The Journal of Pain
Volume 11, Issue 9 , Pages 838-846 , September 2010

Central Sensitization in the Trigeminal Nucleus Caudalis Produced by a Conjugate of Substance P and the A Subunit of Cholera Toxin

  • Robert M. Caudle

      Affiliations

    • Department of Oral and Maxillofacial Surgery, University of Florida College of Dentistry, Gainesville, Florida
    • Department of Neuroscience, University of Florida College of Medicine, McKnight Brain Institute, Gainesville, Florida
    • Corresponding Author InformationAddress reprint requests to Robert M. Caudle, Department of Oral and Maxillofacial Surgery, University of Florida College of Dentistry, PO Box 100416, Gainesville, FL 32610.
    • ,
  • Christopher King

      Affiliations

    • Department of Orthodontics, University of Florida College of Dentistry, Gainesville, Florida
    • ,
  • Todd A. Nolan

      Affiliations

    • Department of Orthodontics, University of Florida College of Dentistry, Gainesville, Florida
    • ,
  • Shelby K. Suckow

      Affiliations

    • Department of Neuroscience, University of Florida College of Medicine, McKnight Brain Institute, Gainesville, Florida
    • ,
  • Charles J. Vierck Jr.

      Affiliations

    • Department of Neuroscience, University of Florida College of Medicine, McKnight Brain Institute, Gainesville, Florida
    • ,
  • John K. Neubert

      Affiliations

    • Department of Neuroscience, University of Florida College of Medicine, McKnight Brain Institute, Gainesville, Florida
    • Department of Orthodontics, University of Florida College of Dentistry, Gainesville, Florida

Received 5 February 2010 ,Revised 11 May 2010 ,Accepted 28 May 2010.

References 

  1. Bozic CR, Lu B, Hopken UE, Gerard C, Gerard NP. Neurogenic amplification of immune complex inflammation. Science. 1996;273:1722–1725
  2. 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
  3. Burstein R, Cutrer MF, Yarnitsky D. The development of cutaneous allodynia during a migraine attack clinical evidence for the sequential recruitment of spinal and supraspinal nociceptive neurons in migraine. Brain. 2000;123(Pt 8):1703–1709
  4. Caudle RM, Mannes AJ, Benoliel R, Eliav E, Iadarola MJ. Intrathecally administered cholera toxin blocks allodynia and hyperalgesia in persistent pain models. J Pain. 2001;2:118–127
  5. Caudle RM, Mannes AJ, Keller J, Perez FM, Suckow SK, Neubert JK. Sensitization of Spinal Cord Nociceptive Neurons with a Conjugate of Substance P and Cholera Toxin. BMC Neurosci. 2007;8:30
  6. Chaban VV, Li J, Ennes HS, Nie J, Mayer EA, McRoberts JA. N-methyl-D-aspartate receptors enhance mechanical responses and voltage-dependent Ca2+ channels in rat dorsal root ganglia neurons through protein kinase C. Neuroscience. 2004;128:347–357
  7. Chen L, Huang LY. Protein kinase C reduces Mg2+ block of NMDA-receptor channels as a mechanism of modulation. Nature. 1992;356:521–523
  8. Chung KM, Suh HW. Pretreatment with cholera or pertussis toxin differentially modulates morphine- and beta-endorphin-induced antinociception in the mouse formalin test. Neuropeptides. 2001;35:197–203
  9. Deberry J, Ness TJ, Robbins MT, Randich A. Inflammation-induced enhancement of the visceromotor reflex to urinary bladder distention: Modulation by endogenous opioids and the effects of early-in-life experience with bladder inflammation. J Pain. 2007;8:914–923
  10. Desmeules JA, Cedraschi C, Rapiti E, Baumgartner E, Finckh A, Cohen P, et al. Neurophysiologic evidence for a central sensitization in patients with fibromyalgia. Arthritis Rheum. 2003;48:1420–1429
  11. Dodick D, Silberstein S. Central sensitization theory of migraine: Clinical implications. Headache. 2006;46(Suppl 4):182–191
  12. Dougherty PM, Palecek J, Paleckova V, Willis WD. Neurokinin 1 and 2 antagonists attenuate the responses and NK1 antagonists prevent the sensitization of primate spinothalamic tract neurons after intradermal capsaicin. J Neurophysiol. 1994;72:1464–1475
  13. Draisci G, Iadarola MJ. Temporal analysis of increases in c-fos, preprodynorphin and preproenkephalin mRNAs in rat spinal cord. Brain Res Mol Brain Res. 1989;6:31–37
  14. Dubner R, Ren K. Brainstem mechanisms of persistent pain following injury. J Orofac Pain. 2004;18:299–305
  15. Fishman PH. Internalization and degradation of cholera toxin by cultured cells: Relationship to toxin action. J Cell Biol. 1982;93:860–865
  16. Ganguly NK, Kaur T. Mechanism of action of cholera toxin & other toxins. Indian J Med Res. 1996;104:28–37
  17. Hao JX, Yu W, Xu XJ. Evidence that spinal endogenous opioidergic systems control the expression of chronic pain-related behaviors in spinally injured rats. Exp Brain Res. 1998;118:259–268
  18. Ji RR, Woolf CJ. Neuronal plasticity and signal transduction in nociceptive neurons: Implications for the initiation and maintenance of pathological pain. Neurobiol Dis. 2001;8:1–10
  19. Jones SL, Gebhart GF. Inhibition of spinal nociceptive transmission from the midbrain, pons and medulla in the rat: Activation of descending inhibition by morphine, glutamate and electrical stimulation. Brain Res. 1988;460:281–296
  20. Kawasaki Y, Kohno T, Zhuang ZY, Brenner GJ, Wang HB, Van der Meer C, et al. Ionotropic and metabotropic receptors, protein kinase A, protein kinase C, and Src contribute to C-fiber-induced ERK activation and cAMP response element-binding protein phosphorylation in dorsal horn neurons, leading to central sensitization. J Neurosci. 2004;24:8310–8321
  21. Klepstad P, Rakvag TT, Kaasa S, Holthe M, Dale O, Borchgrevink PC, et al. The 118 A > G polymorphism in the human mu-opioid receptor gene may increase morphine requirements in patients with pain caused by malignant disease. Acta Anaesthesiol Scand. 2004;48:1232–1239
  22. Latremoliere A, Woolf CJ. Central sensitization: A generator of pain hypersensitivity by central neural plasticity. J Pain. 2009;10:895–926
  23. Lee BH, Park SH, Won R, Park YG, Sohn JH. Antiallodynic effects produced by stimulation of the periaqueductal gray matter in a rat model of neuropathic pain. Neurosci Lett. 2000;291:29–32
  24. Lin Q, Peng YB, Willis WD. Possible role of protein kinase C in the sensitization of primate spinothalamic tract neurons. J Neurosci. 1996;16:3026–3034
  25. Lovati C, D'Amico D, Bertora P. Allodynia in migraine: Frequent random association or unavoidable consequence?. Expert Rev Neurother. 2009;9:395–408
  26. Madland G, Feinmann C. Chronic facial pain: A multidisciplinary problem. J Neurol Neurosurg Psychiatry. 2001;71:716–719
  27. Madland G, Newton-John T, Feinmann C. Chronic idiopathic orofacial pain: I: What is the evidence base?. Br Dent J. 2001;191:22–24
  28. Messersmith DJ, Kim DJ, Iadarola MJ. Transcription factor regulation of prodynorphin gene expression following rat hindpaw inflammation. Brain Res Mol Brain Res. 1998;53:260–269
  29. Neubert K, King C, Malphurs W, Wong F, Weaver JP, Jenkins AC, et al. Characterization of mouse orofacial pain and the effects of lesioning TRPV1-expressing neurons on operant behavior. Mol Pain. 2008;4:43
  30. Neubert JK, Rossi HL, Malphurs W, Vierck CJ, Caudle RM. Differentiation between capsaicin-induced allodynia and hyperalgesia using a thermal operant assay. Behav Brain Res. 2006;170:308–315
  31. Neubert JK, Rossi HL, Pogar J, Jenkins AC, Caudle RM. Effects of mu- and kappa-2 opioid receptor agonists on pain and rearing behaviors. Behav Brain Funct. 2007;3:49
  32. Neubert JK, Widmer CG, Malphurs W, Rossi HL, Vierck CJ, Caudle RM. Use of a novel thermal operant behavioral assay for characterization of orofacial pain sensitivity. Pain. 2005;116:386–395
  33. Newton-John T, Madland G, Feinmann C. Chronic idiopathic orofacial pain: II. What can the general dental practitioner do?. Br Dent J. 2001;191:72–73
  34. Oertel BG, Kettner M, Scholich K, Renne C, Roskam B, Geisslinger G, et al. A Common Human {micro}-Opioid Receptor Genetic Variant Diminishes the Receptor Signaling Efficacy in Brain Regions Processing the Sensory Information of Pain. J Biol Chem. 2009;284:6530–6535
  35. Pietrobon D. Migraine: New molecular mechanisms. Neuroscientist. 2005;11:373–386
  36. Randich A, Mebane H, DeBerry JJ, Ness TJ. Rostral ventral medulla modulation of the visceromotor reflex evoked by urinary bladder distension in female rats. J Pain. 2008;9:920–926
  37. Ren K, Dubner R. Central nervous system plasticity and persistent pain. J Orofac Pain. 1999;13:155–163
  38. Rossi HL, Neubert JK. Effects of environmental enrichment on thermal sensitivity in an operant orofacial pain assay. Behav Brain Res. 2008;187:478–482
  39. Rossi HL, Vierck CJ, Caudle RM, Neubert JK. Characterization of cold sensitivity and thermal preference using an operant orofacial assay. Mol Pain. 2006;2:37
  40. 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
  41. Sessle BJ. Acute and chronic craniofacial pain: Brainstem mechanisms of nociceptive transmission and neuroplasticity, and their clinical correlates. Crit Rev Oral Biol Med. 2000;11:57–91
  42. Shen KF, Crain SM. Cholera toxin-A subunit blocks opioid excitatory effects on sensory neuron action potentials indicating mediation by Gs-linked opioid receptors. Brain Res. 1990;525:225–231
  43. Silberstein SD. Migraine pathophysiology and its clinical implications. Cephalalgia. 2004;24(Suppl 2):2–7
  44. Sluka KA. Activation of the cAMP transduction cascade contributes to the mechanical hyperalgesia and allodynia induced by intradermal injection of capsaicin. Br J Pharmacol. 1997;122:1165–1173
  45. Sluka KA, Rees H, Chen PS, Tsuruoka M, Willis WD. Capsaicin-induced sensitization of primate spinothalamic tract cells is prevented by a protein kinase C inhibitor. Brain Res. 1997;772:82–86
  46. Smith PK, Krohn RI, Hermanson GT, Mallia AK, Gartner FH, Provenzano MD, et al. Measurement of protein using bicinchoninic acid. Anal Biochem. 1985;150:76–85
  47. Sohn JH, Lee BH, Park SH, Ryu JW, Kim BO, Park YG. Microinjection of opiates into the periaqueductal gray matter attenuates neuropathic pain symptoms in rats. Neuroreport. 2000;11:1413–1416
  48. Srikiatkhachorn A. Chronic daily headache: A scientist's perspective. Headache. 2002;42:532–537
  49. Staud R, Bovee CE, Robinson ME, Price DD. Cutaneous C-fiber pain abnormalities of fibromyalgia patients are specifically related to temporal summation. Pain. 2008;139:315–323
  50. Staud R, Craggs JG, Perlstein WM, Robinson ME, Price DD. Brain activity associated with slow temporal summation of C-fiber evoked pain in fibromyalgia patients and healthy controls. Eur J Pain. 2008;12:1078–1089
  51. Staud R, Koo E, Robinson ME, Price DD. Spatial summation of mechanically evoked muscle pain and painful aftersensations in normal subjects and fibromyalgia patients. Pain. 2007;130:177–187
  52. Staud R, Robinson ME, Price DD. Temporal summation of second pain and its maintenance are useful for characterizing widespread central sensitization of fibromyalgia patients. J Pain. 2007;8:893–901
  53. Tingley WG, Roche KW, Thompson AK, Huganir RL. Regulation of NMDA receptor phosphorylation by alternative splicing of the C-terminal domain. Nature. 1993;364:70–73
  54. Vierck CJ, Acosta-Rua AJ, Johnson RD. Bilateral chronic constriction of the sciatic nerve: A model of long-term cold hyperalgesia. J Pain. 2005;6:507–517
  55. Willis WD. Role of neurotransmitters in sensitization of pain responses. Ann NY Acad Sci. 2001;933:142–156
  56. Woolf CJ. The pathophysiology of peripheral neuropathic pain–abnormal peripheral input and abnormal central processing. Acta Neurochir Suppl (Wien). 1993;58:125–130
  57. Woolf CJ, Thompson SW, King AE. Prolonged primary afferent induced alterations in dorsal horn neurones, an intracellular analysis in vivo and in vitro. J Physiol (Paris). 1988;83:255–266
  58. Woolf CJ, Thompson SWN. The induction and maintenance of central sensitization is dependent on N-methyl-D-aspartic acid receptor activation; Implications for the treatment of postinjury pain hypersensitivity states. Pain. 1991;44:293–299
  59. Zoppi M, Maresca M. Symptoms accompanying fibromyalgia. Reumatismo. 2008;60:217–220
  60. Zou X, Lin Q, Willis WD. Role of protein kinase a in phosphorylation of NMDA receptor 1 subunits in dorsal horn and spinothalamic tract neurons after intradermal injection of capsaicin in rats. Neuroscience. 2002;115:775–786
  61. Zou XJ, Lin Q, Willis WD. Enhanced phosphorylation of NMDA receptor 1 subunits in spinal cord dorsal horn and spinothalamic tract neurons after intradermal injection of capsaicin in rats. J Neurosci. 2000;20:6989–6997

 Supported by National Institutes of Health grants NS045614 and DA016562.

PII: S1526-5900(10)00554-7

doi: 10.1016/j.jpain.2010.05.007

The Journal of Pain
Volume 11, Issue 9 , Pages 838-846 , September 2010

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