Table of Contents Author Guidelines Submit a Manuscript
Scientifica
Volume 2012, Article ID 561761, 25 pages
http://dx.doi.org/10.6064/2012/561761
Review Article

The Perception and Endogenous Modulation of Pain

Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ 85724, USA

Received 15 October 2012; Accepted 19 November 2012

Academic Editors: Á. M. Pastor, C. Porcaro, and D. K. Ryugo

Copyright © 2012 Michael H. Ossipov. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. H. Merskey and N. Bogduk, Classification of Chronic Pain: Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms, Task Force on Taxonomy of the IASP, IASP Press, Seattle, Wash, USA, 2nd edition, 1994.
  2. H. L. Fields, “Pain: an unpleasant topic,” Pain, vol. 82, supplement 1, pp. S61–S69, 1999. View at Google Scholar · View at Scopus
  3. J. P. Johansen and H. L. Fields, “Glutamatergic activation of anterior cingulate cortex produces an aversive teaching signal,” Nature Neuroscience, vol. 7, no. 4, pp. 398–403, 2004. View at Publisher · View at Google Scholar · View at Scopus
  4. C. J. Vierck, P. T. Hansson, and R. P. Yezierski, “Clinical and pre-clinical pain assessment: are we measuring the same thing?” Pain, vol. 135, no. 1, pp. 7–10, 2008. View at Publisher · View at Google Scholar · View at Scopus
  5. M. Costigan, J. Scholz, and C. J. Woolf, “Neuropathic pain: a maladaptive response of the nervous system to damage,” Annual Review of Neuroscience, vol. 32, pp. 1–32, 2009. View at Publisher · View at Google Scholar · View at Scopus
  6. B. McCarberg and R. Billington, “Consequences of neuropathic pain: quality-of-life issues and associated costs,” American Journal of Managed Care, vol. 12, supplement 9, pp. S263–S268, 2006. View at Google Scholar · View at Scopus
  7. M. H. Ossipov and F. Porreca, “Challenges in the development of novel treatment strategies for neuropathic pain,” NeuroRx, vol. 2, no. 4, pp. 650–661, 2005. View at Publisher · View at Google Scholar · View at Scopus
  8. M. M. Backonja, G. Irving, and C. Argoff, “Rational multidrug therapy in the treatment of neuropathic pain,” Current Pain and Headache Reports, vol. 10, no. 1, pp. 34–38, 2006. View at Publisher · View at Google Scholar · View at Scopus
  9. N. B. Finnerup, S. H. Sindrup, and T. S. Jensen, “The evidence for pharmacological treatment of neuropathic pain,” Pain, vol. 150, no. 3, pp. 573–581, 2010. View at Publisher · View at Google Scholar · View at Scopus
  10. J. P. Johansen, H. L. Fields, and B. H. Manning, “The affective component of pain in rodents: direct evidence for a contribution of the anterior cingulate cortex,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 14, pp. 8077–8082, 2001. View at Publisher · View at Google Scholar · View at Scopus
  11. A. E. Dubin and A. Patapoutian, “Nociceptors: the sensors of the pain pathway,” Journal of Clinical Investigation, vol. 120, no. 11, pp. 3760–3772, 2010. View at Publisher · View at Google Scholar · View at Scopus
  12. A. I. Basbaum, D. M. Bautista, G. Scherrer, and D. Julius, “Cellular and molecular mechanisms of pain,” Cell, vol. 139, no. 2, pp. 267–284, 2009. View at Publisher · View at Google Scholar · View at Scopus
  13. I. S. Ramsey, M. Delling, and D. E. Clapham, “An introduction to TRP channels,” Annual Review of Physiology, vol. 68, pp. 619–647, 2006. View at Publisher · View at Google Scholar · View at Scopus
  14. M. J. Caterina and D. Julius, “The vanilloid receptor: a molecular gateway to the pain pathway,” Annual Review of Neuroscience, vol. 24, pp. 487–517, 2001. View at Publisher · View at Google Scholar · View at Scopus
  15. A. M. Patwardhan, A. N. Akopian, N. B. Ruparel et al., “Heat generates oxidized linoleic acid metabolites that activate TRPV1 and produce pain in rodents,” Journal of Clinical Investigation, vol. 120, no. 5, pp. 1617–1626, 2010. View at Publisher · View at Google Scholar · View at Scopus
  16. A. M. Patwardhan, P. E. Scotland, A. N. Akopian, and K. M. Hargreaves, “Activation of TRPV1 in the spinal cord by oxidized linoleic acid metabolites contributes to inflammatory hyperalgesia,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 44, pp. 18820–18824, 2009. View at Publisher · View at Google Scholar · View at Scopus
  17. L. de Petrocellis and V. di Marzo, “Lipids as regulators of the activity of transient receptor potential type V1 (TRPV1) channels,” Life Sciences, vol. 77, no. 14, pp. 1651–1666, 2005. View at Publisher · View at Google Scholar · View at Scopus
  18. N. R. Gavva, J. J. S. Treanor, A. Garami et al., “Pharmacological blockade of the vanilloid receptor TRPV1 elicits marked hyperthermia in humans,” Pain, vol. 136, no. 1, pp. 202–210, 2008. View at Publisher · View at Google Scholar · View at Scopus
  19. M. C. Rowbotham, W. Nothaft, W. R. Duan et al., “Oral and cutaneous thermosensory profile of selective TRPV1 inhibition by ABT-102 in a randomized healthy volunteer trial,” Pain, vol. 152, no. 5, pp. 1192–1200, 2011. View at Publisher · View at Google Scholar · View at Scopus
  20. M. E. Kort and P. R. Kym, “TRPV1 antagonists: clinical setbacks and prospects for future development,” Progress in Medicinal Chemistry, vol. 51, pp. 57–70, 2012. View at Google Scholar
  21. A. Garami, Y. P. Shimansky, E. Pakai, D. L. Oliveira, N. R. Gavva, and A. A. Romanovsky, “Contributions of different modes of TRPV1 activation to TRPV1 antagonist-induced hyperthermia,” Journal of Neuroscience, vol. 30, no. 4, pp. 1435–1440, 2010. View at Publisher · View at Google Scholar · View at Scopus
  22. J. Vriens, G. Owsianik, T. Hofmann et al., “TRPM3 is a nociceptor channel involved in the detection of noxious heat,” Neuron, vol. 70, no. 3, pp. 482–494, 2011. View at Publisher · View at Google Scholar · View at Scopus
  23. D. M. Bautista, J. Siemens, J. M. Glazer et al., “The menthol receptor TRPM8 is the principal detector of environmental cold,” Nature, vol. 448, no. 7150, pp. 204–208, 2007. View at Publisher · View at Google Scholar · View at Scopus
  24. K. Kobayashi, T. Fukuoka, K. Obata et al., “Distinct expression of TRPM8, TRPA1, and TRPV1 mRNAs in rat primary afferent neurons with aδ/C-fibers and colocalization with Trk receptors,” Journal of Comparative Neurology, vol. 493, no. 4, pp. 596–606, 2005. View at Publisher · View at Google Scholar · View at Scopus
  25. K. Y. Kwan, A. J. Allchorne, M. A. Vollrath et al., “TRPA1 contributes to cold, mechanical, and chemical nociception but is not essential for hair-cell transduction,” Neuron, vol. 50, no. 2, pp. 277–289, 2006. View at Publisher · View at Google Scholar · View at Scopus
  26. K. Obata, H. Katsura, T. Mizushima et al., “TRPA1 induced in sensory neurons contributes to cold hyperalgesia after inflammation and nerve injury,” Journal of Clinical Investigation, vol. 115, no. 9, pp. 2393–2401, 2005. View at Publisher · View at Google Scholar · View at Scopus
  27. D. M. Bautista, S. E. Jordt, T. Nikai et al., “TRPA1 mediates the inflammatory actions of environmental irritants and proalgesic agents,” Cell, vol. 124, no. 6, pp. 1269–1282, 2006. View at Publisher · View at Google Scholar · View at Scopus
  28. S. Materazzi, C. Fusi, S. Benemei, P. Pedretti, R. Patacchini, B. Nilius et al., “TRPA1 and TRPV4 mediate paclitaxel-induced peripheral neuropathy in mice via a glutathione-sensitive mechanism,” European Journal of Physiology, vol. 463, no. 4, pp. 561–569, 2012. View at Google Scholar
  29. R. Nassini, M. Gees, S. Harrison et al., “Oxaliplatin elicits mechanical and cold allodynia in rodents via TRPA1 receptor stimulation,” Pain, vol. 152, no. 7, pp. 1621–1631, 2011. View at Publisher · View at Google Scholar · View at Scopus
  30. A. Patapoutian, S. Tate, and C. J. Woolf, “Transient receptor potential channels: targeting pain at the source,” Nature Reviews Drug Discovery, vol. 8, no. 1, pp. 55–68, 2009. View at Publisher · View at Google Scholar · View at Scopus
  31. M. Petrus, A. M. Peier, M. Bandell et al., “A role of TRPA1 in mechanical hyperalgesia is revealed by pharmacological inhibition,” Molecular Pain, vol. 3, article 40, 2007. View at Publisher · View at Google Scholar · View at Scopus
  32. B. Kremeyer, F. Lopera, J. J. Cox et al., “A gain-of-function mutation in TRPA1 causes familial episodic pain syndrome,” Neuron, vol. 66, no. 5, pp. 671–680, 2010. View at Publisher · View at Google Scholar · View at Scopus
  33. C. J. Woolf and Q. Ma, “Nociceptors-noxious stimulus detectors,” Neuron, vol. 55, no. 3, pp. 353–364, 2007. View at Publisher · View at Google Scholar · View at Scopus
  34. E. S. Schwartz, J. A. Christianson, X. Chen et al., “Synergistic role of TRPV1 and TRPA1 in pancreatic pain and inflammation,” Gastroenterology, vol. 140, no. 4, pp. 1283–1291, 2011. View at Publisher · View at Google Scholar · View at Scopus
  35. E. L. Andrade, F. C. Meotti, and J. B. Calixto, “TRPA1 antagonists as potential analgesic drugs,” Pharmacology & Therapeutics, vol. 133, pp. 189–204, 2012. View at Google Scholar
  36. E. S. Smith and G. R. Lewin, “Nociceptors: a phylogenetic view,” Journal of Comparative Physiology, vol. 195, no. 12, pp. 1089–1106, 2009. View at Google Scholar
  37. B. Coste, J. Mathur, M. Schmidt et al., “Piezo1 and Piezo2 are essential components of distinct mechanically activated cation channels,” Science, vol. 330, no. 6000, pp. 55–60, 2010. View at Publisher · View at Google Scholar · View at Scopus
  38. B. Coste, B. Xiao, J. S. Santos, R. Syeda, J. Grandl, K. S. Spencer et al., “Piezo proteins are pore-forming subunits of mechanically activated channels,” Nature, vol. 483, pp. 176–181, 2012. View at Google Scholar
  39. A. E. Dubin, M. Schmidt, J. Mathur et al., “Inflammatory signals enhance piezo2-mediated mechanosensitive currents,” Cell Report, vol. 2, no. 3, pp. 511–517, 2012. View at Publisher · View at Google Scholar
  40. H. Merskey, “Clarifying definition of neuropathic pain,” Pain, vol. 96, no. 3, pp. 408–409, 2002. View at Google Scholar · View at Scopus
  41. K. Kawamoto and H. Matsuda, “Nerve growth factor and wound healing,” Progress in Brain Research, vol. 146, pp. 369–384, 2004. View at Publisher · View at Google Scholar · View at Scopus
  42. H. Matsuda, H. Koyama, H. Sato et al., “Role of nerve growth factor in cutaneous wound healing: accelerating effects in normal and healing-impaired diabetic mice,” Journal of Experimental Medicine, vol. 187, no. 3, pp. 297–306, 1998. View at Publisher · View at Google Scholar · View at Scopus
  43. R. Heumann, S. Korsching, C. Bandtlow, and H. Thoenen, “Changes of nerve growth factor synthesis in nonneuronal cells in response to sciatic nerve transection,” Journal of Cell Biology, vol. 104, no. 6, pp. 1623–1631, 1987. View at Google Scholar · View at Scopus
  44. G. R. Lewin and L. M. Mendell, “Nerve growth factor and nociception,” Trends in Neurosciences, vol. 16, no. 9, pp. 353–359, 1993. View at Publisher · View at Google Scholar · View at Scopus
  45. S. B. McMahon, D. L. Bennett, S. Bevan, and M. Koltzenburg, “Inflammatory mediators and modulators of pain,” in Wall and Melzack'S Textbook of Pain, pp. 49–72, Elsevier, London, UK, 5th edition, 2005. View at Google Scholar
  46. R. R. Ji, T. A. Samad, S. X. Jin, R. Schmoll, and C. J. Woolf, “p38 MAPK activation by NGF in primary sensory neurons after inflammation increases TRPV1 levels and maintains heat hyperalgesia,” Neuron, vol. 36, no. 1, pp. 57–68, 2002. View at Publisher · View at Google Scholar · View at Scopus
  47. Y. Indo, “Genetics of congenital insensitivity to pain with anhidrosis (CIPA) or hereditary sensory and autonomic neuropathy type IV: clinical, biological and molecular aspects of mutations in TRKA (NTRK1) gene encoding the receptor tyrosine kinase for nerve growth factor,” Clinical Autonomic Research, vol. 12, supplement 1, pp. I20–I32, 2002. View at Google Scholar · View at Scopus
  48. S. Flohr, P. Ewers, G. R. Fink, J. Weis, and A. Krüttgen, “Impaired neurotrophin-3 signaling in a TrkAII mutant associated with hereditary polyneuropathy,” Experimental Neurology, vol. 224, no. 1, pp. 318–320, 2010. View at Publisher · View at Google Scholar · View at Scopus
  49. E. Einarsdottir, A. Carlsson, J. Minde et al., “A mutation in the nerve growth factor beta gene (NGFB) causes loss of pain perception,” Human Molecular Genetics, vol. 13, no. 8, pp. 799–805, 2004. View at Publisher · View at Google Scholar · View at Scopus
  50. J. Minde, G. Toolanen, T. Andersson et al., “Familial insensitivity to pain (HSAN V) and a mutation in the NGFB gene. A neurophysiological and pathological study,” Muscle and Nerve, vol. 30, no. 6, pp. 752–760, 2004. View at Publisher · View at Google Scholar · View at Scopus
  51. O. P. Carvalho, G. K. Thornton, J. Hertecant et al., “A novel NGF mutation clarifies the molecular mechanism and extends the phenotypic spectrum of the HSAN5 neuropathy,” Journal of Medical Genetics, vol. 48, no. 2, pp. 131–135, 2011. View at Publisher · View at Google Scholar · View at Scopus
  52. A. Wada, E. Wanke, F. Gullo, and E. Schiavon, “Voltage-dependent Nav1.7 sodium channels: multiple roles in adrenal chromaffin cells and peripheral nervous system,” Acta Physiologica, vol. 192, no. 2, pp. 221–231, 2008. View at Publisher · View at Google Scholar · View at Scopus
  53. S. D. Dib-Hajj, Y. Yang, and S. G. Waxman, “Chapter 4 genetics and molecular pathophysiology of Nav1.7-related pain syndromes,” Advances in Genetics, vol. 63, pp. 85–110, 2008. View at Publisher · View at Google Scholar · View at Scopus
  54. S. G. Waxman and S. Dib-Hajj, “Erythermalgia: molecular basis for an inherited pain syndrome,” Trends in Molecular Medicine, vol. 11, no. 12, pp. 555–562, 2005. View at Publisher · View at Google Scholar · View at Scopus
  55. Y. Yang, Y. Wang, S. Li et al., “Mutations in SCN9A, encoding a sodium channel alpha subunit, in patients with primary erythermalgia,” Journal of Medical Genetics, vol. 41, no. 3, pp. 171–174, 2004. View at Google Scholar · View at Scopus
  56. R. Dabby, “Pain disorders and erythromelalgia caused by voltage-gated sodium channel mutations,” Current Neurology and Neuroscience Reports, vol. 12, no. 1, pp. 76–83, 2012. View at Google Scholar
  57. A. Lampert, “Resurgent currents turn painfully exciting,” Journal of Physiology, vol. 589, no. 4, pp. 773–774, 2011. View at Publisher · View at Google Scholar · View at Scopus
  58. A. Lampert, A. O. O'Reilly, P. Reeh, and A. Leffler, “Sodium channelopathies and pain,” Pflugers Archiv European Journal of Physiology, vol. 460, no. 2, pp. 249–263, 2010. View at Publisher · View at Google Scholar · View at Scopus
  59. N. Skeik, T. W. Rooke, M. D. Davis et al., “Severe case and literature review of primary erythromelalgia: novel SCN9A gene mutation,” Vascular Medicine, vol. 17, pp. 44–49, 2012. View at Publisher · View at Google Scholar
  60. A. Wada, “Roles of voltage-dependent sodium channels in neuronal development, pain, and neurodegeneration,” Journal of Pharmacological Sciences, vol. 102, no. 3, pp. 253–268, 2006. View at Publisher · View at Google Scholar · View at Scopus
  61. Y. P. Goldberg, J. Macfarlane, M. L. Macdonald et al., “Loss-of-function mutations in the Nav1.7 gene underlie congenital indifference to pain in multiple human populations,” Clinical Genetics, vol. 71, no. 4, pp. 311–319, 2007. View at Publisher · View at Google Scholar · View at Scopus
  62. S. G. Waxman, “Nav1.7, its mutations, and the syndromes that they cause,” Neurology, vol. 69, no. 6, pp. 505–507, 2007. View at Publisher · View at Google Scholar · View at Scopus
  63. J. J. Cox, F. Reimann, A. K. Nicholas et al., “An SCN9A channelopathy causes congenital inability to experience pain,” Nature, vol. 444, no. 7121, pp. 894–898, 2006. View at Publisher · View at Google Scholar · View at Scopus
  64. K. B. Nilsen, A. K. Nicholas, C. G. Woods, S. I. Mellgren, M. Nebuchennykh, and J. Aasly, “Two novel SCN9A mutations causing insensitivity to pain,” Pain, vol. 143, no. 1, pp. 155–158, 2009. View at Publisher · View at Google Scholar · View at Scopus
  65. J. J. Cox, J. Sheynin, Z. Shorer et al., “Congenital insensitivity to pain: novel SCN9A missense and in-frame deletion mutations,” Human Mutation, vol. 31, no. 9, pp. E1670–E1686, 2010. View at Publisher · View at Google Scholar · View at Scopus
  66. M. Kurban, M. Wajid, Y. Shimomura, and A. M. Christiano, “A nonsense mutation in the SCN9A gene in congenital insensitivity to pain,” Dermatology, vol. 221, no. 2, pp. 179–183, 2010. View at Publisher · View at Google Scholar · View at Scopus
  67. A. Ma and A. Turner, “A life without pain: congenital insensitivity to pain due to compound heterozygous SCN9A mutation,” Journal of Paediatrics and Child Health, vol. 48, no. 3, pp. 285–286, 2012. View at Publisher · View at Google Scholar
  68. R. Staud, D. D. Price, D. Janicke et al., “Two novel mutations of SCN9A (Nav1.7) are associated with partial congenital insensitivity to pain,” European Journal of Pain, vol. 15, no. 3, pp. 223–230, 2011. View at Publisher · View at Google Scholar · View at Scopus
  69. R. Yuan, X. Zhang, Q. Deng et al., “Two novel SCN9A gene heterozygous mutations may cause partial deletion of pain perception,” Pain Medicine, vol. 12, no. 10, pp. 1510–1514, 2011. View at Publisher · View at Google Scholar
  70. S. D. Dib-Hajj, J. A. Black, and S. G. Waxman, “Voltage-gated sodium channels: therapeutic targets for pain,” Pain Medicine, vol. 10, no. 7, pp. 1260–1269, 2009. View at Publisher · View at Google Scholar · View at Scopus
  71. J. J. Clare, “Targeting voltage-gated sodium channels for pain therapy,” Expert Opinion on Investigational Drugs, vol. 19, no. 1, pp. 45–62, 2010. View at Publisher · View at Google Scholar · View at Scopus
  72. Y. Goldberg, S. Pimstone, R. Namdari et al., “Human Mendelian pain disorders: a key to discovery and validation of novel analgesics,” Clinical Genetics, vol. 82, no. 4, pp. 367–373, 2012. View at Publisher · View at Google Scholar
  73. G. Klement, O. Babich, O. Larsson, P. E. Lund, A. Malmberg, L. Sandberg et al., “Identification of Novel NaV1. 7 Antagonists Using High Throughput Screening Platforms,” Combinatorial Chemistry & High Throughput Screening, vol. 15, no. 9, pp. 713–720, 2012. View at Publisher · View at Google Scholar
  74. Y. P. Goldberg, N. Price, R. Namdari, C. J. Cohen, M. H. Lamers, C. Winters et al., “Treatment of Nav1. 7-mediated pain in inherited erythromelalgia using a novel sodium channel blocker,” Pain, vol. 153, pp. 80–85, 2012. View at Google Scholar
  75. J. Lai, J. C. Hunter, and F. Porreca, “The role of voltage-gated sodium channels in neuropathic pain,” Current Opinion in Neurobiology, vol. 13, no. 3, pp. 291–297, 2003. View at Publisher · View at Google Scholar · View at Scopus
  76. L. Sangameswaran, L. M. Fish, B. D. Koch et al., “A novel tetrodotoxin-sensitive, voltage-gated sodium channel expressed in rat and human dorsal root ganglia,” The Journal of Biological Chemistry, vol. 272, no. 23, pp. 14805–14809, 1997. View at Publisher · View at Google Scholar · View at Scopus
  77. S. G. Waxman, “Sodium channels, the electrogenisome and the electrogenistat: lessons and questions from the clinic,” The Journal of Physiology, vol. 590, no. 11, pp. 2601–2612, 2012. View at Publisher · View at Google Scholar
  78. T. R. Cummins, J. R. Howe, and S. G. Waxman, “Slow closed-state inactivation: a novel mechanism underlying ramp currents in cells expressing the hNE/PN1 sodium channel,” Journal of Neuroscience, vol. 18, no. 23, pp. 9607–9619, 1998. View at Google Scholar · View at Scopus
  79. R. I. Herzog, T. R. Cummins, F. Ghassemi, S. D. Dib-Hajj, and S. G. Waxman, “Distinct repriming and closed-state inactivation kinetics of Nav1.6 and Nav1.7 sodium channels in mouse spinal sensory neurons,” Journal of Physiology, vol. 551, no. 3, pp. 741–750, 2003. View at Publisher · View at Google Scholar · View at Scopus
  80. D. S. Krafte and A. W. Bannon, “Sodium channels and nociception: recent concepts and therapeutic opportunities,” Current Opinion in Pharmacology, vol. 8, no. 1, pp. 50–56, 2008. View at Publisher · View at Google Scholar · View at Scopus
  81. M. Renganathan, T. R. Cummins, and S. G. Waxman, “Contribution of Nav 1.8 sodium channels to action potential electrogenesis in DRG neurons,” Journal of Neurophysiology, vol. 86, no. 2, pp. 629–640, 2001. View at Google Scholar · View at Scopus
  82. C. Han, J. G. Hoeijmakers, S. Liu, M. M. Gerrits, R. H. Te Morsche, G. Lauria et al., “Functional profiles of SCN9A variants in dorsal root ganglion neurons and superior cervical ganglion neurons correlate with autonomic symptoms in small fibre neuropathy,” Brain, vol. 135, no. 9, pp. 2613–2628, 2012. View at Publisher · View at Google Scholar
  83. A. M. Rush, S. D. Dib-Hajj, S. Liu, T. R. Cummins, J. A. Black, and S. G. Waxman, “A single sodium channel mutation produces hyper- or hypoexcitability in different types of neurons,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 21, pp. 8245–8250, 2006. View at Publisher · View at Google Scholar · View at Scopus
  84. R. I. Herzog, T. R. Cummins, and S. G. Waxman, “Persistent TTX-resistant Na+ current affects resting potential and response to depolarization in simulated spinal sensory neurons,” Journal of Neurophysiology, vol. 86, no. 3, pp. 1351–1364, 2001. View at Google Scholar · View at Scopus
  85. F. Porreca, J. Lai, D. Bian et al., “A comparison of the potential role of the tetrodotoxin-insensitive sodium channels, PN3/SNS and NaN/SNS2, in rat models of chronic pain,” Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 14, pp. 6740–6744, 1999. View at Google Scholar · View at Scopus
  86. F. Porreca, J. Lai, D. Bian et al., “A comparison of the potential role of the tetrodotoxin- insensitive sodium channels, PN3/SNS and NaN/SNS2, in rat models of chronic pain,” Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 18, article 10548, 1999. View at Google Scholar · View at Scopus
  87. S. C. Apfel, S. Schwartz, B. T. Adornato et al., “Efficacy and safety of recombinant human nerve growth factor in patients with diabetic polyneuropathy: a randomized controlled trial,” Journal of the American Medical Association, vol. 284, no. 17, pp. 2215–2221, 2000. View at Google Scholar · View at Scopus
  88. B. G. Petty, D. R. Cornblath, B. T. Adornato et al., “The effect of systemically administered recombinant human nerve growth factor in healthy human subjects,” Annals of Neurology, vol. 36, no. 2, pp. 244–246, 1994. View at Publisher · View at Google Scholar · View at Scopus
  89. S. C. Apfel, “Is the therapeutic application of neurotrophic factors dead?” Annals of Neurology, vol. 51, no. 1, pp. 8–11, 2002. View at Publisher · View at Google Scholar · View at Scopus
  90. G. Schifitto, C. Yiannoutsos, D. M. Simpson et al., “Long-term treatment with recombinant nerve growth factor for HIV-associated sensory neuropathy,” Neurology, vol. 57, no. 7, pp. 1313–1316, 2001. View at Google Scholar · View at Scopus
  91. N. Katz, D. G. Borenstein, C. Birbara et al., “Efficacy and safety of tanezumab in the treatment of chronic low back pain,” Pain, vol. 152, no. 10, pp. 2248–2258, 2011. View at Publisher · View at Google Scholar · View at Scopus
  92. A. Cattaneo, “Tanezumab, a recombinant humanized mAb against nerve growth factor for the treatment of acute and chronic pain,” Current Opinion in Molecular Therapeutics, vol. 12, no. 1, pp. 94–106, 2010. View at Google Scholar · View at Scopus
  93. M. T. Brown, F. T. Murphy, D. M. Radin, I. Davignon, M. D. Smith, and C. R. West, “Tanezumab reduces osteoarthritic knee pain: results of a randomized, double-blind, placebo-controlled phase III trial,” The Journal of Pain, vol. 13, no. 8, pp. 790–798, 2012. View at Google Scholar
  94. N. E. Lane, T. J. Schnitzer, C. A. Birbara et al., “Tanezumab for the treatment of pain from osteoarthritis of the knee,” New England Journal of Medicine, vol. 363, no. 16, pp. 1521–1531, 2010. View at Publisher · View at Google Scholar · View at Scopus
  95. M. Zorbas, S. Hurst, D. Shelton, M. Evans, D. Finco, and M. Butt, “A multiple-dose toxicity study of tanezumab in cynomolgus monkeys,” Regulatory Toxicology and Pharmacology, vol. 59, no. 2, pp. 334–342, 2011. View at Publisher · View at Google Scholar · View at Scopus
  96. P. Bautista and L. Buckley, “Summary minutes of the arthritis advisory committee meeting,” Center for Drug Evaluation and Research, White Oak Conference Center, Silver Spring, Maryland, 2012, http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ArthritisAdvisoryCommittee/UCM307879.pdf.
  97. A. I. Basbaum, D. M. Bautista, G. Scherrer, and D. Julius, “Cellular and molecular mechanisms of pain,” Cell, vol. 139, no. 2, pp. 267–284, 2009. View at Publisher · View at Google Scholar · View at Scopus
  98. A. I. Basbaum and T. Jessell, “The perception of pain,” in Principles of Neural Sciences, E. R. Kandel, J. Schwartz, and T. Jessell, Eds., pp. 472–491, Appleton and Lange, New York, NY, USA, 2000. View at Google Scholar
  99. A. I. Basbaum and D. Julius, “Toward better pain control,” Scientific American, vol. 294, no. 6, pp. 60–67, 2006. View at Google Scholar · View at Scopus
  100. O. Cheunsuang and R. Morris, “Spinal lamina I neurons that express neurokinin 1 receptors: morphological analysis,” Neuroscience, vol. 97, no. 2, pp. 335–345, 2000. View at Publisher · View at Google Scholar · View at Scopus
  101. R. Suzuki, S. Morcuende, M. Webber, S. P. Hunt, and A. H. Dickenson, “Superficial NK1-expressing neurons control spinal excitability through activation of descending pathways,” Nature Neuroscience, vol. 5, no. 12, pp. 1319–1326, 2002. View at Publisher · View at Google Scholar · View at Scopus
  102. H. Adwanikar, G. Ji, W. Li, H. Doods, W. D. Willis, and V. Neugebauer, “Spinal CGRP1 receptors contribute to supraspinally organized pain behavior and pain-related sensitization of amygdala neurons,” Pain, vol. 132, no. 1, pp. 53–66, 2007. View at Publisher · View at Google Scholar · View at Scopus
  103. R. Suzuki and A. Dickenson, “Spinal and supraspinal contributions to central sensitization in peripheral neuropathy,” NeuroSignals, vol. 14, no. 4, pp. 175–181, 2005. View at Publisher · View at Google Scholar · View at Scopus
  104. R. Suzuki, W. Rahman, S. P. Hunt, and A. H. Dickenson, “Descending facilitatory control of mechanically evoked responses is enhanced in deep dorsal horn neurones following peripheral nerve injury,” Brain Research, vol. 1019, no. 1, pp. 68–76, 2004. View at Publisher · View at Google Scholar · View at Scopus
  105. A. Latremoliere and C. J. Woolf, “Central Sensitization: a Generator of Pain Hypersensitivity by Central Neural Plasticity,” Journal of Pain, vol. 10, no. 9, pp. 895–926, 2009. View at Publisher · View at Google Scholar · View at Scopus
  106. R. Ruscheweyh, O. Wilder-Smith, R. Drdla, X. G. Liu, and J. Sandkühler, “Long-term potentiation in spinal nociceptive pathways as a novel target for pain therapy,” Molecular Pain, vol. 7, article 20, 2011. View at Publisher · View at Google Scholar · View at Scopus
  107. R. Drdla and J. Sandkühler, “Long-term potentiation at C-fibre synapses by low-level presynaptic activity in vivo,” Molecular Pain, vol. 4, article 18, 2008. View at Publisher · View at Google Scholar · View at Scopus
  108. P. W. Mantyh, D. R. Clohisy, M. Koltzenburg, and S. P. Hunt, “Molecular mechanisms of cancer pain,” Nature Reviews Cancer, vol. 2, no. 3, pp. 201–209, 2002. View at Google Scholar · View at Scopus
  109. M. L. Nichols, B. J. Allen, S. D. Rogers et al., “Transmission of chronic nociception by spinal neurons expressing the substance P receptor,” Science, vol. 286, no. 5444, pp. 1558–1561, 1999. View at Publisher · View at Google Scholar · View at Scopus
  110. R. Hill, “NK1 (substance P) receptor antagonists—why are they not analgesic in humans?” Trends in Pharmacological Sciences, vol. 21, no. 7, pp. 244–246, 2000. View at Publisher · View at Google Scholar · View at Scopus
  111. K. Rost, F. Fleischer, and K. Nieber, “Neurokinin 1 receptor antagonists—between hope and disappointment,” Medizinische Monatsschrift fur Pharmazeuten, vol. 29, no. 6, pp. 200–205, 2006. View at Google Scholar · View at Scopus
  112. S. H. Sindrup, A. Graf, and N. Sfikas, “The NK1-receptor antagonist TKA731 in painful diabetic neuropathy: a randomised, controlled trial,” European Journal of Pain, vol. 10, no. 6, pp. 567–571, 2006. View at Publisher · View at Google Scholar · View at Scopus
  113. R. Suzuki and A. H. Dickenson, “Differential pharmacological modulation of the spontaneous stimulus-independent activity in the rat spinal cord following peripheral nerve injury,” Experimental Neurology, vol. 198, no. 1, pp. 72–80, 2006. View at Publisher · View at Google Scholar · View at Scopus
  114. R. Suzuki, L. J. Rygh, and A. H. Dickenson, “Bad news from the brain: descending 5-HT pathways that control spinal pain processing,” Trends in Pharmacological Sciences, vol. 25, no. 12, pp. 613–617, 2004. View at Publisher · View at Google Scholar · View at Scopus
  115. H. K. Beecher, “Pain in men wounded in battle,” Annals of Surgery, vol. 123, no. 1, pp. 96–105, 1946. View at Google Scholar
  116. U. Bingel and I. Tracey, “Imaging CNS modulation of pain in humans,” Physiology, vol. 23, no. 6, pp. 371–380, 2008. View at Publisher · View at Google Scholar · View at Scopus
  117. R. Melzack and K. L. Casey, “Sensory, motivational and central control determinants of pain,” in The Skin Senses, D. R. Kenshalo, Ed., pp. 423–443, Charles C. Thomas, Springfield, Ill, USA, 1968. View at Google Scholar
  118. R. D. Treede, D. R. Kenshalo, R. H. Gracely, and A. K. P. Jones, “The cortical representation of pain,” Pain, vol. 79, no. 2, pp. 105–111, 1999. View at Publisher · View at Google Scholar · View at Scopus
  119. Y. Oshiro, A. S. Quevedo, J. G. McHaffie, R. A. Kraft, and R. C. Coghill, “Brain mechanisms supporting spatial discrimination of pain,” Journal of Neuroscience, vol. 27, no. 13, pp. 3388–3394, 2007. View at Publisher · View at Google Scholar · View at Scopus
  120. R. D. Treede, A. V. Apkarian, B. Bromm, J. D. Greenspan, and F. A. Lenz, “Cortical representation of pain: functional characterization of nociceptive areas near the lateral sulcus,” Pain, vol. 87, no. 2, pp. 113–119, 2000. View at Publisher · View at Google Scholar · View at Scopus
  121. M. Ploner, H. J. Freund, and A. Schnitzler, “Pain affect without pain sensation in a patient with a postcentral lesion,” Pain, vol. 81, no. 1, pp. 211–214, 1999. View at Publisher · View at Google Scholar · View at Scopus
  122. S. Laureys, M. E. Faymonville, P. Peigneux et al., “Cortical processing of noxious somatosensory stimuli in the persistent vegetative state,” NeuroImage, vol. 17, no. 2, pp. 732–741, 2002. View at Publisher · View at Google Scholar · View at Scopus
  123. C. J. Labuda and P. N. Fuchs, “A behavioral test paradigm to measure the aversive quality of inflammatory and neuropathic pain in rats,” Experimental Neurology, vol. 163, no. 2, pp. 490–494, 2000. View at Publisher · View at Google Scholar · View at Scopus
  124. E. L. Foltz and L. E. White Jr., “Pain "relief" by frontal cingulumotomy,” Journal of Neurosurgery, vol. 19, pp. 89–100, 1962. View at Google Scholar · View at Scopus
  125. P. Rainville, G. H. Duncan, D. D. Price, B. Carrier, and M. C. Bushnell, “Pain affect encoded in human anterior cingulate but not somatosensory cortex,” Science, vol. 277, no. 5328, pp. 968–971, 1997. View at Publisher · View at Google Scholar · View at Scopus
  126. C. Qu, T. King, A. Okun, J. Lai, H. L. Fields, and F. Porreca, “Lesion of the rostral anterior cingulate cortex eliminates the aversiveness of spontaneous neuropathic pain following partial or complete axotomy,” Pain, vol. 152, no. 7, pp. 1641–1648, 2011. View at Publisher · View at Google Scholar · View at Scopus
  127. T. King, C. Qu, A. Okun, O. K. Melemedjian, E. K. Mandell, I. Y. Maskaykina et al., “Contribution of PKMzeta-dependent and independent amplification to components of experimental neuropathic pain,” Pain, vol. 153, no. 6, pp. 1263–1273, 2012. View at Google Scholar
  128. K. Tachibana, R. Kato, K. Tsuruga, K. Takita, T. Hashimoto, and Y. Morimoto, “Altered synaptic transmission in rat anterior cingulate cortex following peripheral nerve injury,” Brain Research, vol. 1238, no. C, pp. 53–58, 2008. View at Publisher · View at Google Scholar · View at Scopus
  129. J. Fan, X. Wu, Z. Cao, S. Chen, C. Owyang, and Y. Li, “Up-regulation of anterior cingulate cortex NR2B receptors contributes to visceral pain responses in rats,” Gastroenterology, vol. 136, no. 5, pp. 1732–e3, 2009. View at Publisher · View at Google Scholar · View at Scopus
  130. Z. Cao, X. Wu, S. Chen et al., “Anterior cingulate cortex modulates visceral pain as measured by visceromotor responses in viscerally hypersensitive rats,” Gastroenterology, vol. 134, no. 2, pp. 535–543, 2008. View at Publisher · View at Google Scholar · View at Scopus
  131. N. Yan, B. Cao, J. Xu, C. Hao, X. Zhang, and Y. Li, “Glutamatergic activation of anterior cingulate cortex mediates the affective component of visceral pain memory in rats,” Neurobiology of Learning and Memory, vol. 97, no. 1, pp. 156–164, 2012. View at Google Scholar
  132. Z. Wang, S. Bradesi, J. R. Charles et al., “Functional brain activation during retrieval of visceral pain-conditioned passive avoidance in the rat,” Pain, vol. 152, no. 12, pp. 2746–2756, 2011. View at Google Scholar
  133. N. I. Eisenberger, “The pain of social disconnection: examining the shared neural underpinnings of physical and social pain,” Nature Reviews Neuroscience, vol. 13, pp. 421–434, 2012. View at Google Scholar
  134. P. Riva, J. H. Wirth, and K. D. Williams, “The consequences of pain: the social and physical pain overlap on psychological responses,” European Journal of Social Psychology, vol. 41, no. 6, pp. 681–687, 2011. View at Publisher · View at Google Scholar · View at Scopus
  135. E. Kross, M. G. Berman, W. Mischel, E. E. Smith, and T. D. Wager, “Social rejection shares somatosensory representations with physical pain,” Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 15, pp. 6270–6275, 2011. View at Publisher · View at Google Scholar · View at Scopus
  136. C. Keysers, J. H. Kaas, and V. Gazzola, “Somatosensation in social perception,” Nature Reviews Neuroscience, vol. 11, no. 6, pp. 417–428, 2010. View at Publisher · View at Google Scholar · View at Scopus
  137. N. Danziger and J. C. Willer, “Tension-type headache as the unique pain experience of a patient with congenital insensitivity to pain,” Pain, vol. 117, no. 3, pp. 478–483, 2005. View at Publisher · View at Google Scholar · View at Scopus
  138. L. Mazzola, J. Isnard, R. Peyron, and F. Mauguière, “Stimulation of the human cortex and the experience of pain: Wilder Penfield's observations revisited,” Brain, vol. 135, pp. 631–640, 2012. View at Google Scholar
  139. L. Mazzola, J. Isnard, and F. Mauguière, “Somatosensory and pain responses to stimulation of the second somatosensory area (SII) in humans. A comparison with SI and insular responses,” Cerebral Cortex, vol. 16, no. 7, pp. 960–968, 2006. View at Publisher · View at Google Scholar · View at Scopus
  140. K. Ostrowsky, M. Magnin, P. Ryvlin, J. Isnard, M. Guenot, and F. Mauguière, “Representation of pain and somatic sensation in the human insula: a study of responses to direct electrical cortical stimulation,” Cerebral Cortex, vol. 12, no. 4, pp. 376–385, 2002. View at Google Scholar · View at Scopus
  141. L. Mazzola, J. Isnard, R. Peyron, M. Guénot, and F. Mauguière, “Somatotopic organization of pain responses to direct electrical stimulation of the human insular cortex,” Pain, vol. 146, no. 1, pp. 99–104, 2009. View at Publisher · View at Google Scholar · View at Scopus
  142. A. D. Craig, “Pain mechanisms: labeled lines versus convergence in central processing,” Annual Review of Neuroscience, vol. 26, pp. 1–30, 2003. View at Publisher · View at Google Scholar · View at Scopus
  143. A. D. Craig, M. C. Bushnell, E. T. Zhang, and A. Blomqvist, “A thalamic nucleus specific for pain and temperature sensation,” Nature, vol. 372, no. 6508, pp. 770–773, 1994. View at Google Scholar · View at Scopus
  144. A. C. Chen, “Pain perception and its genesis in the human brain,” Acta Physiologica Sinica, vol. 60, no. 5, pp. 677–685, 2008. View at Google Scholar
  145. J. Isnard, M. Magnin, J. Jung, F. Mauguire, and L. Garcia-Larrea, “Does the insula tell our brain that we are in pain?” Pain, vol. 152, no. 4, pp. 946–951, 2011. View at Publisher · View at Google Scholar · View at Scopus
  146. A. D. Craig, “A new view of pain as a homeostatic emotion,” Trends in Neurosciences, vol. 26, no. 6, pp. 303–307, 2003. View at Publisher · View at Google Scholar · View at Scopus
  147. M. Frot, M. Magnin, F. Mauguière, and L. Garcia-Larrea, “Human SII and posterior insula differently encode thermal laser stimuli,” Cerebral Cortex, vol. 17, no. 3, pp. 610–620, 2007. View at Publisher · View at Google Scholar · View at Scopus
  148. J. D. Greenspan, R. R. Lee, and F. A. Lenz, “Pain sensitivity alterations as a function of lesion location in the parasylvian cortex,” Pain, vol. 81, no. 3, pp. 273–282, 1999. View at Publisher · View at Google Scholar · View at Scopus
  149. C. J. Starr, L. Sawaki, G. F. Wittenberg et al., “Roles of the insular cortex in the modulation of pain: insights from brain lesions,” Journal of Neuroscience, vol. 29, no. 9, pp. 2684–2694, 2009. View at Publisher · View at Google Scholar · View at Scopus
  150. L. M. Chen, “Imaging of pain,” International Anesthesiology Clinics, vol. 45, no. 2, pp. 39–57, 2007. View at Publisher · View at Google Scholar · View at Scopus
  151. J. T. Francis, S. Xu, and J. K. Chapin, “Proprioceptive and cutaneous representations in the rat ventral posterolateral thalamus,” Journal of Neurophysiology, vol. 99, no. 5, pp. 2291–2304, 2008. View at Publisher · View at Google Scholar · View at Scopus
  152. U. Bingel, M. Quante, R. Knab, B. Bromm, C. Weiller, and C. Büchel, “Single trial fMRI reveals significant contralateral bias in responses to laser pain within thalamus and somatosensory cortices,” NeuroImage, vol. 18, no. 3, pp. 740–748, 2003. View at Publisher · View at Google Scholar · View at Scopus
  153. M. Schreckenberger, T. Siessmeier, A. Viertmann et al., “The unpleasantness of tonic pain is encoded by the insular cortex,” Neurology, vol. 64, no. 7, pp. 1175–1183, 2005. View at Google Scholar · View at Scopus
  154. R. Peyron, M. Frot, F. Schneider et al., “Role of operculoinsular cortices in human pain processing: converging evidence from PET, fMRI, dipole modeling, and intracerebral recordings of evoked potentials,” NeuroImage, vol. 17, no. 3, pp. 1336–1346, 2002. View at Publisher · View at Google Scholar · View at Scopus
  155. K. Tsou and C. S. Jang, “Studies on the site of analgesic action of morphine by intracerebral,” Scientia Sinica, vol. 13, pp. 1099–1109, 1964. View at Google Scholar · View at Scopus
  156. D. V. Reynolds, “Surgery in the rat during electrical analgesia induced by focal brain stimulation,” Science, vol. 164, no. 3878, pp. 444–445, 1969. View at Google Scholar · View at Scopus
  157. Y. Hosobuchi, J. E. Adams, and R. Linchitz, “Pain relief by electrical stimulation of the central gray matter in humans and its reversal by naloxone,” Science, vol. 197, no. 4299, pp. 183–186, 1977. View at Google Scholar · View at Scopus
  158. D. E. Richardson and H. Akil, “Pain reduction by electrical brain stimulation in man. I. Acute administration in periaqueductal and periventricular sites,” Journal of Neurosurgery, vol. 47, no. 2, pp. 178–183, 1977. View at Google Scholar · View at Scopus
  159. D. E. Richardson and H. Akil, “Long term results of periventricular gray self-stimulation,” Neurosurgery, vol. 1, no. 2, pp. 199–202, 1977. View at Google Scholar · View at Scopus
  160. N. H. Raskin, Y. Hosobuchi, and S. Lamb, “Headache may arise from perturbation of brain,” Headache, vol. 27, no. 8, pp. 416–420, 1987. View at Google Scholar · View at Scopus
  161. E. A. C. Pereira, A. L. Green, K. M. Bradley et al., “Regional cerebral perfusion differences between periventricular grey, thalamic and dual target deep brain stimulation for chronic neuropathic pain,” Stereotactic and Functional Neurosurgery, vol. 85, no. 4, pp. 175–183, 2007. View at Publisher · View at Google Scholar · View at Scopus
  162. E. A. C. Pereira, G. Lu, S. Wang et al., “Ventral periaqueductal grey stimulation alters heart rate variability in humans with chronic pain,” Experimental Neurology, vol. 223, no. 2, pp. 574–581, 2010. View at Publisher · View at Google Scholar · View at Scopus
  163. K. Gao, Y. H. H. Kim, and P. Mason, “Serotonergic pontomedullary neurons are not activated by antinociceptive stimulation in the periaqueductal gray,” Journal of Neuroscience, vol. 17, no. 9, pp. 3285–3292, 1997. View at Google Scholar · View at Scopus
  164. J. C. Yeung, T. L. Yaksh, and T. A. Rudy, “Concurrent mapping of brain sites for sensitivity to the direct application of morphine and focal electrical stimulation in the production of antinociception in the rat,” Pain, vol. 4, no. 1, pp. 23–40, 1977. View at Publisher · View at Google Scholar · View at Scopus
  165. A. J. Waters and B. M. Lumb, “Inhibitory effects evoked from both the lateral and ventrolateral periaqueductal grey are selective for the nociceptive responses of rat dorsal horn neurones,” Brain Research, vol. 752, no. 1, pp. 239–249, 1997. View at Publisher · View at Google Scholar · View at Scopus
  166. C. Gauriau and J. F. Bernard, “Pain pathways and parabrachial circuits in the rat,” Experimental Physiology, vol. 87, no. 2, pp. 251–258, 2002. View at Publisher · View at Google Scholar · View at Scopus
  167. A. Mobascher, J. Brinkmeyer, T. Warbrick et al., “Brain activation patterns underlying fast habituation to painful laser stimuli,” International Journal of Psychophysiology, vol. 75, no. 1, pp. 16–24, 2010. View at Publisher · View at Google Scholar · View at Scopus
  168. R. Peyron, B. Laurent, and L. García-Larrea, “Functional imaging of brain responses to pain. A review and meta-analysis,” Clinical Neurophysiology, vol. 30, no. 5, pp. 263–288, 2000. View at Publisher · View at Google Scholar · View at Scopus
  169. S. W. G. Derbyshire and J. Osborn, “Offset analgesia is mediated by activation in the region of the periaqueductal grey and rostral ventromedial medulla,” NeuroImage, vol. 47, no. 3, pp. 1002–1006, 2009. View at Publisher · View at Google Scholar · View at Scopus
  170. Z. Q. Zhao, “Neural mechanism underlying acupuncture analgesia,” Progress in Neurobiology, vol. 85, no. 4, pp. 355–375, 2008. View at Publisher · View at Google Scholar · View at Scopus
  171. M. M. Heinricher, I. Tavares, J. L. Leith, and B. M. Lumb, “Descending control of nociception: specificity, recruitment and plasticity,” Brain Research Reviews, vol. 60, no. 1, pp. 214–225, 2009. View at Publisher · View at Google Scholar · View at Scopus
  172. U. Bingel, J. Lorenz, E. Schoell, C. Weiller, and C. Büchel, “Mechanisms of placebo analgesia: rACC recruitment of a subcortical antinociceptive network,” Pain, vol. 120, no. 1-2, pp. 8–15, 2006. View at Publisher · View at Google Scholar · View at Scopus
  173. J. K. Zubieta and C. S. Stohler, “Neurobiological mechanisms of placebo responses,” Annals of the New York Academy of Sciences, vol. 1156, pp. 198–210, 2009. View at Publisher · View at Google Scholar · View at Scopus
  174. D. Bajic and H. K. Proudfit, “Projections of neurons in the periaqueductal gray to pontine and medullary catecholamine cell groups involved in the modulation of nociception,” Journal of Comparative Neurology, vol. 405, pp. 359–379, 1999. View at Google Scholar
  175. F. Odeh and M. Antal, “The projections of the midbrain periaqueductal grey to the pons and medulla oblongata in rats,” European Journal of Neuroscience, vol. 14, no. 8, pp. 1275–1286, 2001. View at Publisher · View at Google Scholar · View at Scopus
  176. P. B. Osborne, C. W. Vaughan, H. I. Wilson, and M. J. Christie, “Opioid inhibition of rat periaqueductal grey neurones with identified projections to rostral ventromedial medulla in vitro,” Journal of Physiology, vol. 490, part 2, pp. 383–389, 1996. View at Google Scholar · View at Scopus
  177. F. Odeh, M. Antal, and A. Zagon, “Heterogeneous synaptic inputs from the ventrolateral periaqueductal gray matter to neurons responding to somatosensory stimuli in the rostral ventromedial medulla of rats,” Brain Research, vol. 959, no. 2, pp. 287–294, 2003. View at Publisher · View at Google Scholar · View at Scopus
  178. H. L. Fields, A. I. Basbaum, and M. M. Heinricher, “Central nervous system mechanisms of pain modulation,” in Textbook of Pain, vol. 5, pp. 125–142, Churchill Livingstone, Edinburgh, Scotland, 2005. View at Google Scholar
  179. H. L. Fields, “Pain modulation: expectation, opioid analgesia and virtual pain,” Progress in Brain Research, vol. 122, pp. 245–253, 2000. View at Google Scholar · View at Scopus
  180. M. M. Morgan, K. L. Whittier, D. M. Hegarty, and S. A. Aicher, “Periaqueductal gray neurons project to spinally projecting GABAergic neurons in the rostral ventromedial medulla,” Pain, vol. 140, no. 2, pp. 376–386, 2008. View at Publisher · View at Google Scholar · View at Scopus
  181. S. A. Aicher, S. M. Hermes, K. L. Whittier, and D. M. Hegarty, “Descending projections from the rostral ventromedial medulla (RVM) to trigeminal and spinal dorsal horns are morphologically and neurochemically distinct,” Journal of Chemical Neuroanatomy, vol. 43, no. 2, pp. 103–111, 2012. View at Publisher · View at Google Scholar
  182. A. A. Calejesan, S. J. Kim, and M. Zhuo, “Descending facilitatory modulation of a behavioral nociceptive response by stimulation in the adult rat anterior cingulate cortex,” European Journal of Pain, vol. 4, no. 1, pp. 83–96, 2000. View at Publisher · View at Google Scholar · View at Scopus
  183. L. A. Bee and A. H. Dickenson, “Rostral ventromedial medulla control of spinal sensory processing in normal and pathophysiological states,” Neuroscience, vol. 147, no. 3, pp. 786–793, 2007. View at Publisher · View at Google Scholar · View at Scopus
  184. L. P. Vera-Portocarrero, M. H. Ossipov, J. Lai, T. King, and F. Porreca, “Descending facilitatory pathways from the rostroventromedial medulla mediate naloxone-precipitated withdrawal in morphine-dependent rats,” Journal of Pain, vol. 12, no. 6, pp. 667–676, 2011. View at Publisher · View at Google Scholar · View at Scopus
  185. C. Rivat, L. P. Vera-Portocarrero, M. M. Ibrahim et al., “Spinal NK-1 receptor-expressing neurons and descending pathways support fentanyl-induced pain hypersensitivity in a rat model of postoperative pain,” European Journal of Neuroscience, vol. 29, no. 4, pp. 727–737, 2009. View at Publisher · View at Google Scholar · View at Scopus
  186. L. P. Vera-Portocarrero, J. X. Yie, J. Kowal, M. H. Ossipov, T. King, and F. Porreca, “Descending facilitation from the rostral ventromedial medulla maintains visceral pain in rats with experimental pancreatitis,” Gastroenterology, vol. 130, no. 7, pp. 2155–2164, 2006. View at Publisher · View at Google Scholar · View at Scopus
  187. M. Ambriz-Tututi, S. L. Cruz, H. Urquiza-Marín, and V. Granados-Soto, “Formalin-induced long-term secondary allodynia and hyperalgesia are maintained by descending facilitation,” Pharmacology Biochemistry and Behavior, vol. 98, no. 3, pp. 417–424, 2011. View at Publisher · View at Google Scholar · View at Scopus
  188. M. de Felice, R. Sanoja, R. Wang et al., “Engagement of descending inhibition from the rostral ventromedial medulla protects against chronic neuropathic pain,” Pain, vol. 152, no. 12, pp. 2701–2709, 2011. View at Publisher · View at Google Scholar · View at Scopus
  189. R. Sanoja, H. Vanegas, and V. Tortorici, “Critical role of the rostral ventromedial medulla in early spinal events leading to chronic constriction injury neuropathy in rats,” Journal of Pain, vol. 9, no. 6, pp. 532–542, 2008. View at Publisher · View at Google Scholar · View at Scopus
  190. R. M. Edelmayer, T. W. Vanderah, L. Majuta et al., “Medullary pain facilitating neurons mediate allodynia in headache-related pain,” Annals of Neurology, vol. 65, no. 2, pp. 184–193, 2009. View at Publisher · View at Google Scholar · View at Scopus
  191. M. de Felice, M. H. Ossipov, and F. Porreca, “Persistent medication-induced neural adaptations, descending facilitation, and medication overuse headache,” Current Opinion in Neurology, vol. 24, no. 3, pp. 193–196, 2011. View at Publisher · View at Google Scholar · View at Scopus
  192. H. Vanegas and H. G. Schaible, “Descending control of persistent pain: inhibitory or facilitatory?” Brain Research Reviews, vol. 46, no. 3, pp. 295–309, 2004. View at Publisher · View at Google Scholar · View at Scopus
  193. U. Bingel, E. Schoell, and C. Büchel, “Imaging pain modulation in health and disease,” Current Opinion in Neurology, vol. 20, no. 4, pp. 424–431, 2007. View at Publisher · View at Google Scholar · View at Scopus
  194. C. D. King, F. Wong, T. Currie, A. P. Mauderli, R. B. Fillingim, and J. L. Riley III, “Deficiency in endogenous modulation of prolonged heat pain in patients with irritable bowel syndrome and temporomandibular disorder,” Pain, vol. 143, no. 3, pp. 172–178, 2009. View at Publisher · View at Google Scholar · View at Scopus
  195. A. Pielsticker, G. Haag, M. Zaudig, and S. Lautenbacher, “Impairment of pain inhibition in chronic tension-type headache,” Pain, vol. 118, no. 1, pp. 215–223, 2005. View at Publisher · View at Google Scholar · View at Scopus
  196. H. L. Felds, J. Bry, I. Hentall, and G. Zorman, “The activity of neurons in the rostral medulla of the rat during withdrawal from noxious heat,” Journal of Neuroscience, vol. 3, no. 12, pp. 2545–2552, 1983. View at Google Scholar · View at Scopus
  197. H. L. Fields, A. Malick, and R. Burstein, “Dorsal horn projection targets of ON and OFF cells in the rostral ventromedial medulla,” Journal of Neurophysiology, vol. 74, no. 4, pp. 1742–1759, 1995. View at Google Scholar · View at Scopus
  198. H. L. Fields, S. D. Anderson, C. H. Clanton, and A. I. Basbaum, “Nucleus raphe magnus: a common mediator of opiate- and stimulus-produced analgesia,” Transactions of the American Neurological Association, vol. 101, pp. 208–210, 1976. View at Google Scholar · View at Scopus
  199. S. D. Anderson, A. I. Basbaum, and H. L. Fields, “Response of medullary raphe neurons to peripheral stimulation and to systemic opiates,” Brain Research, vol. 123, no. 2, pp. 363–368, 1977. View at Publisher · View at Google Scholar · View at Scopus
  200. H. L. Fields, A. I. Basbaum, C. H. Clanton, and S. D. Anderson, “Nucleus raphe magnus inhibition of spinal cord dorsal horn neurons,” Brain Research, vol. 126, no. 3, pp. 441–453, 1977. View at Publisher · View at Google Scholar · View at Scopus
  201. H. Vanegas, N. M. Barbaro, and H. L. Fields, “Tail-flick related activity in medullospinal neurons,” Brain Research, vol. 321, no. 1, pp. 135–141, 1984. View at Publisher · View at Google Scholar · View at Scopus
  202. F. G. Fang, C. M. Haws, K. Drasner, A. Williamson, and H. L. Fields, “Opioid peptides (DAGO-enkephalin, dynorphin A(1–13), BAM 22P) microinjected into the rat brainstem: comparison of their antinoceptive effect and their effect on neuronal firing in the rostral ventromedial medulla,” Brain Research, vol. 501, no. 1, pp. 116–128, 1989. View at Google Scholar · View at Scopus
  203. M. M. Heinricher, C. M. Haws, and H. L. Fields, “Evidence for GABA-mediated control of putative nociceptive modulating neurons in the rostral ventromedial medulla: iontophoresis of bicuculline eliminates the off-cell pause,” Somatosensory and Motor Research, vol. 8, no. 3, pp. 215–225, 1991. View at Google Scholar · View at Scopus
  204. A. K. Gilbert and K. B. J. Franklin, “GABAergic modulation of descending inhibitory systems from the rostral ventromedial medulla (RVM). Dose-response analysis of nociception and neurological deficits,” Pain, vol. 90, no. 1, pp. 25–36, 2001. View at Publisher · View at Google Scholar · View at Scopus
  205. J. L. Moreau and H. L. Fields, “Evidence for GABA involvement in midbrain control of medullary neurons that modulate nociceptive transmission,” Brain Research, vol. 397, no. 1, pp. 37–46, 1986. View at Google Scholar · View at Scopus
  206. E. Vazquez, W. Escobar, K. Ramirez, and H. Vanegas, “A nonopioid analgesic acts upon the PAG-RVM axis to reverse inflammatory hyperalgesia,” European Journal of Neuroscience, vol. 25, no. 2, pp. 471–479, 2007. View at Publisher · View at Google Scholar · View at Scopus
  207. I. D. Meng, J. P. Johansen, I. Harasawa, and H. L. Fields, “Kappa opioids inhibit physiologically identified medullary pain modulating neurons and reduce morphine antinociception,” Journal of Neurophysiology, vol. 93, no. 3, pp. 1138–1144, 2005. View at Publisher · View at Google Scholar · View at Scopus
  208. M. M. Heinricher and M. J. Neubert, “Neural basis for the hyperalgesic action of cholecystokinin in the rostral ventromedial medulla,” Journal of Neurophysiology, vol. 92, no. 4, pp. 1982–1989, 2004. View at Publisher · View at Google Scholar · View at Scopus
  209. M. M. Heinricher, S. McGaraughty, and V. Tortorici, “Circuitry underlying antiopioid actions of cholecystokinin within the rostral ventromedial medulla,” Journal of Neurophysiology, vol. 85, no. 1, pp. 280–286, 2001. View at Google Scholar · View at Scopus
  210. W. Zhang, S. Gardell, D. Zhang et al., “Neuropathic pain is maintained by brainstem neurons co-expressing opioid and cholecystokinin receptors,” Brain, vol. 132, no. 3, pp. 778–787, 2009. View at Publisher · View at Google Scholar · View at Scopus
  211. T. M. Marshall, D. S. Herman, T. M. Largent-Milnes, H. Badghisi, K. Zuber, S. C. Holt et al., “Activation of descending pain-facilitatory pathways from the rostral ventromedial medulla by cholecystokinin elicits release of prostaglandin-E(2) in the spinal cord,” Pain, vol. 153, no. 1, pp. 86–94, 2012. View at Google Scholar
  212. C. J. Kovelowski, M. H. Ossipov, H. Sun, J. Lai, T. P. Malan, and F. Porreca, “Supraspinal cholecystokinin may drive tonic descending facilitation mechanisms to maintain neuropathic pain in the rat,” Pain, vol. 87, no. 3, pp. 265–273, 2000. View at Publisher · View at Google Scholar · View at Scopus
  213. T. King, L. Vera-Portocarrero, T. Gutierrez et al., “Unmasking the tonic-aversive state in neuropathic pain,” Nature Neuroscience, vol. 12, no. 11, pp. 1364–1366, 2009. View at Google Scholar · View at Scopus
  214. S. Potrebic, A. H. Ahn, K. Skinner, H. L. Fields, and A. I. Basbaum, “Peptidergic nociceptors of both trigeminal and dorsal root ganglia express serotonin 1D receptors: implications for the selective antimigraine action of triptans,” Journal of Neuroscience, vol. 23, no. 34, pp. 10988–10997, 2003. View at Google Scholar · View at Scopus
  215. V. G. J. M. VanderHorst and B. Ulfhake, “The organization of the brainstem and spinal cord of the mouse: relationships between monoaminergic, cholinergic, and spinal projection systems,” Journal of Chemical Neuroanatomy, vol. 31, no. 1, pp. 2–36, 2006. View at Publisher · View at Google Scholar · View at Scopus
  216. G. Kato, T. Yasaka, T. Katafuchi et al., “Direct GABAergic and glycinergic inhibition of the substantia gelatinosa from the rostral ventromedial medulla revealed by in vivo patch-clamp analysis in rats,” Journal of Neuroscience, vol. 26, no. 6, pp. 1787–1794, 2006. View at Publisher · View at Google Scholar · View at Scopus
  217. R. Y. Moore, “The anatomy of central serotonin neuron systems in the rat brain,” in Serotonin Neurotransmission and Behavior, B. L. Jacobs and A. Gelperin, Eds., pp. 35–71, MIT Press, Cambridge, UK, 1981. View at Google Scholar
  218. M. Cui, Y. Feng, D. J. McAdoo, and W. D. Willis, “Periaqueductal gray stimulation-induced inhibition of nociceptive dorsal horn neurons in rats is associated with the release of norepinephrine, serotonin, and amino acids,” Journal of Pharmacology and Experimental Therapeutics, vol. 289, no. 2, pp. 868–876, 1999. View at Google Scholar · View at Scopus
  219. R. Suzuki, W. Rahman, L. J. Rygh, M. Webber, S. P. Hunt, and A. H. Dickenson, “Spinal-supraspinal serotonergic circuits regulating neuropathic pain and its treatment with gabapentin,” Pain, vol. 117, no. 3, pp. 292–303, 2005. View at Publisher · View at Google Scholar · View at Scopus
  220. M. Sasaki, H. Obata, K. Kawahara, S. Saito, and F. Goto, “Peripheral 5-HT2A receptor antagonism attenuates primary thermal hyperalgesia and secondary mechanical allodynia after thermal injury in rats,” Pain, vol. 122, no. 1, pp. 130–136, 2006. View at Publisher · View at Google Scholar · View at Scopus
  221. K. Bannister, L. A. Bee, and A. H. Dickenson, “Preclinical and early clinical investigations related to monoaminergic pain modulation,” Neurotherapeutics, vol. 6, no. 4, pp. 703–712, 2009. View at Publisher · View at Google Scholar · View at Scopus
  222. W. Rahman, K. Bannister, L. A. Bee, and A. H. Dickenson, “A pronociceptive role for the 5-HT2 receptor on spinal nociceptive transmission: an in vivo electrophysiological study in the rat,” Brain Research, vol. 1382, pp. 29–36, 2011. View at Publisher · View at Google Scholar · View at Scopus
  223. W. Rahman, C. S. Bauer, K. Bannister, J. L. Vonsy, A. C. Dolphin, and A. H. Dickenson, “Descending serotonergic facilitation and the antinociceptive effects of pregabalin in a rat model of osteoarthritic pain,” Molecular pain, vol. 5, article 45, 2009. View at Google Scholar · View at Scopus
  224. H. Viisanen and A. Pertovaara, “Roles of the rostroventromedial medulla and the spinal 5-HT1A receptor in descending antinociception induced by motor cortex stimulation in the neuropathic rat,” Neuroscience Letters, vol. 476, no. 3, pp. 133–137, 2010. View at Publisher · View at Google Scholar · View at Scopus
  225. A. Dogrul, M. H. Ossipov, and F. Porreca, “Differential mediation of descending pain facilitation and inhibition by spinal 5HT-3 and 5HT-7 receptors,” Brain Research, vol. 1280, pp. 52–59, 2009. View at Publisher · View at Google Scholar · View at Scopus
  226. A. Brenchat, L. Romero, M. García et al., “5-HT7 receptor activation inhibits mechanical hypersensitivity secondary to capsaicin sensitization in mice,” Pain, vol. 141, no. 3, pp. 239–247, 2009. View at Publisher · View at Google Scholar · View at Scopus
  227. S. Doly, J. Fischer, M. J. Brisorgueil, D. Vergé, and M. Conrath, “Pre- and postsynaptic localization of the 5-HT7 receptor in rat dorsal spinal cord: immunocytochemical evidence,” Journal of Comparative Neurology, vol. 490, no. 3, pp. 256–269, 2005. View at Publisher · View at Google Scholar · View at Scopus
  228. P. A. Pierce, G. X. Xie, J. D. Levine, and S. J. Peroutka, “5-hydroxytryptamine receptor subtype messenger RNAs in rat peripheral sensory and sympathetic ganglia: a polymerase chain reaction study,” Neuroscience, vol. 70, no. 2, pp. 553–559, 1996. View at Google Scholar · View at Scopus
  229. S. B. Potrebic, H. L. Fields, and P. Mason, “Serotonin immunoreactivity is contained in one physiological cell class in the rat rostral ventromedial medulla,” Journal of Neuroscience, vol. 14, no. 3, pp. 1655–1665, 1994. View at Google Scholar · View at Scopus
  230. S. B. Potrebic, P. Mason, and H. L. Fields, “The density and distribution of serotonergic appositions onto identified neurons in the rat rostral ventromedial medulla,” Journal of Neuroscience, vol. 15, no. 5, part 1, pp. 3273–3283, 1995. View at Google Scholar · View at Scopus
  231. H. Foo and P. Mason, “Brainstem modulation of pain during sleep and waking,” Sleep Medicine Reviews, vol. 7, no. 2, pp. 145–154, 2003. View at Publisher · View at Google Scholar · View at Scopus
  232. P. Mason, “Contributions of the medullary raphe and ventromedial reticular region to pain modulation and other homeostatic functions,” Annual Review of Neuroscience, vol. 24, pp. 737–777, 2001. View at Publisher · View at Google Scholar · View at Scopus
  233. N. P. Pedersen, C. W. Vaughan, and M. J. Christie, “Opioid receptor modulation of GABAergic and serotonergic spinally projecting neurons of the rostral ventromedial medulla in mice,” Journal of Neurophysiology, vol. 106, no. 2, pp. 731–740, 2011. View at Publisher · View at Google Scholar
  234. F. Wei, R. Dubner, S. Zou et al., “Molecular depletion of descending serotonin unmasks its novel facilitatory role in the development of persistent pain,” Journal of Neuroscience, vol. 30, no. 25, pp. 8624–8636, 2010. View at Publisher · View at Google Scholar · View at Scopus
  235. M. Hossaini, J. A. Goos, S. K. Kohli, and J. C. Holstege, “Distribution of glycine/GABA neurons in the ventromedial medulla with descending spinal projections and evidence for an ascending glycine/GABA projection,” PLoS One, vol. 7, no. 4, article e35293, 2012. View at Publisher · View at Google Scholar
  236. C. W. Winkler, S. M. Hermes, C. I. Chavkin, C. T. Drake, S. F. Morrison, and S. A. Aicher, “Kappa opioid receptor (KOR) and GAD67 immunoreactivity are found in OFF and NEUTRAL cells in the rostral ventromedial medulla,” Journal of Neurophysiology, vol. 96, no. 6, pp. 3465–3473, 2006. View at Publisher · View at Google Scholar · View at Scopus
  237. K. Miki, Q. Q. Zhou, W. Guo et al., “Changes in gene expression and neuronal phenotype in brain stem pain modulatory circuitry after inflammation,” Journal of Neurophysiology, vol. 87, no. 2, pp. 750–760, 2002. View at Google Scholar · View at Scopus
  238. T. S. Brink and P. Mason, “Raphe magnus neurons respond to noxious colorectal distension,” Journal of Neurophysiology, vol. 89, no. 5, pp. 2506–2515, 2003. View at Publisher · View at Google Scholar · View at Scopus
  239. T. S. Brink and P. Mason, “Role for raphe magnus neuronal responses in the behavioral reactions to colorectal distension,” Journal of Neurophysiology, vol. 92, no. 4, pp. 2302–2311, 2004. View at Publisher · View at Google Scholar · View at Scopus
  240. S. Sikandar and A. H. Dickenson, “Pregabalin modulation of spinal and brainstem visceral nociceptive processing,” Pain, vol. 152, no. 10, pp. 2312–2322, 2011. View at Publisher · View at Google Scholar · View at Scopus
  241. D. L. Hammond, G. M. Tyce, and T. L. Yaksh, “Efflux of 5-hydroxytryptamine and noradrenaline into spinal cord superfusates during stimulation of the rat medulla,” Journal of Physiology, vol. 359, pp. 151–162, 1985. View at Google Scholar · View at Scopus
  242. D. Budai, I. Harasawa, and H. L. Fields, “Midbrain periaqueductal gray (PAG) inhibits nociceptive inputs to sacral dorsal horn nociceptive neurons through α2-adrenergic receptors,” Journal of Neurophysiology, vol. 80, no. 5, pp. 2244–2254, 1998. View at Google Scholar · View at Scopus
  243. P. J. Camarata and T. L. Yaksh, “Characterization of the spinal adrenergic receptors mediating the spinal effects produced by the microinjection of morphine into the periaqueductal gray,” Brain Research, vol. 336, no. 1, pp. 133–142, 1985. View at Publisher · View at Google Scholar · View at Scopus
  244. T. L. Yaksh, “Pharmacology of spinal adrenergic systems which modulate spinal nociceptive processing,” Pharmacology Biochemistry and Behavior, vol. 22, no. 5, pp. 845–858, 1985. View at Google Scholar · View at Scopus
  245. N. M. Barbaro, D. L. Hammond, and H. L. Fields, “Effects of intrathecally administered methysergide and yohimbine on microstimulation-produced antinociception in the rat,” Brain Research, vol. 343, no. 2, pp. 223–229, 1985. View at Google Scholar · View at Scopus
  246. D. L. Hammond and T. L. Yaksh, “Antagonism of stimulation-produced antinociception by intrathecal administration of methysergide or phentolamine,” Brain Research, vol. 298, no. 2, pp. 329–337, 1984. View at Publisher · View at Google Scholar · View at Scopus
  247. A. Pertovaara, “Noradrenergic pain modulation,” Progress in Neurobiology, vol. 80, no. 2, pp. 53–83, 2006. View at Publisher · View at Google Scholar · View at Scopus
  248. M. H. Ossipov, S. Harris, P. Lloyd, and E. Messineo, “An isobolographic analysis of the antinociceptive effect of systemically and intrathecally administered combinations of clonidine and opiates,” Journal of Pharmacology and Experimental Therapeutics, vol. 255, no. 3, pp. 1107–1116, 1990. View at Google Scholar · View at Scopus
  249. M. H. Ossipov, S. Harris, P. Lloyd, E. Messineo, B. S. Lin, and J. Bagley, “Antinociceptive interaction between opioids and medetomidine: systemic additivity and spinal synergy,” Anesthesiology, vol. 73, no. 6, pp. 1227–1235, 1990. View at Google Scholar · View at Scopus
  250. C. A. Fairbanks, L. S. Stone, K. F. Kitto, H. Oanh Nguyen, I. J. Posthumus, and G. L. Wilcox, “α2C-Adrenergic receptors mediate spinal analgesia and adrenergic-opioid synergy,” Journal of Pharmacology and Experimental Therapeutics, vol. 300, no. 1, pp. 282–290, 2002. View at Publisher · View at Google Scholar · View at Scopus
  251. M. Gassner, R. Ruscheweyh, and J. Sandkühler, “Direct excitation of spinal GABAergic interneurons by noradrenaline,” Pain, vol. 145, no. 1, pp. 204–210, 2009. View at Publisher · View at Google Scholar · View at Scopus
  252. J. C. Eisenach, S. DuPen, M. Dubois, R. Miguel, and D. Allin, “Epidural clonidine analgesia for intractable cancer pain,” Pain, vol. 61, no. 3, pp. 391–399, 1995. View at Publisher · View at Google Scholar · View at Scopus
  253. J. C. Eisenach, D. D. Hood, and R. Curry, “Intrathecal, but not intravenous, clonidine reduces experimental thermal or capsaicin-induced pain and hyperalgesia in normal volunteers,” Anesthesia and Analgesia, vol. 87, no. 3, pp. 591–596, 1998. View at Google Scholar · View at Scopus
  254. E. Bruinstroop, G. Cano, V. G. Vanderhorst et al., “Spinal projections of the A5, A6 (locus coeruleus), and A7 noradrenergic cell groups in rats,” Journal of Comparative Neurology, vol. 520, no. 9, pp. 1985–2001, 2012. View at Publisher · View at Google Scholar
  255. J. E. Holden and H. K. Proudfit, “Enkephalin neurons that project to the A7 catecholamine cell group are located in nuclei that modulate nociception: ventromedial medulla,” Neuroscience, vol. 83, no. 3, pp. 929–947, 1998. View at Publisher · View at Google Scholar · View at Scopus
  256. D. C. Yeomans and H. K. Proudfit, “Projections of substance P-immunoreactive neurons located in the ventromedial medulla to the A7 noradrenergic nucleus of the rat demonstrated using retrograde tracing combined with immunocytochemistry,” Brain Research, vol. 532, no. 1, pp. 329–332, 1990. View at Google Scholar · View at Scopus
  257. I. D. Hentall, R. Mesigil, A. Pinzon, and B. R. Noga, “Temporal and spatial profiles of pontine-evoked monoamine release in the rat's spinal cord,” Journal of Neurophysiology, vol. 89, no. 6, pp. 2943–2951, 2003. View at Publisher · View at Google Scholar · View at Scopus
  258. H. Viisanen and A. Pertovaara, “Influence of peripheral nerve injury on response properties of locus coeruleus neurons and coeruleospinal antinociception in the rat,” Neuroscience, vol. 146, no. 4, pp. 1785–1794, 2007. View at Publisher · View at Google Scholar · View at Scopus
  259. M. Tanaka, Y. Matsumoto, T. Murakami, Y. Hisa, and Y. Ibata, “The origins of catecholaminergic innervation in the rostral ventromedial medulla oblongata of the rat,” Neuroscience Letters, vol. 207, no. 1, pp. 53–56, 1996. View at Publisher · View at Google Scholar · View at Scopus
  260. J. E. Holden, E. J. Schwartz, and H. K. Proudfit, “Microinjection of morphine in the A7 catecholamine cell group produces opposing effects on nociception that are mediated by α1- and α2- adrenoceptors,” Neuroscience, vol. 91, no. 3, pp. 979–990, 1999. View at Publisher · View at Google Scholar · View at Scopus
  261. J. M. Cedarbaum and G. K. Aghajanian, “Afferent projections to the rat locus coeruleus as determined by a retrograde tracing technique,” Journal of Comparative Neurology, vol. 178, no. 1, pp. 1–16, 1978. View at Google Scholar · View at Scopus
  262. K. Nuseir and H. K. Proudfit, “Bidirectional modulation of nociception by GABA neurons in the dorsolateral pontine tegmentum that tonically inhibit spinally projecting noradrenergic A7 neurons,” Neuroscience, vol. 96, no. 4, pp. 773–783, 2000. View at Publisher · View at Google Scholar · View at Scopus
  263. Y. Muto, A. Sakai, A. Sakamoto, and H. Suzuki, “Activation of NK1 receptors in the locus coeruleus induces analgesia through noradrenergic-mediated descending inhibition in a rat model of neuropathic pain,” British Journal of Pharmacology, vol. 166, no. 3, pp. 1047–1057, 2012. View at Publisher · View at Google Scholar
  264. P. W. Howorth, S. R. Thornton, V. O'Brien et al., “Retrograde viral vector-mediated inhibition of pontospinal noradrenergic neurons causes hyperalgesia in rats,” Journal of Neuroscience, vol. 29, no. 41, pp. 12855–12864, 2009. View at Publisher · View at Google Scholar · View at Scopus
  265. W. Ma and J. C. Eisenach, “Chronic constriction injury of sciatic nerve induces the up-regulation of descending inhibitory noradrenergic innervation to the lumbar dorsal horn of mice,” Brain Research, vol. 970, no. 1, pp. 110–118, 2003. View at Publisher · View at Google Scholar · View at Scopus
  266. Y. Omiya, M. Yuzurihara, Y. Suzuki, Y. Kase, and T. Kono, “Role of α2-adrenoceptors in enhancement of antinociceptive effect in diabetic mice,” European Journal of Pharmacology, vol. 592, no. 1–3, pp. 62–66, 2008. View at Publisher · View at Google Scholar · View at Scopus
  267. S. Ide, M. Minami, K. Ishihara, G. R. Uhl, I. Sora, and K. Ikeda, “Mu opioid receptor-dependent and independent components in effects of tramadol,” Neuropharmacology, vol. 51, no. 3, pp. 651–658, 2006. View at Publisher · View at Google Scholar · View at Scopus
  268. R. B. Raffa, H. Buschmann, T. Christoph, G. Eichenbaum, W. Englberger, C. M. Flores et al., “Mechanistic and functional differentiation of tapentadol and tramadol,” Expert Opinion on Pharmacotherapy, vol. 13, no. 10, pp. 1437–1449, 2012. View at Google Scholar
  269. R. B. Raffa, E. Friderichs, W. Reimann et al., “Complementary and synergistic antinociceptive interaction between the enantiomers of tramadol,” Journal of Pharmacology and Experimental Therapeutics, vol. 267, no. 1, pp. 331–340, 1993. View at Google Scholar · View at Scopus
  270. N. Attal, G. Cruccu, R. Baron et al., “EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision,” European Journal of Neurology, vol. 17, no. 9, pp. 1113–1123, 2010. View at Publisher · View at Google Scholar · View at Scopus
  271. W. Leppert, “Tramadol as an analgesic for mild to moderate cancer pain,” Pharmacological Reports, vol. 61, no. 6, pp. 978–992, 2009. View at Google Scholar · View at Scopus
  272. C. T. Hartrick and R. J. Rozek, “Tapentadol in pain management: a μ-Opioid receptor agonist and noradrenaline reuptake inhibitor,” CNS Drugs, vol. 25, no. 5, pp. 359–370, 2011. View at Publisher · View at Google Scholar · View at Scopus
  273. T. M. Tzschentke, T. Christoph, W. Schröder et al., “Tapentadol: with two mechanisms of action in one molecule effective against nociceptive and neuropathic pain: preclinical overview,” Schmerz, vol. 25, no. 1, pp. 19–25, 2011. View at Publisher · View at Google Scholar · View at Scopus
  274. G. Varrassi, F. Marinangeli, A. Piroli, S. Coaccioli, and A. Paladini, “Strong analgesics: working towards an optimal balance between efficacy and side effects,” European Journal of Pain, vol. 14, no. 4, pp. 340–342, 2010. View at Publisher · View at Google Scholar · View at Scopus
  275. D. M. Pierce and E. Shipstone, “Pharmacology update: tapentadol for neuropathic pain,” The American Journal of Hospice & Palliative Care, vol. 29, no. 8, pp. 663–666, 2012. View at Publisher · View at Google Scholar
  276. J. A. Micó, D. Ardid, E. Berrocoso, and A. Eschalier, “Antidepressants and pain,” Trends in Pharmacological Sciences, vol. 27, no. 7, pp. 348–354, 2006. View at Publisher · View at Google Scholar · View at Scopus
  277. C. K. Jones, S. C. Peters, and H. E. Shannon, “Efficacy of duloxetine, a potent and balanced serotonergic and noradrenergic reuptake inhibitor, in inflammatory and acute pain models in rodents,” Journal of Pharmacology and Experimental Therapeutics, vol. 312, no. 2, pp. 726–732, 2005. View at Publisher · View at Google Scholar · View at Scopus
  278. M. Maizels and B. McCarberg, “Antidepressants and antiepileptic drugs for chronic non-cancer pain,” American Family Physician, vol. 71, no. 3, pp. 483–490, 2005. View at Google Scholar · View at Scopus
  279. T. Smith and R. A. Nicholson, “Review of duloxetine in the management of diabetic peripheral neuropathic pain,” Vascular Health and Risk Management, vol. 3, no. 6, pp. 833–844, 2007. View at Google Scholar · View at Scopus
  280. L. M. Arnold, “Duloxetine and other antidepressants in the treatment of patients with fibromyalgia,” Pain Medicine, vol. 8, supplement 2, pp. S63–S74, 2007. View at Publisher · View at Google Scholar · View at Scopus
  281. A. S. Chappell, M. J. Ossanna, H. Liu-Seifert et al., “Duloxetine, a centrally acting analgesic, in the treatment of patients with osteoarthritis knee pain: a 13-week, randomized, placebo-controlled trial,” Pain, vol. 146, no. 3, pp. 253–260, 2009. View at Publisher · View at Google Scholar · View at Scopus
  282. M. di Franco, C. Iannuccelli, F. Atzeni et al., “Pharmacological treatment of fibromyalgia,” Clinical and Experimental Rheumatology, vol. 28, no. 6, pp. S110–S116, 2010. View at Google Scholar · View at Scopus
  283. A. Lloyd, C. S. Boomershine, E. H. Choy, A. Chandran, and G. Zlateva, “The cost-effectiveness of pregabalin in the treatment of fibromyalgia: US perspective,” Journal of Medical Economic, vol. 15, no. 3, pp. 481–492, 2012. View at Google Scholar
  284. R. A. Moore, P. J. Wiffen, S. Derry, and H. J. McQuay, “Gabapentin for chronic neuropathic pain and fibromyalgia in adults,” Cochrane Database of Systematic Reviews, vol. 3, Article ID CD007938, 2011. View at Google Scholar · View at Scopus
  285. K. I. Hayashida, H. Obata, K. Nakajima, and J. C. Eisenach, “Gabapentin acts within the locus coeruleus to alleviate neuropathic pain,” Anesthesiology, vol. 109, no. 6, pp. 1077–1084, 2008. View at Publisher · View at Google Scholar · View at Scopus
  286. K. I. Hayashida, S. DeGoes, R. Curry, and J. C. Eisenach, “Gabapentin activates spinal noradrenergic activity in rats and humans and reduces hypersensitivity after surgery,” Anesthesiology, vol. 106, no. 3, pp. 557–562, 2007. View at Publisher · View at Google Scholar · View at Scopus
  287. I. Tracey and P. W. Mantyh, “The cerebral signature for pain perception and its modulation,” Neuron, vol. 55, no. 3, pp. 377–391, 2007. View at Publisher · View at Google Scholar · View at Scopus
  288. H. K. Beecher, “The powerful placebo,” Journal of the American Medical Association, vol. 159, no. 17, pp. 1602–1606, 1955. View at Google Scholar · View at Scopus
  289. S. Becker, W. Gandhi, and P. Schweinhardt, “Cerebral interactions of pain and reward and their relevance for chronic pain,” Neuroscience Letters, vol. 520, no. 2, pp. 182–187, 2012. View at Google Scholar
  290. S. Leknes, J. C. W. Brooks, K. Wiech, and I. Tracey, “Pain relief as an opponent process: a psychophysical investigation,” European Journal of Neuroscience, vol. 28, no. 4, pp. 794–801, 2008. View at Publisher · View at Google Scholar · View at Scopus
  291. Z. W. Pavlovic and R. J. Bodnar, “Opioid supraspinal analgesic synergy between the amygdala and periaqueductal gray in rats,” Brain Research, vol. 779, no. 1, pp. 158–169, 1998. View at Publisher · View at Google Scholar · View at Scopus
  292. F. J. Helmstetter, S. A. Tershner, L. H. Poore, and P. S. F. Bellgowan, “Antinociception following opioid stimulation of the basolateral amygdala is expressed through the periaqueductal gray and rostral ventromedial medulla,” Brain Research, vol. 779, no. 1, pp. 104–118, 1998. View at Publisher · View at Google Scholar · View at Scopus
  293. P. Petrovic and M. Ingvar, “Imaging cognitive modulation of pain processing,” Pain, vol. 95, no. 1, pp. 1–5, 2002. View at Publisher · View at Google Scholar · View at Scopus
  294. L. Colloca and F. Benedetti, “Placebos and painkillers: is mind as real as matter?” Nature Reviews Neuroscience, vol. 6, no. 7, pp. 545–552, 2005. View at Publisher · View at Google Scholar · View at Scopus
  295. J. K. Zubieta, J. A. Bueller, L. R. Jackson et al., “Placebo effects mediated by endogenous opioid activity on μ-opioid receptors,” Journal of Neuroscience, vol. 25, no. 34, pp. 7754–7762, 2005. View at Publisher · View at Google Scholar · View at Scopus
  296. P. Petrovic, E. Kalso, K. M. Petersson, and M. Ingvar, “Placebo and opioid analgesia—imaging a shared neuronal network,” Science, vol. 295, no. 5560, pp. 1737–1740, 2002. View at Publisher · View at Google Scholar · View at Scopus
  297. F. Eippert, U. Bingel, E. D. Schoell et al., “Activation of the opioidergic descending pain control system underlies placebo analgesia,” Neuron, vol. 63, no. 4, pp. 533–543, 2009. View at Publisher · View at Google Scholar · View at Scopus
  298. T. D. Wager, J. K. Rilling, E. E. Smith et al., “Placebo-induced changes in fMRI in the anticipation and experience of pain,” Science, vol. 303, no. 5661, pp. 1162–1167, 2004. View at Publisher · View at Google Scholar · View at Scopus
  299. D. D. Price, J. Craggs, G. Nicholas Verne, W. M. Perlstein, and M. E. Robinson, “Placebo analgesia is accompanied by large reductions in pain-related brain activity in irritable bowel syndrome patients,” Pain, vol. 127, no. 1, pp. 63–72, 2007. View at Publisher · View at Google Scholar · View at Scopus
  300. D. J. Scott, C. S. Stohler, C. M. Egnatuk, H. Wang, R. A. Koeppe, and J. K. Zubieta, “Individual differences in reward responding explain placebo-induced expectations and effects,” Neuron, vol. 55, no. 2, pp. 325–336, 2007. View at Publisher · View at Google Scholar · View at Scopus
  301. P. S. Lyby, J. T. Forsberg, O. Åsli, and M. A. Flaten, “Induced fear reduces the effectiveness of a placebo intervention on pain,” Pain, vol. 153, pp. 1114–1121, 2012. View at Google Scholar
  302. F. Benedetti, M. Lanotte, L. Lopiano, and L. Colloca, “When words are painful: unraveling the mechanisms of the nocebo effect,” Neuroscience, vol. 147, no. 2, pp. 260–271, 2007. View at Publisher · View at Google Scholar · View at Scopus
  303. F. Benedetti, A. Pollo, L. Lopiano, M. Lanotte, S. Vighetti, and I. Rainero, “Conscious expectation and unconscious conditioning in analgesic, motor, and hormonal placebo/nocebo responses,” Journal of Neuroscience, vol. 23, no. 10, pp. 4315–4323, 2003. View at Google Scholar · View at Scopus
  304. L. Colloca and F. Benedetti, “Nocebo hyperalgesia: how anxiety is turned into pain,” Current Opinion in Anaesthesiology, vol. 20, no. 5, pp. 435–439, 2007. View at Publisher · View at Google Scholar · View at Scopus
  305. J. R. Keltner, A. Furst, C. Fan, R. Redfern, B. Inglis, and H. L. Fields, “Isolating the modulatory effect of expectation on pain transmission: a functional magnetic resonance imaging study,” Journal of Neuroscience, vol. 26, no. 16, pp. 4437–4443, 2006. View at Publisher · View at Google Scholar · View at Scopus
  306. S. Leknes and I. Tracey, “A common neurobiology for pain and pleasure,” Nature Reviews Neuroscience, vol. 9, no. 4, pp. 314–320, 2008. View at Publisher · View at Google Scholar · View at Scopus
  307. S. Leknes, M. Lee, C. Berna, J. Andersson, and I. Tracey, “Relief as a reward: hedonic and neural responses to safety from pain,” PLoS ONE, vol. 6, no. 4, Article ID e17870, 2011. View at Publisher · View at Google Scholar · View at Scopus
  308. M. N. Baliki, P. Y. Geha, H. L. Fields, and A. V. Apkarian, “Predicting value of pain and analgesia: nucleus accumbens response to noxious stimuli changes in the presence of chronic pain,” Neuron, vol. 66, no. 1, pp. 149–160, 2010. View at Publisher · View at Google Scholar · View at Scopus
  309. D. Talmi, P. Dayan, S. J. Kiebel, C. D. Frith, and R. J. Dolan, “How humans integrate the prospects of pain and reward during choice,” Journal of Neuroscience, vol. 29, no. 46, pp. 14617–14626, 2009. View at Publisher · View at Google Scholar · View at Scopus
  310. D. Le Bars, A. H. Dickenson, and J. M. Besson, “Diffuse noxious inhibitory controls (DNIC). II. Lack of effect on non-convergent neurones, supraspinal involvement and theoretical implications,” Pain, vol. 6, no. 3, pp. 305–327, 1979. View at Publisher · View at Google Scholar · View at Scopus
  311. D. Le Bars, A. H. Dickenson, and J. M. Besson, “Diffuse noxious inhibitory controls (DNIC). I. Effects on dorsal horn convergent neurones in the rat,” Pain, vol. 6, no. 3, pp. 283–304, 1979. View at Publisher · View at Google Scholar · View at Scopus
  312. D. Le Bars, D. Chitour, and E. Kraus, “Effect of naloxone upon diffuse noxious inhibitory controls (DNIC) in the rat,” Brain Research, vol. 204, no. 2, pp. 387–402, 1981. View at Publisher · View at Google Scholar · View at Scopus
  313. L. Villanueva and D. Le Bars, “The activation of bulbo-spinal controls by peripheral nociceptive inputs: diffuse noxious inhibitory controls,” Biological Research, vol. 28, no. 1, pp. 113–125, 1995. View at Google Scholar · View at Scopus
  314. D. Lima, A. Albino-Teixeira, and I. Tavares, “The caudal medullary ventrolateral reticular formation in nociceptive-cardiovascular integration. An experimental study in the rat,” Experimental Physiology, vol. 87, no. 2, pp. 267–274, 2002. View at Publisher · View at Google Scholar · View at Scopus
  315. D. Lima and A. Almeida, “The medullary dorsal reticular nucleus as a pronociceptive centre of the pain control system,” Progress in Neurobiology, vol. 66, no. 2, pp. 81–108, 2002. View at Publisher · View at Google Scholar · View at Scopus
  316. H. Leite-Almeida, A. Valle-Fernandes, and A. Almeida, “Brain projections from the medullary dorsal reticular nucleus: an anterograde and retrograde tracing study in the rat,” Neuroscience, vol. 140, no. 2, pp. 577–595, 2006. View at Publisher · View at Google Scholar · View at Scopus
  317. A. Almeida, I. Tavares, D. Lima, and A. Coimbra, “Descending projections from the medullary dorsal reticular nucleus make synaptic contacts with spinal cord lamina I cells projecting to that nucleus: an electron microscopic tracer study in the rat,” Neuroscience, vol. 55, no. 4, pp. 1093–1106, 1993. View at Publisher · View at Google Scholar · View at Scopus
  318. L. Monconduit, C. Desbois, and L. Villanueva, “The integrative role of the rat medullary subnucleus reticularis dorsalis in nociception,” European Journal of Neuroscience, vol. 16, no. 5, pp. 937–944, 2002. View at Publisher · View at Google Scholar · View at Scopus
  319. D. Le Bars, “The whole body receptive field of dorsal horn multireceptive neurones,” Brain Research Reviews, vol. 40, no. 1–3, pp. 29–44, 2002. View at Publisher · View at Google Scholar · View at Scopus
  320. L. Villanueva, “Diffuse Noxious Inhibitory Control (DNIC) as a tool for exploring dysfunction of endogenous pain modulatory systems,” Pain, vol. 143, no. 3, pp. 161–162, 2009. View at Publisher · View at Google Scholar · View at Scopus
  321. N. Julien, P. Goffaux, P. Arsenault, and S. Marchand, “Widespread pain in fibromyalgia is related to a deficit of endogenous pain inhibition,” Pain, vol. 114, no. 1, pp. 295–302, 2005. View at Publisher · View at Google Scholar · View at Scopus
  322. L. Arendt-Nielsen, H. Nie, M. B. Laursen et al., “Sensitization in patients with painful knee osteoarthritis,” Pain, vol. 149, no. 3, pp. 573–581, 2010. View at Publisher · View at Google Scholar · View at Scopus
  323. S. S. Olesen, C. Brock, A. L. Krarup et al., “Descending inhibitory pain modulation is impaired in patients with chronic pancreatitis,” Clinical Gastroenterology and Hepatology, vol. 8, no. 8, pp. 724–730, 2010. View at Publisher · View at Google Scholar · View at Scopus
  324. A. S. Leffler, E. Kosek, T. Lerndal, B. Nordmark, and P. Hansson, “Somatosensory perception and function of diffuse noxious inhibitory controls (DNIC) in patients suffering from rheumatoid arthritis,” European Journal of Pain, vol. 6, no. 2, pp. 161–176, 2002. View at Publisher · View at Google Scholar · View at Scopus
  325. A. S. Leffler, P. Hansson, and E. Kosek, “Somatosensory perception in a remote pain-free area and function of diffuse noxious inhibitory controls (DNIC) in patients suffering from long-term trapezius myalgia,” European Journal of Pain, vol. 6, no. 2, pp. 149–159, 2002. View at Publisher · View at Google Scholar · View at Scopus
  326. R. Moont, Y. Crispel, R. Lev, D. Pud, and D. Yarnitsky, “Temporal changes in cortical activation during conditioned pain modulation (CPM), a LORETA study,” Pain, vol. 152, no. 7, pp. 1469–1477, 2011. View at Publisher · View at Google Scholar · View at Scopus
  327. G. H. Song, V. Venkatraman, K. Y. Ho, M. W. L. Chee, K. G. Yeoh, and C. H. Wilder-Smith, “Cortical effects of anticipation and endogenous modulation of visceral pain assessed by functional brain MRI in irritable bowel syndrome patients and healthy controls,” Pain, vol. 126, no. 1–3, pp. 79–90, 2006. View at Publisher · View at Google Scholar · View at Scopus
  328. R. Moont, D. Pud, E. Sprecher, G. Sharvit, and D. Yarnitsky, “'Pain inhibits pain' mechanisms: is pain modulation simply due to distraction?” Pain, vol. 150, no. 1, pp. 113–120, 2010. View at Publisher · View at Google Scholar · View at Scopus
  329. R. Landau, J. C. Kraft, L. Y. Flint et al., “An experimental paradigm for the prediction of Post-Operative Pain (PPOP),” Journal of Visualized Experiments, no. 35, article e1671, 2010. View at Publisher · View at Google Scholar · View at Scopus
  330. D. Yarnitsky, Y. Crispel, E. Eisenberg et al., “Prediction of chronic post-operative pain: pre-operative DNIC testing identifies patients at risk,” Pain, vol. 138, no. 1, pp. 22–28, 2008. View at Publisher · View at Google Scholar · View at Scopus
  331. S. Cathcart, A. H. Winefield, K. Lushington, and P. Rolan, “Noxious inhibition of temporal summation is impaired in chronic tension-type headache,” Headache, vol. 50, no. 3, pp. 403–412, 2010. View at Publisher · View at Google Scholar · View at Scopus
  332. R. Lev, Y. Granovsky, and D. Yarnitsky, “Orbitofrontal disinhibition of pain in migraine with aura: an interictal EEG-mapping study,” Cephalalgia, vol. 30, no. 8, pp. 910–918, 2010. View at Publisher · View at Google Scholar · View at Scopus
  333. P. Rossi, M. Serrao, A. Perrotta, F. Pierelli, G. Sandrini, and G. Nappi, “Neurophysiological approach to central pain modulation in primary headaches,” Journal of Headache and Pain, vol. 6, no. 4, pp. 191–194, 2005. View at Publisher · View at Google Scholar · View at Scopus