The Journal of Pain
Volume 10, Issue 4 , Pages 380-390 , April 2009

siRNA-Mediated Knockdown of the NR1 Subunit Gene of the NMDA Receptor Attenuates Formalin-Induced Pain Behaviors in Adult Rats

  • Sandra M. Garraway

      Affiliations

    • Department of Pharmacology, Weill Cornell Medical College, New York, New York
  • ,
  • Qinghao Xu

      Affiliations

    • Department of Neuroscience, Weill Cornell Medical College, New York, New York
  • ,
  • Charles E. Inturrisi

      Affiliations

    • Department of Pharmacology, Weill Cornell Medical College, New York, New York
    • Department of Neuroscience, Weill Cornell Medical College, New York, New York
    • Corresponding Author InformationAddress reprint requests to Dr Charles E. Inturrisi, Department of Pharmacology, Weill Cornell Medical College, 1300 York Avenue, Room LC-524, New York, NY 10065-4896.

Received 11 June 2008 ,Revised 28 August 2008 ,Accepted 18 September 2008.

References 

  1. Brenner GJ, Ji RR, Shaffer S, Woolf CJ. Peripheral noxious stimulation induces phosphorylation of the NMDA receptor NR1 subunit at the PKC-dependent site, serine-896, in spinal cord dorsal horn neurons. Eur J Neurosci. 2004;20:375–384
  2. Chacur M, Milligan ED, Gazda LS, Armstrong C, Wang H, Tracey KJ, et al. A new model of sciatic inflammatory neuritis (SIN): Induction of unilateral and bilateral mechanical allodynia following acute unilateral peri-sciatic immune activation in rats. Pain. 2001;94:231–244
  3. Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL. Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods. 1994;53:55–63
  4. Chaplan SR, Malmberg AB, Yaksh TL. Efficacy of spinal NMDA receptor antagonism in formalin hyperalgesia and nerve injury evoked allodynia in the rat. J Pharmacol Exp Ther. 1997;280:829–838
  5. Chapman V, Buritova J, Honore P, Besson JM. Physiological contributions of neurokinin 1 receptor activation, and interactions with NMDA receptors, to inflammatory-evoked spinal c-Fos expression. J Neurophysiol. 1996;76:1817–1827
  6. Chapman V, Dickenson AH. Time-related roles of excitatory amino acid receptors during persistent noxiously evoked responses of rat dorsal horn neurones. Brain Res. 1995;703:45–50
  7. Chen J, Luo C, Li H, Chen H. Primary hyperalgesia to mechanical and heat stimuli following subcutaneous bee venom injection into the plantar surface of hindpaw in the conscious rat: A comparative study with the formalin test. Pain. 1999;83:67–76
  8. Chen L, Huang LY. Protein kinase C reduces Mg2+ block of NMDA-receptor channels as a mechanism of modulation. Nature. 1992;356:521–523
  9. Coderre TJ, Fundytus ME, McKenna JE, Dalal S, Melzack R. The formalin test: A validation of the weighted-scores method of behavioural pain rating. Pain. 1993;54:43–50
  10. Coderre TJ, Melzack R. The contribution of excitatory amino acids to central sensitization and persistent nociception after formalin-induced tissue injury. J Neurosci. 1992;12:3665–3670
  11. Davis AM, Inturrisi CE. Attenuation of hyperalgesia by LY235959, a competitive N-methyl-D-aspartate receptor antagonist. Brain Res. 2001;894:150–153
  12. Dickenson AH, Sullivan AF. Peripheral origins and central modulation of subcutaneous formalin-induced activity of rat dorsal horn neurones. Neurosci Lett. 1987;83:207–211
  13. Du J, Zhou S, Coggeshall RE, Carlton SM. N-methyl-D-aspartate-induced excitation and sensitization of normal and inflamed nociceptors. Neuroscience. 2003;118:547–562
  14. Dubuisson D, Dennis SG. The formalin test: A quantitative study of the analgesic effects of morphine, meperidine, and brain stem stimulation in rats and cats. Pain. 1977;4:161–174
  15. Elliott K, Hynansky A, Inturrisi CE. Dextromethorphan attenuates and reverses analgesic tolerance to morphine. Pain. 1994;59:361–368
  16. Fire A, Xu S, Montgomery MK, Kostas SA, Driver SE, Mello CC. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature. 1998;391:806–811
  17. Forrest D, Yuzaki M, Soares HD, Ng L, Luk DC, Sheng M, et al. Targeted disruption of NMDA receptor 1 gene abolishes NMDA response and results in neonatal death. Neuron. 1994;13:325–338
  18. Garraway SM, Xu Q, Inturrisi CE. Design and evaluation of small interfering RNAs that target expression of the N-methyl-D-aspartate receptor NR1 subunit gene in the spinal cord dorsal horn. J Pharmacol Exp Ther. 2007;322:982–988
  19. Guo W, Zou SP, Ikeda T, Dubner R, Ren K. Rapid and lasting increase in serine phosphorylation of rat spinal cord NMDAR1 and GluR1 subunits after peripheral inflammation. Thalamus Relat Syst. 2005;3:9–18
  20. Haley JE, Sullivan AF, Dickenson AH. Evidence for spinal N-methyl-D-aspartate receptor involvement in prolonged chemical nociception in the rat. Brain Res. 1990;518:218–226
  21. Hama A, Woon Lee J, Sagen J. Differential efficacy of intrathecal NMDA receptor antagonists on inflammatory mechanical and thermal hyperalgesia in rats. Eur J Pharmacol. 2003;459:49–58
  22. Hargreaves K, Dubner R, Brown F, Flores C, Joris J. A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain. 1988;32:77–88
  23. Henry JL, Yashpal K, Pitcher GM, Chabot J, Coderre TJ. Evidence for tonic activation of NK-1 receptors during the second phase of the formalin test in the Rat. J Neurosci. 1999;19:6588–6598
  24. Henry JL, Yashpal K, Pitcher GM, Coderre TJ. Physiological evidence that the 'interphase' in the formalin test is due to active inhibition. Pain. 1999;82:57–63
  25. Hsu SM, Raine L, Fanger H. Use of avidin-biotin-peroxidase complex (ABC) in immunoperoxidase techniques: A comparison between ABC and unlabeled antibody (PAP) procedures. J Histochem Cytochem. 1981;29:577–580
  26. Ishii T, Moriyoshi K, Sugihara H, Sakurada K, Kadotani H, Yokoi M, et al. Molecular characterization of the family of the N-methyl-D-aspartate receptor subunits. J Biol Chem. 1993;268:2836–2843
  27. Kaspar BK, Vissel B, Bengoechea T, Crone S, Randolph-Moore L, Muller R, et al. Adeno-associated virus effectively mediates conditional gene modification in the brain. Proc Natl Acad Sci U S A. 2002;99:2320–2325
  28. Kim HW, Kwon YB, Roh DH, Yoon SY, Han HJ, Kim KW, et al. Intrathecal treatment with sigma1 receptor antagonists reduces formalin-induced phosphorylation of NMDA receptor subunit 1 and the second phase of formalin test in mice. Br J Pharmacol. 2006;148:490–498
  29. Lan JY, Skeberdis VA, Jover T, Grooms SY, Lin Y, Araneda RC, et al. Protein kinase C modulates NMDA receptor trafficking and gating. Nat Neurosci. 2001;4:382–390
  30. Lee IO, Yukhananov R, Standaert DG, Crosby G. NMDA-R1 antisense oligodeoxynucleotides modify formalin-induced nociception and spinal c-Fos expression in rat spinal cord. Pharmacol Biochem Behav. 2004;79:183–188
  31. Lieberman J, Song E, Lee SK, Shankar P. Interfering with disease: Opportunities and roadblocks to harnessing RNA interference. Trends Mol Med. 2003;9:397–403
  32. Mannino CA, South SM, Quinones-Jenab V, Inturrisi CE. Estradiol replacement in ovariectomized rats is antihyperalgesic in the formalin test. J Pain. 2007;8:334–342
  33. Mao J, Price DD, Hayes RL, Lu J, Mayer DJ. Differential roles of NMDA and non-NMDA receptor activation in induction and maintenance of thermal hyperalgesia in rats with painful peripheral mononeuropathy. Brain Res. 1992;598:271–278
  34. McCall WD, Tanner KD, Levine JD. Formalin induces biphasic activity in C-fibers in the rat. Neurosci Lett. 1996;208:45–48
  35. Milligan ED, Twining C, Chacur M, Biedenkapp J, O'Connor K, Poole S, et al. Spinal glia and proinflammatory cytokines mediate mirror-image neuropathic pain in rats. J Neurosci. 2003;23:1026–1040
  36. Monyer H, Sprengel R, Schoepfer R, Herb A, Higuchi M, Lomeli H, et al. Heteromeric NMDA receptors: Molecular and functional distinction of subtypes. Science. 1992;256:1217–1221
  37. Puig S, Sorkin LS. Formalin-evoked activity in identified primary afferent fibers: systemic lidocaine suppresses phase-2 activity. Pain. 1996;64:345–355
  38. Scott DB, Blanpied TA, Ehlers MD. Coordinated PKA and PKC phosphorylation suppresses RXR-mediated ER retention and regulates the surface delivery of NMDA receptors. Neuropharmacology. 2003;45:755–767
  39. Shimoyama N, Shimoyama M, Davis AM, Monaghan DT, Inturrisi CE. An antisense oligonucleotide to the N-methyl-D-aspartate (NMDA) subunit NMDAR1 attenuates NMDA-induced nociception, hyperalgesia, and morphine tolerance. J Pharmacol Exp Ther. 2005;312:834–840
  40. Shimoyama N, Shimoyama M, Elliott KJ, Inturrisi CE. d-Methadone is antinociceptive in the rat formalin test. J Pharmacol Exp Ther. 1997;283:648–652
  41. Sivilotti L, Woolf CJ. The contribution of GABAA and glycine receptors to central sensitization: Disinhibition and touch-evoked allodynia in the spinal cord. J Neurophysiol. 1994;72:169–179
  42. South SM, Kohno T, Kaspar BK, Hegarty D, Vissel B, Drake CT, et al. A conditional deletion of the NR1 subunit of the NMDA receptor in adult spinal cord dorsal horn reduces NMDA currents and injury-induced pain. J Neurosci. 2003;23:5031–5040
  43. Tan PH, Yang LC, Shih HC, Lan KC, Cheng JT. Gene knockdown with intrathecal siRNA of NMDA receptor NR2B subunit reduces formalin-induced nociception in the rat. Gene Ther. 2005;12:59–66
  44. Watakabe A, Ichinohe N, Ohsawa S, Hashikawa T, Komatsu Y, Rockland KS, et al. Comparative analysis of layer-specific genes in Mammalian neocortex. Cereb Cortex. 2007;17:1918–1933
  45. Woolf CJ. Central sensitization: Uncovering the relation between pain and plasticity. Anesthesiology. 2007;106:864–867
  46. Woolf CJ, Costigan M. Transcriptional and posttranslational plasticity and the generation of inflammatory pain. Proc Natl Acad Sci U S A. 1999;96:7723–7730
  47. Woolf CJ, Shortland P, Sivilotti LG. Sensitization of high mechanothreshold superficial dorsal horn and flexor motor neurones following chemosensitive primary afferent activation. Pain. 1994;58:141–155
  48. Woolf CJ, Thompson SW. The induction and maintenance of central sensitization is dependent on N-methyl-D-aspartic acid receptor activation: Implications for the treatment of post-injury pain hypersensitivity states. Pain. 1991;44:293–299
  49. Yaksh TL, Ozaki G, McCumber D, Rathbun M, Svensson C, Malkmus S, et al. An automated flinch detecting system for use in the formalin nociceptive bioassay. J Appl Physiol. 2001;90:2386–2402
  50. Zhao J, Seereeram A, Nassar MA, Levato A, Pezet S, Hathaway G, et al. Nociceptor-derived brain-derived neurotrophic factor regulates acute and inflammatory but not neuropathic pain. Mol Cell Neurosci. 2006;31:539–548

 Supported in part by NIDA grants DA001457 and DA000198 (CEI), NIDA training grant DA007274, and a minority supplement to DA001457 (SG) and NIDA center grant DA005130.

PII: S1526-5900(08)00796-7

doi: 10.1016/j.jpain.2008.09.013

The Journal of Pain
Volume 10, Issue 4 , Pages 380-390 , April 2009