ATP Synthase Expression in the Rat Dorsal Root Ganglion After Sciatic Nerve Injury and Analgesic Effects of Intrathecal ATP

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Abstract

Mitochondrial ATP synthase has multiple interdependent biological functions in neurons. Among them, ATP generation and regulation are the most important. The present study investigated whether the expression of mitochondrial ATP synthase correlates with symptoms of neuropathic pain in adult rats after axotomy, and whether intrathecal ATP administration is therapeutic in these neuropathic rats. Male Sprague–Dawley rats received left sciatic nerve transection (axotomy) and were randomly designated to a control (sham-operated) group, a neuropathic pain group (axotomy), a neuropathic pain and intrathecal sterile saline group, and a neuropathic pain and intrathecal ATP group. The thermal and mechanical sensitivity tests were performed at 1, 3, 5, and 7 days after axotomy. Left L4–L5 dorsal root ganglions (DRGs) were harvested to assess mitochondrial ATP synthase by immunoblotting and immunohistochemistry. After nerve injury, the expression of mitochondrial ATP synthase was decreased in protein extracts and was found mainly in C-fiber and A-δ fiber neurons of the DRGs. The decreased expression of mitochondrial ATP synthase and its subcellular localization were related to thermal and mechanical hyperalgesia. Administration of intrathecal ATP significantly attenuated thermal and mechanical hypersensitivity throughout the experimental period, which suggests its potential role in the treatment of neuropathic pain.

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References

  • Abbracchio MP, Burnstock G, Boeynaems JM, Barnard EA, Boyer JL, Kennedy C, Knight GE, Fumagalli M, Gachet C, Jacobson KA (2006) International Union of Pharmacology LVIII: update on the P2Y G protein-coupled nucleotide receptors: from molecular mechanisms and pathophysiology to therapy. Pharmacol Rev 58(3):281

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Abrahams JP, Leslie AG, Lutter R, Walker JE (1994) Structure at 2.8 A resolution of F1-ATPase from bovine heart mitochondria. Nature 370(6491):621–628

    Article  CAS  PubMed  Google Scholar 

  • Amaya F, Decosterd I, Samad TA, Plumpton C, Tate S, Mannion RJ, Costigan M, Woolf CJ (2000) Diversity of expression of the sensory neuron-specific TTX-resistant voltage-gated sodium ion channels SNS and SNS2. Mol Cell Neurosci 15(4):331–342. doi:10.1006/mcne.1999.0828

    Article  CAS  PubMed  Google Scholar 

  • Baba H, Doubell TP, Woolf CJ (1999) Peripheral inflammation facilitates Abeta fiber-mediated synaptic input to the substantia gelatinosa of the adult rat spinal cord. J Neurosci 19(2):859–867

    CAS  PubMed  Google Scholar 

  • Bernier LP, Ase AR, Chevallier S, Blais D, Zhao Q, Boue-Grabot E, Logothetis D, Seguela P (2008a) Phosphoinositides regulate P2X4 ATP-gated channels through direct interactions. J Neurosci 28(48):12938

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Bernier LP, Ase AR, Tong X, Hamel E, Blais D, Zhao Q, Logothetis DE, Seguela P (2008b) Direct modulation of P2X1 receptor-channels by the lipid phosphatidylinositol 4, 5-bisphosphate. Mol Pharmacol 74(3):785

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Boyer PD (1997) The ATP synthase-a splendid molecular machine. Annu Rev Biochem 66(1):717–749

    Article  CAS  PubMed  Google Scholar 

  • Burnstock G (2000) P2X receptors in sensory neurones. Br J Anaesth 84(4):476

    Article  CAS  PubMed  Google Scholar 

  • Burnstock G (2009) Purines and sensory nerves. Sensory Nerves 194:333–392

    Article  CAS  Google Scholar 

  • Calabresi P, Marfia GA, Centonze D, Pisani A, Bernardi G, Koehler RC (1999) Sodium influx plays a major role in the membrane depolarization induced by oxygen and glucose deprivation in rat striatal spiny neurons editorial comment. Stroke 30(1):171

    Article  CAS  PubMed  Google Scholar 

  • Catterall WA, Coty WA, Pedersen PL (1973) Adenosine triphosphatase from rat liver mitochondria. 3. Subunit composition. J Biol Chem 248(21):7427–7431

    CAS  PubMed  Google Scholar 

  • Chen KH, Yang CH, Cheng JT, Wu CH, Sy WD, Lin CR (2010) Altered neuronatin expression in the rat dorsal root ganglion after sciatic nerve transection. J Biomed Sci 17:41. doi:10.1186/1423-0127-17-41

    Article  PubMed  Google Scholar 

  • Costigan M, Befort K, Karchewski L, Griffin RS, D’Urso D, Allchorne A, Sitarski J, Mannion JW, Pratt RE, Woolf CJ (2002) Replicate high-density rat genome oligonucleotide microarrays reveal hundreds of regulated genes in the dorsal root ganglion after peripheral nerve injury. BMC Neurosci 3:16

    Article  PubMed Central  PubMed  Google Scholar 

  • Danbolt NC (2001) Glutamate uptake. Review 1082 refs. Prog Neurobiol 65:1–105

    Article  CAS  PubMed  Google Scholar 

  • Flatters SJ, Bennett GJ (2006) Studies of peripheral sensory nerves in paclitaxel-induced painful peripheral neuropathy: evidence for mitochondrial dysfunction. Pain 122(3):245–257. doi:10.1016/j.pain.2006.01.037

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Gerevich Z, Borvendeg SJ, Schroder W, Franke H, Wirkner K, Norenberg W, Furst S, Gillen C, Illes P (2004) Inhibition of N-type voltage-activated calcium channels in rat dorsal root ganglion neurons by P2Y receptors is a possible mechanism of ADP-induced analgesia. J Neurosci 24(4):797

    Article  CAS  PubMed  Google Scholar 

  • Gu JG, MacDermott AB (1997) Activation of ATP P2X receptors elicits glutamate release from sensory neuron synapses. Nature 389(6652):749–753

    Article  CAS  PubMed  Google Scholar 

  • Hilgemann DW (1997) Cytoplasmic ATP-dependent regulation of ion transporters and channels: mechanisms and messengers. Annu Rev Physiol 59(1):193–220

    Article  CAS  PubMed  Google Scholar 

  • Hokfelt T, Zhang X, Wiesenfeld-Hallin Z (1994) Messenger plasticity in primary sensory neurons following axotomy and its functional implications. Trends Neurosci 17(1):22–30

    Article  CAS  PubMed  Google Scholar 

  • Khakh BS, North RA (2006) P2X receptors as cell-surface ATP sensors in health and disease. Nature 442(7102):527–532

    Article  CAS  PubMed  Google Scholar 

  • Latremoliere A, Woolf CJ (2009) Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J pain 10(9):895–926. doi:10.1016/j.jpain.2009.06.012

    Article  PubMed Central  PubMed  Google Scholar 

  • Lawson SN (2002) Phenotype and function of somatic primary afferent nociceptive neurones with C-, A [delta]-or A [alpha]/[beta]-fibres. Exp Physiol 87(02):239–244

    Article  CAS  PubMed  Google Scholar 

  • Lekan HA, Chung K, Yoon YW, Chung JM, Coggeshall RE (1997) Loss of dorsal root ganglion cells concomitant with dorsal root axon sprouting following segmental nerve lesions. Neuroscience 81(2):527–534

    Article  CAS  PubMed  Google Scholar 

  • Li P, Calejesan AA, Zhuo M (1998) ATP P2 × Receptors and Sensory Synaptic Transmission Between Primary Afferent Fibers and Spinal Dorsal Horn Neurons in Rats. J Neurophysiol 80(6):3356

    CAS  PubMed  Google Scholar 

  • Lin CR, Yang CH, Huang CE, Wu CH, Chen YS, Sheen-Chen SM, Huang HW, Chen KH (2011) GADD45A protects against cell death in dorsal root ganglion neurons following peripheral nerve injury. J Neurosci Res 89(5):689–699. doi:10.1002/jnr.22589

    Article  CAS  PubMed  Google Scholar 

  • Ma QP (2002) Expression of capsaicin receptor (VR1) by myelinated primary afferent neurons in rats. Neurosci Lett 319(2):87–90

    Article  CAS  PubMed  Google Scholar 

  • Malin SA, Molliver DC (2010) Gi- and Gq-coupled ADP (P2Y) receptors act in opposition to modulate nociceptive signaling and inflammatory pain behavior. Mol Pain 6:21. doi:10.1186/1744-8069-6-21

    Article  PubMed Central  PubMed  Google Scholar 

  • Mitchell P (1972) Chemiosmotic coupling in energy transduction: a logical development of biochemical knowledge. J Bioenergetics 3(1):5–24

    Article  CAS  Google Scholar 

  • Nakagawa T, Wakamatsu K, Maeda S, Shirakawa H, Kaneko S (2008) Differential contribution of spinal mitogen-activated protein kinases to the phase of long-lasting allodynia evoked by intrathecal administration of ATP in rats. Biol Pharma Bull 31(6):1164–1168

    Article  CAS  Google Scholar 

  • Nicholls DG (2004) Mitochondrial dysfunction and glutamate excitotoxicity studied in primary neuronal cultures. Curr Mol Med 4(2):149–177

    Article  CAS  PubMed  Google Scholar 

  • Okada M, Nakagawa T, Minami M, Satoh M (2002) Analgesic effects of intrathecal administration of P2Y nucleotide receptor agonists UTP and UDP in normal and neuropathic pain model rats. J Pharmacol Exp Ther 303(1):66

    Article  CAS  PubMed  Google Scholar 

  • Ribeiro JA, Sebastiao AM, De Mendonca A (2002) Adenosine receptors in the nervous system: pathophysiological implications. Prog Neurobiol 68(6):377–392

    Article  CAS  PubMed  Google Scholar 

  • Rigoulet M (1990) Control processes in oxidative phosphorylation: kinetic constraints and stoichiometry. Biochim Biophys Acta 1018(2–3):185–189

    Article  CAS  PubMed  Google Scholar 

  • Rohacs T, Thyagarajan B, Lukacs V (2008) Phospholipase C mediated modulation of TRPV1 channels. Mol Neurobiol 37(2–3):153–163. doi:10.1007/s12035-008-8027-y

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Sawynok J, Liu XJ (2003) Adenosine in the spinal cord and periphery: release and regulation of pain. Prog Neurobiol 69(5):313–340

    Article  CAS  PubMed  Google Scholar 

  • Stanfa LC, Kontinen VK, Dickenson AH (2000) Effects of spinally administered P2X receptor agonists and antagonists on the responses of dorsal horn neurones recorded in normal, carrageenan-inflamed and neuropathic rats. Br J Pharmacol 129(2):351–359

    Article  CAS  PubMed  Google Scholar 

  • Suh BC, Leal K, Hille B (2010) Modulation of High-Voltage Activated Ca2 + Channels by Membrane Phosphatidylinositol 4, 5-Bisphosphate. Neuron 67(2):224–238

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Tao YX, Gu J, Stephens RL (2005) Role of spinal cord glutamate transporter during normal sensory transmission and pathological pain states. Molecular Pain 1(1):30

    Article  PubMed Central  PubMed  Google Scholar 

  • Thore S, Wuttke A, Tengholm A (2007) Rapid turnover of phosphatidylinositol-4, 5-bisphosphate in insulin-secreting cells mediated by Ca2+ and the ATP-to-ADP ratio. Diabetes 56(3):818

    Article  CAS  PubMed  Google Scholar 

  • Tsuda M, Ueno S, Inoue K (1999) In vivo pathway of thermal hyperalgesia by intrathecal administration of α, β-methylene ATP in mouse spinal cord: involvement of the glutamate-NMDA receptor system. Br J Pharmacol 127(2):449–456

    Article  CAS  PubMed  Google Scholar 

  • Winter J, Forbes CA, Sternberg J, Lindsay RM (1988) Nerve growth factor (NGF) regulates adult rat cultured dorsal root ganglion neuron responses to the excitotoxin capsaicin. Neuron 1(10):973–981

    Article  CAS  PubMed  Google Scholar 

  • Xiao HS, Huang QH, Zhang FX, Bao L, Lu YJ, Guo C, Yang L, Huang WJ, Fu G, Xu SH, Cheng XP, Yan Q, Zhu ZD, Zhang X, Chen Z, Han ZG, Zhang X (2002) Identification of gene expression profile of dorsal root ganglion in the rat peripheral axotomy model of neuropathic pain. Proc Natl Acad Sci USA 99(12):8360–8365

    Article  CAS  PubMed  Google Scholar 

  • Zhao Q, Logothetis DE, Seguela P (2007) Regulation of ATP-gated P2X receptors by phosphoinositides. Pflugers Arch 455(1):181–185

    Article  CAS  PubMed  Google Scholar 

  • Zheng H, Xiao WH, Bennett GJ (2011) Functional deficits in peripheral nerve mitochondria in rats with paclitaxel- and oxaliplatin-evoked painful peripheral neuropathy. Exp Neurol 232(2):154–161. doi:10.1016/j.expneurol.2011.08.016

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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Acknowledgments

This work was supported in part by Grant Nos. 870641, 880891-3, 891251, and 8A1011 from Chang Gung Memorial Hospital Research, Kaohsiung, Taiwan, and by Grant Nos. 96-2628-B-182A-005-MY3, 98-2314-B-182A-035-MY2, 100-2314-B-182A-037, 101-2314-B-182A-014-, and 101-2314-B-182A-068-MY3 from the Taiwan National Science Council Research, Taipei, Taiwan.

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Correspondence to Chung-Ren Lin or Chien-Hui Yang.

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Kuan-Hung Chen and Chung-Ren Lin have contributed equally to this project and should be considered co-first authors.

Chung-Ren Lin and Chien-Hui Yang have contributed equally to this project and should be considered co-corresponding authors.

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Chen, KH., Lin, CR., Cheng, JT. et al. Altered Mitochondrial ATP Synthase Expression in the Rat Dorsal Root Ganglion After Sciatic Nerve Injury and Analgesic Effects of Intrathecal ATP. Cell Mol Neurobiol 34, 51–59 (2014). https://doi.org/10.1007/s10571-013-9986-8

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