Sensory Nerves pp 451-491 | Cite as

The Role of Peptides in Central Sensitization

  • V.S. SeyboldEmail author
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 194)


Peptides released in the spinal cord from the central terminals of nociceptors contribute to the persistent hyperalgesia that defines the clinical experience of chronic pain. Using substance P (SP) and calcitonin gene-related peptide (CGRP) as examples, this review addresses the multiple mechanisms through which peptidergic neurotransmission contributes to the development and maintenance of chronic pain. Activation of CGRP receptors on terminals of primary afferent neurons facilitates transmitter release and receptors on spinal neurons increases glutamate activation of AMPA receptors. Both effects are mediated by cAMP-dependent mechanisms. Substance P activates neurokinin receptors (3 subtypes) which couple to phospholipase C and the generation of the intracellular messengers whose downstream effects include depolarizing the membrane and facilitating the function of AMPA and NMDA receptors. Activation of neurokinin-1 receptors also increases the synthesis of prostaglandins whereas activation of neurokinin-3 receptors increases the synthesis of nitric oxide. Both products act as retrograde messengers across synapses and facilitate nociceptive signaling in the spinal cord. Whereas these cellular effects of CGRP and SP at the level of the spinal cord contribute to the development of increased synaptic strength between nociceptors and spinal neurons in the pathway for pain, the different intracellular signaling pathways also activate different transcription factors. The activated transcription factors initiate changes in the expression of genes that contribute to long-term changes in the excitability of spinal and maintain hyperalgesia.


Calcitonin gene-related peptide Substance P Neurokinin Spinal cord Hyperalgesia NFAT CREB Receptor Inflammation 





Cyclic AMP


Ca2+/calmodulin-dependent protein kinase


Calcitonin gene-related peptide




Cyclic AMP response element


Cyclic AMP response element binding protein


Calcitonin receptor-like receptor


Extracellular-signal-regulated kinase


Messenger RNA


Nuclear factor of activated T cells


Neurokinin 1


Neurokinin 2


Neurokinin 3


Neurokinin A


Neurokinin B


Nitric oxide synthase


Nonsteroidal anti-inflammatory drug


Phosphorylated cyclic AMP response element binding protein


Prostaglandin E2


Preprotachykinin A


Receptor activity modifying protein


Receptor component protein


Substance P


  1. Aanonsen LM, Kajander KC, Bennett GJ, Seybold VS (1992) Autoradiographic analysis of 125I-substance P binding in rat spinal cord following chronic constriction injury of the sciatic nerve. Brain Res 596:259–268PubMedGoogle Scholar
  2. Abbadie C, Brown JL, Mantyh PW, Basbaum AI (1996) Spinal cord substance P receptor immunoreactivity increases in both inflammatory and nerve injury models of persistent pain. Neuroscience 70:201–209PubMedGoogle Scholar
  3. Abbadie C, Trafton J, Liu H, Mantyh PW, Basbaum AI (1997) Inflammation increases the distribution of dorsal horn neurons that internalize the neurokinin-1 receptor in response to noxious and non-noxious stimulation. J Neurosci 17:8049–8060PubMedGoogle Scholar
  4. Abrahams LG, Reutter MA, McCarson KE, Seybold VS (1999) Cyclic AMP regulates the expression of neurokinin1 receptors by neonatal rat spinal neurons in culture. J Neurochem 73:50–58PubMedGoogle Scholar
  5. Adwanikar H, Ji G, Li W, Doods H, Willis WD, Neugebauer V (2007) Spinal CGRP1 receptors contribute to supraspinally organized pain behavior and pain-related sensitization of amygdala neurons. Pain 132:53–66PubMedGoogle Scholar
  6. Agnati LF, Leo G, Zanardi A, Genedani S, Rivera A, Fuxe K, Guidolin D (2006) Volume transmission and wiring transmission from cellular to molecular networks: history and perspectives. Acta Physiol 187:329–344Google Scholar
  7. Allen DT, Kiernan JA (1994) Permeation of proteins from the blood into peripheral nerves and ganglia. Neuroscience 59:755–764PubMedGoogle Scholar
  8. Allen BJ, Rogers SD, Ghilardi JR, Menning PM, Kuskowski MA, Basbaum AI, Simone DA, Mantyh PW (1997) Noxious cutaneous thermal stimuli induce a graded release of endogenous substance P in the spinal cord: imaging peptide action in vivo. J Neurosci 17:5921–5927PubMedGoogle Scholar
  9. Amara SG, Jonas V, Rosenfeld MG, Ong ES, Evans RM (1982) Alternative RNA processing in calcitonin gene expression generates mRNAs encoding different polypeptide products. Nature 298:240–244PubMedGoogle Scholar
  10. Amara SG, Arriza JL, Leff SE, Swanson LW, Evans RM, Rosenfeld MG (1985) Expression in brain of a messenger RNA encoding a novel neuropeptide homologous to calcitonin gene-related peptide. Science 229:1094–1097PubMedGoogle Scholar
  11. Amir R, Devor M (1996) Chemically mediated cross-excitation in rat dorsal root ganglia. J Neurosci 16:4733–4741PubMedGoogle Scholar
  12. Anderson LE, Seybold VS (2000) Phosphorylated cAMP response element binding protein increases in neurokinin-1 receptor-immunoreactive neurons in rat spinal cord in response to formalin-induced nociception. Neurosci Lett 283:29–32PubMedGoogle Scholar
  13. Anderson LE, Seybold VS (2004) Calcitonin gene-related peptide regulates gene transcription in primary afferent neurons. J Neurochem 91:1417–1429PubMedGoogle Scholar
  14. Andreeva L, Rang HP (1993) Effect of bradykinin and prostaglandins on the release of calcitonin gene-related peptide-like immunoreactivity from the rat spinal cord in vitro. Br J Pharmacol 108:185–190PubMedGoogle Scholar
  15. Beiche F, Brune K, Geisslinger G, Goppelt-Struebe M (1998) Expression of cyclooxygenase isoforms in the rat spinal cord and their regulation during adjuvant-induced arthritis. Inflamm Res 47:482–487PubMedGoogle Scholar
  16. Bird GC, Han JS, Fu Y, Adwanikar H, Willis WD, Neugebauer V (2006) Pain-related synaptic plasticity in spinal dorsal horn neurons: role of CGRP. Mol Pain 2:31PubMedGoogle Scholar
  17. Bowden JJ, Garland AM, Baluk P, Lefevre P, Grady EF, Vigna SR, Bunnett NW, McDonald DM (1994) Direct observation of substance P-induced internalization of neurokinin 1 (NK1) receptors at sites of inflammation. Proc Natl Acad Sci USA 91:8964–8968PubMedGoogle Scholar
  18. Bowie D, Feltz P, Schlichter R (1994) Subpopulations of neonatal rat sensory neurons express functional neurotransmitter receptors which elevate intracellular calcium. Neuroscience 58:141–149PubMedGoogle Scholar
  19. Brosenitsch TA, Salgado-Commissariat D, Kunze DL, Katz DM (1998) A role for L-type calcium channels in developmental regulation of transmitter phenotype in primary sensory neurons. J Neurosci 18:1047–1055PubMedGoogle Scholar
  20. Brown JL, Liu H, Maggio JE, Vigna SR, Mantyh PW, Basbaum AI (1995) Morphological characterization of substance P receptor-immunoreactive neurons in the rat spinal cord and trigeminal nucleus caudalis. J Comp Neurol 356:327–344PubMedGoogle Scholar
  21. Burbach GJ, Kim KH, Zivony AS, Kim A, Aranda J, Wright S, Naik SM, Caughman SW, Ansel JC, Armstrong CA (2001) The neurosensory tachykinins substance P and neurokinin A directly induce keratinocyte nerve growth factor. J Invest Dermatol 117:1075–1082PubMedGoogle Scholar
  22. Cao YQ, Mantyh PW, Carlson EJ, Gillespie AM, Epstein CJ, Basbaum AI (1998) Primary afferent tachykinins are required to experience moderate to intense pain. Nature 392:390–394PubMedGoogle Scholar
  23. Carlton SM, Zhou S, Coggeshall RE (1996) Localization and activation of substance P receptors in unmyelinated axons of rat glabrous skin. Brain Res 734:103–108PubMedGoogle Scholar
  24. Chan CF, Sun WZ, Lin JK, Lin-Shiau SY (2000) Activation of transcription factors of nuclear factor kappa B, activator protein-1 and octamer factors in hyperalgesia. Eur J Pharmacol 402:61–68PubMedGoogle Scholar
  25. Chapman V, Dickenson AH (1992) The spinal and peripheral roles of bradykinin and prostaglandins in nociceptive processing in the rat. Eur J Pharmacol 219:427–433PubMedGoogle Scholar
  26. Charlton CG, Helke CJ (1985) Characterization and segmental distribution of 125I-Bolton-Hunter-labeled substance P binding sites in rat spinal cord. J Neurosci 5:1293–1299PubMedGoogle Scholar
  27. Chen L, Huang LY (1992) Protein kinase C reduces Mg2+ block of NMDA-receptor channels as a mechanism of modulation. Nature 356:521–523PubMedGoogle Scholar
  28. Coderre TJ, Melzack R (1991) Central neural mediators of secondary hyperalgesia following heat injury in rats: neuropeptides and excitatory amino acids. Neurosci Lett 131:71–74PubMedGoogle Scholar
  29. Cook AJ, Woolf CJ, Wall PD, McMahon SB (1987) Dynamic receptive field plasticity in rat spinal cord dorsal horn following C-primary afferent input. Nature 325:151–153PubMedGoogle Scholar
  30. Cridland RA, Henry JL (1988) Facilitation of the tail-flick reflex by noxious cutaneous stimulation in the rat: antagonism by a substance P analogue. Brain Res 462:15–21Google Scholar
  31. Cumberbatch MJ, Chizh BA, Headley PM (1995) Modulation of excitatory amino acid responses by tachykinins and selective tachykinin receptor agonists in the rat spinal cord. Br J Pharmacol 115:1005–1012PubMedGoogle Scholar
  32. De Felipe C, Herrero JF, O'Brien JA, Palmer JA, Doyle CA, Smith AJ, Laird JM, Belmonte C, Cervero F, Hunt SP (1998) Altered nociception, analgesia and aggression in mice lacking the receptor for substance P. Nature 392:394–397PubMedGoogle Scholar
  33. De Koninck Y, Ribeiro-da-Silva A, Henry JL, Cuello AC (1992) Spinal neurons exhibiting a specific nociceptive response receive abundant substance P-containing synaptic contacts. Proc Natl Acad Sci USA 89: 5073–5077PubMedGoogle Scholar
  34. Ding YQ, Shigemoto R, Takada M, Ohishi H, Nakanishi S, Mizuno N (1996) Localization of the neuromedin K receptor (NK3) in the central nervous system of the rat. J Comp Neurol 364:290–310PubMedGoogle Scholar
  35. Dolan S, Kelly JG, Huan M, Nolan AM (2003) Transient up-regulation of spinal cyclooxygenase-2 and neuronal nitric oxide synthase following surgical inflammation. Anesthesiology 98:170–180PubMedGoogle Scholar
  36. Donaldson LF, Harmar AJ, McQueen DS, Seckl JR (1992) Increased expression of preprotachykinin, calcitonin gene-related peptide, but not vasoactive intestinal peptide messenger RNA in dorsal root ganglia during the development of adjuvant monoarthritis in the rat. Molec Brain Res 16:143–149PubMedGoogle Scholar
  37. Dougherty PM, Willis WD (1991) Enhancement of spinothalamic neuron responses to chemical and mechanical stimuli following combined micro-iontophoretic application of N-methyl-D-aspartic acid and substance P. Pain 47:85–93PubMedGoogle Scholar
  38. Dougherty PM, Palecek J, Palecková V, Willis WD (1994) Neurokinin 1 and 2 antagonists attenuate the responses and NK1 antagonists prevent the sensitization of primate spinothalamic tract neurons after intradermal capsaicin. J Neurophysiol 72:1464–1475PubMedGoogle Scholar
  39. Duggan AW, Hendry IA, Morton CR, Hutchison WD, Zhao ZQ (1988) Cutaneous stimuli releasing immunoreactive substance P in the dorsal horn of the cat. Brain Res 451:261–273PubMedGoogle Scholar
  40. Duggan AW, Hope PJ, Jarrott B, Schaible HG, Fleetwood-Walker SM (1990) Release, spread and persistence of immunoreactive neurokinin A in the dorsal horn of the cat following noxious cutaneous stimulation. Studies with antibody microprobes. Neuroscience 35:195–202Google Scholar
  41. Duggan AW, Riley RC, Mark MA, MacMillan SJ, Schaible HG (1995) Afferent volley patterns and the spinal release of immunoreactive substance P in the dorsal horn of the anaesthetized spinal cat. Neuroscience 65:849–858PubMedGoogle Scholar
  42. Durham PL (2004) CGRP receptor antagonists: a new choice for acute treatment of migraine? Curr Opin Investig Drugs 5:731–735PubMedGoogle Scholar
  43. Edvinsson L (2005) Clinical data on the CGRP antagonist BIBN4096BS for treatment of migraine attacks. CNS Drug Rev 11:69–76PubMedGoogle Scholar
  44. Edvinsson L, Cantera L, Jansen-Olesen I, Uddman R (1997) Expression of calcitonin gene-related peptide1 receptor mRNA in human trigeminal ganglia and cerebral arteries. Neurosci Lett 229:209–211PubMedGoogle Scholar
  45. Esteban JA, Shi SH, Wilson C, Nuriya M, Huganir RL, Malinow R (2003) PKA phosphorylation of AMPA receptor subunits controls synaptic trafficking underlying plasticity. Nat Neurosci 6:136–143PubMedGoogle Scholar
  46. Evans BN, Rosenblatt MI, Mnayer LO, Oliver KR, Dickerson IM (2000) CGRP-RCP, a novel protein required for signal transduction at calcitonin gene-related peptide and adrenomedullin receptors. J Biol Chem 275:31438–31443PubMedGoogle Scholar
  47. Fang L, Wu J, Lin Q, Willis WD (2002) Calcium-calmodulin-dependent protein kinase II contributes to spinal cord central sensitization. J Neurosci 22:4196–204PubMedGoogle Scholar
  48. Fields RD, Eshete F, Stevens B, Itoh K (1997) Action potential-dependent regulation of gene expression: temporal specificity in Ca2+, cAMP-responsive element binding proteins, and mitogen-activated protein kinase signaling. J Neurosci 17:7252–7266PubMedGoogle Scholar
  49. Fleetwood-Walker SM, Mitchell R, Hope PJ, El-Yassir N, Molony V, Bladon CM (1990) The involvement of neurokinin receptor subtypes in somatosensory processing in the superficial dorsal horn of the cat. Brain Res 519:169–182. Erratum in: Brain Res (1992) 579:357PubMedGoogle Scholar
  50. Galeazza MT, O'Brien TD, Johnson KH, Seybold VS (1991) Islet amyloid polypeptide (IAPP) competes for two binding sites of CGRP. Peptides 12:585–491PubMedGoogle Scholar
  51. Galeazza MT, Stucky CL, Seybold VS (1992) Changes in [125I]hCGRP binding in rat spinal cord in an experimental model of acute, peripheral inflammation. Brain Res 591:198–208PubMedGoogle Scholar
  52. Galeazza MT, Garry MG, Yost HJ, Strait KA, Hargreaves KM, Seybold VS (1995) Plasticity in the synthesis and storage of substance P and calcitonin gene-related peptide in primary afferent neurons during peripheral inflammation. Neuroscience 66:443–458PubMedGoogle Scholar
  53. Gamse R, Saria A (1986) Nociceptive behavior after intrathecal injections of substance P, neurokinin A and calcitonin gene-related peptide in mice. Neurosci Lett 70:143–147PubMedGoogle Scholar
  54. Garry MG, Hargreaves KM (1992) Enhanced release of immunoreactive CGRP and substance P from spinal dorsal horn slices occurs during carrageenan inflammation. Brain Res 582:139–142PubMedGoogle Scholar
  55. Garry MG, Miller KE, Seybold VS (1989) Lumbar dorsal root ganglia of the cat: a quantitative study of peptide immunoreactivity and cell size. J Comp Neurol 284:36–47PubMedGoogle Scholar
  56. Gerard NP, Garraway LA, Eddy RL Jr, Shows TB, Iijima H, Paquet JL, Gerard C (1991) Human substance P receptor (NK-1): organization of the gene, chromosome localization, and functional expression of cDNA clones. Biochemistry 30:10640–10646PubMedGoogle Scholar
  57. Gerber G, Kangrga I, Ryu PD, Larew JS, Randic M (1989) Multiple effects of phorbol esters in the rat spinal dorsal horn. J Neurosci 9:3606–3617PubMedGoogle Scholar
  58. Graef IA, Mermelstein PG, Stankunas K, Neilson JR, Deisseroth K, Tsien RW, Crabtree GR (1999) L-type calcium channels and GSK-3 regulate the activity of NF-ATc4 in hippocampal neurons. Nature 401:703–708PubMedGoogle Scholar
  59. Graef IA, Chen F, Crabtree GR (2001) NFAT signaling in vertebrate development. Curr Opin Genet Dev 11:505–512PubMedGoogle Scholar
  60. Groth RD, Mermelstein PG (2003) Brain-derived neurotrophic factor activation of NFAT (nuclear factor of activated T cells)-dependent transcription: a role for the transcription factor NFATc4 in neurotrophin-mediated gene expression. J Neurosci 23:8125–8134PubMedGoogle Scholar
  61. Groth RD, Coicou LG, Mermelstein PG, Seybold VS (2007) Neurotrophin activation of NFAT-dependent transcription contributes to the regulation of pro-nociceptive genes. J Neurochem 102:1162–1174PubMedGoogle Scholar
  62. Gu XL, Yu LC (2007) The colocalization of CGRP receptor and AMPA receptor in the spinal dorsal horn neuron of rat: a morphological and electrophysiological study. Neurosci Lett 414:237–241PubMedGoogle Scholar
  63. Guo W, Zou S, Guan Y, Ikeda T, Tal M, Dubner R, Ren K (2002) Tyrosine phosphorylation of the NR2B subunit of the NMDA receptor in the spinal cord during the development and maintenance of inflammatory hyperalgesia. J Neurosci 22:6208–6217PubMedGoogle Scholar
  64. Henry JL (1976) Effects of substance P on functionally identified units in cat spinal cord. Brain Res 114:439–451PubMedGoogle Scholar
  65. Hershey AD, Dykema PE, Krause JE (1991) Organization, structure and expression of the gene encoding the rat substance P receptor. J Biol Chem 266:4366–4374PubMedGoogle Scholar
  66. Hill R (2000) NK1 (substance P) receptor antagonists – why are they not analgesic in humans? Trends Pharmacol Sci 21:244–246PubMedGoogle Scholar
  67. Hökfelt T, Ljungdahl A, Terenius L, Elde R, Nilsson G (1977) Immunohistochemical analysis of peptide pathways possibly related to pain and analgesia: enkephalin and substance P. Proc Natl Acad Sci USA 74:3081–3085PubMedGoogle Scholar
  68. Honore P, Menning PM, Rogers SD, Nichols ML, Basbaum AI, Besson JM, Mantyh PW (1999) Spinal substance P receptor expression and internalization in acute, short-term, and long-term inflammatory pain states. J Neurosci 19:7670–7678Google Scholar
  69. Hua XY, Chen P, Marsala M, Yaksh TL (1999) Intrathecal substance P-induced thermal hyperalgesia and spinal release of prostaglandin E2 and amino acids. Neuroscience 89:525–534PubMedGoogle Scholar
  70. Hunt SP, Kelly JS, Emson PC, Kimmel JR, Miller RJ, Wu JY (1981) An immunohistochemical study of neuronal populations containing neuropeptides or gamma-aminobutyrate within the superficial layers of the rat dorsal horn. Neuroscience 6:1883–1898PubMedGoogle Scholar
  71. Hunt SP, Pini A, Evan G (1987) Induction of c-fos-like protein in spinal cord neurons following sensory stimulation. Nature 328:632–634PubMedGoogle Scholar
  72. Hylden JL, Nahin RL, Traub RJ, Dubner R (1989) Expansion of receptive fields of spinal lamina I projection neurons in rats with unilateral adjuvant-induced inflammation: the contribution of dorsal horn mechanisms. Pain 37:229–243PubMedGoogle Scholar
  73. Iadarola MJ, Brady LS, Draisci G, Dubner R (1988) Enhancement of dynorphin gene expression in spinal cord following experimental inflammation: stimulus specificity, behavioral parameters and opioid receptor binding. Pain 35:313–326PubMedGoogle Scholar
  74. Inagaki S, Kito S, Kubota Y, Girgis S, Hillyard CJ, MacIntyre I (1986) Autoradiographic localization of calcitonin gene-related peptide binding sites in human and rat brains. Brain Res 374:287–298PubMedGoogle Scholar
  75. Inoue K, Nakazawa K, Inoue K, Fujimori K (1995) Nonselective cation channels coupled with tachykinin receptors in rat sensory neurons. J Neurophysiol 73:736–742PubMedGoogle Scholar
  76. Inoue T, Mashimo T, Shibuta S, Yoshiya I (1997) Intrathecal administration of a new nitric oxide donor, NOC-18, produces acute thermal hyperalgesia in the rat. J Neurol Sci 153:1–7PubMedGoogle Scholar
  77. Ji RR, Rupp F (1997) Phosphorylation of transcription factor CREB in rat spinal cord after formalin-induced hyperalgesia: relationship to c-fos induction. J Neurosci 17:1776–1785PubMedGoogle Scholar
  78. Ji RR, Baba H, Brenner GJ, Woolf CJ (1999) Nociceptive-specific activation of ERK in spinal neurons contributes to pain hypersensitivity. Nat Neurosci 2:1114–1119PubMedGoogle Scholar
  79. Ji RR, Kohno T, Moore KA, Woolf CJ (2003) Central sensitization and LTP: do pain and memory share similar mechanisms? Trends Neuro Sci 26:696–705Google Scholar
  80. Jia YP, Seybold VS (1997) Spinal NK2 receptors contribute to the increased excitability of the nociceptive flexor reflex during persistent peripheral inflammation. Brain Res 751:169–174PubMedGoogle Scholar
  81. Johansson O, Hökfelt T, Pernow B, Jeffcoate SL, White N, Steinbusch HW, Verhofstad AA, Emson PC, Spindel E (1981) Immunohistochemical support for three putative transmitters in one neuron: coexistence of 5-hydroxytryptamine, substance P- and thyrotropin releasing hormone-like immunoreactivity in medullary neurons projecting to the spinal cord. Neuroscience 6:1857–1881PubMedGoogle Scholar
  82. Juaneda C, Dumont Y, Quirion R (2000) The molecular pharmacology of CGRP and related peptide receptor subtypes. Trends Pharmacol Sci 21:432–438PubMedGoogle Scholar
  83. Jurna I, Spohrer B, Bock R (1992) Intrathecal injection of acetylsalicylic acid, salicylic acid and indomethacin depresses C fibre-evoked activity in the rat thalamus and spinal cord. Pain 49:249–256PubMedGoogle Scholar
  84. Kangrga I, Randic M (1990) Tachykinins and calcitonin gene-related peptide enhance release of endogenous glutamate and aspartate from the rat spinal dorsal horn slice. J Neurosci 10:2026–2038PubMedGoogle Scholar
  85. Kessler W, Kirchhoff C, Reeh PW, Handwerker HO (1992) Excitation of cutaneous afferent nerve endings in vitro by a combination of inflammatory mediators and conditioning effect of substance P. Exp Brain Res 91:467–476PubMedGoogle Scholar
  86. Khasabov SG, Rogers SD, Ghilardi JR, Peters CM, Mantyh PW, Simone DA (2002) Spinal neurons that possess the substance P receptor are required for the development of central sensitization. J Neurosci 22:9086–9098PubMedGoogle Scholar
  87. Kitto KF, Haley JE, Wilcox GL (1992) Involvement of nitric oxide in spinally mediated hyperalgesia in the mouse. Neurosci Lett 148:1–5PubMedGoogle Scholar
  88. Krause JE, Bu JY, Takeda Y, Blount P, Raddatz R, Sachais BS, Chou KB, Takeda J, McCarson K, DiMaggio D (1993) Structure, expression and second messenger-mediated regulation of the human and rat substance P receptors and their genes. Regul Pept 46:59–66PubMedGoogle Scholar
  89. Krause JE, Staveteig PT, Mentzer JN, Schmidt SK, Tucker JB, Brodbeck RM, Bu JY, Karpitskiy VV (1997) Functional expression of a novel human neurokinin-3 receptor homolog that binds [3H]senktide and [125I-MePhe7]neurokinin B, and is responsive to tachykinin peptide agonists. Proc Natl Acad Sci USA 94:310–315PubMedGoogle Scholar
  90. Kruger L, Mantyh PW, Sternini C, Brecha NC, Mantyh CR (1988) Calcitonin gene-related peptide (CGRP) in the rat central nervous system: patterns of immunoreactivity and receptor binding sites. Brain Res 463:223–244PubMedGoogle Scholar
  91. Laird J (2001) Gut feelings about tachykinins NK1 receptor antagonists. Trends Pharmacol Sci 22:169PubMedGoogle Scholar
  92. Laird JM, Hargreaves RJ, Hill RG (1993) Effect of RP 67580, a non-peptide neurokinin1 receptor antagonist, on facilitation of a nociceptive spinal flexion reflex in the rat. Br J Pharmacol 109:713–718PubMedGoogle Scholar
  93. Lam HH, Hanley DF, Trapp BD, Saito S, Raja S, Dawson TM, Yamaguchi H (1996) Induction of spinal cord neuronal nitric oxide synthase (NOS) after formalin injection in the rat hind paw. Neurosci Lett 210:201–204PubMedGoogle Scholar
  94. Larson AA (1988) Desensitization to intrathecal substance P in mice: possible involvement of opioids. Pain 32:367–374PubMedGoogle Scholar
  95. Lazar P, Reddington M, Streit W, Raivich G, Kreutzberg GW (1991) The action of calcitonin gene-related peptide on astrocyte morphology and cyclic AMP accumulation in astrocyte cultures from neonatal rat brain. Neurosci Lett 130:99–102PubMedGoogle Scholar
  96. Le Greves P, Nyberg F, Terenius L, Hökfelt T (1985) Calcitonin gene-related peptide is a potent inhibitor of substance P degradation. Eur J Pharmacol 115:309–311PubMedGoogle Scholar
  97. Lee SE, Kim JH (2007) Involvement of substance P and calcitonin gene-related peptide in development and maintenance of neuropathic pain from spinal nerve injury model of rat. Neurosci Res 58:245–249PubMedGoogle Scholar
  98. Lever IJ, Grant AD, Pezet S, Gerard NP, Brain SD, Malcangio M (2003) Basal and activity-induced release of substance P from primary afferent fibres in NK1 receptor knockout mice: evidence for negative feedback. Neuropharmacology 45:1101–1110PubMedGoogle Scholar
  99. Li HS, Zhao ZQ (1998) Small sensory neurons in the rat dorsal root ganglia express functional NK-1 tachykinin receptor. Eur J Neurosci 10:1292–1299PubMedGoogle Scholar
  100. Light AR, Perl ER (1979) Spinal termination of functionally identified primary afferent neurons with slowly conducting myelinated fibers. J Comp Neurol 186:133–150PubMedGoogle Scholar
  101. Linden DR, Seybold VS (1999) Spinal neurokinin3 receptors mediate thermal but not mechanical hyperalgesia via nitric oxide. Pain 80:309–317PubMedGoogle Scholar
  102. Linden DR, Jia YP, Seybold VS (1999) Spinal neurokin3 receptors facilitate the nociceptive flexor reflex via a pathway involving nitric oxide. Pain 80:301–308PubMedGoogle Scholar
  103. Linden DR, Chell MJ, El-Fakahany EE, Seybold VS (2000a) Neurokinin(3) receptors couple to the activation of neuronal nitric-oxide synthase in stably transfected Chinese hamster ovary cells. J Pharmacol Exp Ther 293:559–568PubMedGoogle Scholar
  104. Linden DR, Reutter MA, McCarson KE, Seybold VS (2000b) Time-dependent changes in neurokinin(3) receptors and tachykinins during adjuvant-induced peripheral inflammation in the rat. Neuroscience 98:801–811PubMedGoogle Scholar
  105. Liu X, Sandkuhler J (1997) Characterization of long-term potentiation of C-fiber-evoked potentials in spinal dorsal horn of adult rat: essential role of NK1 and NK2 receptors. J Neurophysiol 78:1973–1982PubMedGoogle Scholar
  106. Liu H, Brown JL, Jasmin L, Maggio JE, Vigna SR, Mantyh PW, Basbaum AI (1994) Synaptic relationship between substance P and the substance P receptor: light and electron microscopic characterization of the mismatch between neuropeptides and their receptors. Proc Natl Acad Sci USA 91:1009–1013PubMedGoogle Scholar
  107. Liu JY, Hu JH, Zhu QG, Li FQ, Sun HJ (2006) Substance P receptor expression in human skin keratinocytes and fibroblasts. Br J Dermatol 155:657–662PubMedGoogle Scholar
  108. Lofgren O, Yu LC, Theodorsson E, Hansson P, Lundeberg T (1997) Intrathecal CGRP(8–37) results in a bilateral increase in hindpaw withdrawal latency in rats with a unilateral thermal injury. Neuropeptides 31:601–607PubMedGoogle Scholar
  109. Lonze BE, Ginty DD (2002) Function and regulation of CREB family transcription factors in the nervous system. Neuron 35:605–623PubMedGoogle Scholar
  110. Lundberg JM, Rudehill A, Sollevi A, Fried G, Wallin G (1989) Co-release of neuropeptide Y and noradrenaline from pig spleen in vivo: importance of subcellular storage, nerve impulse frequency and pattern, feedback regulation and resupply by axonal transport. Neuroscience. 28:475–486PubMedGoogle Scholar
  111. Ma W, Chabot JG, Powell KJ, Jhamandas K, Dickerson IM, Quirion R (2003) Localization and modulation of calcitonin gene-related peptide-receptor component protein-immunoreactive cells in the rat central and peripheral nervous systems. Neuroscience 120:677–694PubMedGoogle Scholar
  112. Ma W, Quirion R (2001) Increased phosphorylation of cyclic AMP response element-binding protein (CREB) in the superficial dorsal horn neurons following partial sciatic nerve ligation. Pain 93:295–301PubMedGoogle Scholar
  113. Malmberg AB, Yaksh TL (1992a) Hyperalgesia mediated by spinal glutamate or substance P receptor blocked by spinal cyclooxygenase inhibition. Science 257:1276–1279PubMedGoogle Scholar
  114. Malmberg AB, Yaksh TL (1992b) Antinociceptive actions of spinal nonsteroidal anti-inflammatory agents on the formalin test in the rat. J Pharmacol Exp Ther 263:136–146PubMedGoogle Scholar
  115. Malmberg AB, Yaksh TL (1993) Spinal nitric oxide synthesis inhibition blocks NMDA-induced thermal hyperalgesia and produces antinociception in the formalin test in rats. Pain 54:291–300PubMedGoogle Scholar
  116. Malmberg AB, Yaksh TL (1995) Cyclooxygenase inhibition and the spinal release of prostaglandin E2 and amino acids evoked by paw formalin injection: a microdialysis study in unanesthetized rats. J Neurosci 15:2768–2776PubMedGoogle Scholar
  117. Mantyh PW, Gates T, Mantyh CR, Maggio JE (1989) Autoradiographic localization and characterization of tachykinin receptor binding sites in the rat brain and peripheral tissues. J Neurosci 9:258–279PubMedGoogle Scholar
  118. Mantyh PW, Rogers SD, Honore P, Allen BJ, Ghilardi JR, Li J, Daughters RS, Lappi DA, Wiley RG, Simone DA (1997) Inhibition of hyperalgesia by ablation of lamina I spinal neurons expressing the substance P receptor. Science 278:275–279PubMedGoogle Scholar
  119. Mao J, Coghill RC, Kellstein DE, Frenk H, Mayer DJ (1992) Calcitonin gene-related peptide enhances substance P-induced behaviors via metabolic inhibition: in vivo evidence for a new mechanism of neuromodulation. Brain Res 574:157–163PubMedGoogle Scholar
  120. Marksteiner J, Sperk G, Krause JE (1992) Distribution of neurons expressing neurokinin B in the rat brain: immunohistochemistry and in situ hybridization. J Comp Neurol 317:341–356PubMedGoogle Scholar
  121. Matsumura K, Watanabe Y, Imai-Matsumura K, Connolly M, Koyama Y, Onoe H, Watanabe Y (1992) Mapping of prostaglandin E2 binding sites in rat brain using quantitative autoradiography. Brain Res 581:292–298PubMedGoogle Scholar
  122. Matsumura K, Watanabe Y, Onoe H, Watanabe Y (1995) Prostacyclin receptor in the brain and central terminals of the primary sensory neurons: an autoradiographic study using a stable prostacyclin analogue [3H]iloprost. Neuroscience 65:493–503PubMedGoogle Scholar
  123. Mayer ML, Westbrook GL, Guthrie PB (1984) Voltage-dependent block by Mg2+ of NMDA responses in spinal cord neurones. Nature 309:261–263PubMedGoogle Scholar
  124. McCarson KE (1999) Central and peripheral expression of neurokinin-1 and neurokinin-3 receptor and substance P-encoding messenger RNAs: peripheral regulation during formalin-induced inflammation and lack of neurokinin receptor expression in primary afferent sensory neurons. Neuroscience 93:361–370PubMedGoogle Scholar
  125. McCarson KE, Krause JE (1994) NK-1 and NK-3 type tachykinin receptor mRNA expression in the rat spinal cord dorsal horn is increased during adjuvant or formalin-induced nociception. J Neurosci 1994 14:712–720Google Scholar
  126. McCarthy PW, Lawson SN (1989) Cell type and conduction velocity of rat primary sensory neurons with substance P-like immunoreactivity. Neuroscience 28:745–753PubMedGoogle Scholar
  127. McCarthy PW, Lawson SN (1990) Cell type and conduction velocity of rat primary sensory neurons with calcitonin gene-related peptide-like immunoreactivity. Neuroscience 34:623–632PubMedGoogle Scholar
  128. McLatchie LM, Fraser NJ, Main MJ, Wise A, Brown J, Thompson N, Solari R, Lee MG, Foord SM (1998) RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor. Nature 393:333–339PubMedGoogle Scholar
  129. Meller ST, Gebhart GF (1994) Spinal mediators of hyperalgesia. Drugs 47:10–20PubMedGoogle Scholar
  130. Mermelstein PG, Bito H, Deisseroth K, Tsien RW (2000) Critical dependence of cAMP response element-binding protein phosphorylation on L-type calcium channels supports a selective response to EPSPs in preference to action potentials. J Neurosci 20:266–273PubMedGoogle Scholar
  131. Messersmith DJ, Kim DJ, Iadarola MJ (1998) Transcription factor regulation of prodynorphin gene expression following rat hindpaw inflammation. Mol Brain Res 53:260–269PubMedGoogle Scholar
  132. Miletic G, Pankratz MT, Miletic V (2002) Increases in the phosphorylation of cyclic AMP response element binding protein (CREB) and decreases in the content of calcineurin accompany thermal hyperalgesia following chronic constriction injury in rats. Pain 99:493–500PubMedGoogle Scholar
  133. Minami T, Nishihara I, Uda R, Ito S, Hyodo M, Hayaishi O (1994a) Involvement of glutamate receptors in allodynia induced by prostaglandins E2 and F2 alpha injected into conscious mice. Pain 57:225–231PubMedGoogle Scholar
  134. Minami T, Uda R, Horiguchi S, Ito S, Hyodo M, Hayaishi O (1994b) Allodynia evoked by intrathecal administration of prostaglandin E2 to conscious mice. Pain 57:217–223PubMedGoogle Scholar
  135. Moochhala SM, Sawynok J (1984) Hyperalgesia produced by intrathecal substance P and related peptides: desensitization and cross desensitization. Br J Pharmacol 82:381–388PubMedGoogle Scholar
  136. Moreno MJ, Cohen Z, Stanimirovic DB, Hamel E (1999) Functional calcitonin gene-related peptide type 1 and adrenomedullin receptors in human trigeminal ganglia, brain vessels, and cerebromicrovascular or astroglial cells in culture. J Cereb Blood Flow Metab 19:1270–1278PubMedGoogle Scholar
  137. Moreno MJ, Terrón JA, Stanimirovic DB, Doods H, Hamel E (2002) Characterization of calcitonin gene-related peptide (CGRP) receptors and their receptor-activity-modifying proteins (RAMPs) in human brain microvascular and astroglial cells in culture. Neuropharmacology 42:270–280PubMedGoogle Scholar
  138. Moriyoshi K, Masu M, Ishii T, Shigemoto R, Mizuno N, Nakanishi S (1991) Molecular cloning and characterization of the rat NMDA receptor. Nature 354:31–37PubMedGoogle Scholar
  139. Morrison CF, McAllister J, Dobson SP, Mulderry PK, Quinn JP (1994) An activator element within the preprotachykinin-A promoter. Mol Cell Neurosci 5:165–175PubMedGoogle Scholar
  140. Morton CR, Hutchison WD (1989) Release of sensory neuropeptides in the spinal cord: studies with calcitonin gene-related peptide and galanin. Neuroscience 31:807–815PubMedGoogle Scholar
  141. Mulderry PK Ghatei MA, Spokes RA, Jones PM, Pierson AM, Hamid QA, Kanse S, Amara SG, Burrin JM, Legon S et al (1988) Differential expression of alpha-CGRP and beta-CGRP by primary sensory neurons and enteric autonomic neurons of the rat. Neuroscience 25:195–205Google Scholar
  142. Munro FE, Fleetwood-Walker SM, Parker RM, Mitchell R (1993) The effects of neurokinin receptor antagonists on mustard oil-evoked activation of rat dorsal horn neurons. Neuropeptides 25:299–305PubMedGoogle Scholar
  143. Murase K, Ryu PD, Randic M (1989) Excitatory and inhibitory amino acids and peptide-induced responses in acutely isolated rat spinal dorsal horn neurons. Neurosci Lett 103:56–63PubMedGoogle Scholar
  144. Nakajima Y, Tsuchida K, Negishi M, Ito S, Nakanishi S (1992) Direct linkage of three tachykinin receptors to stimulation of both phosphatidylinositol hydrolysis and cyclic AMP cascades in transfected Chinese hamster ovary cells. J Biol Chem. 267:2437–2442PubMedGoogle Scholar
  145. Neugebauer V, Schaible HG (1990) Evidence for a central component in the sensitization of spinal neurons with joint input during development of acute arthritis in cat's knee. J Neurophysiol 64:299–311PubMedGoogle Scholar
  146. Neugebauer V, Rumenapp P, Schaible HG (1996) The role of spinal neurokinin-2 receptors in the processing of nociceptive information from the joint and in the generation and maintenance of inflammation-evoked hyperexcitability of dorsal horn neurons in the rat. Eur J Neurosci 8:249–260PubMedGoogle Scholar
  147. Noguchi K, Senba E, Morita Y, Sato M, Tohyama M (1990) Co-expression of alpha-CGRP and beta-CGRP mRNAs in the rat dorsal root ganglion cells. Neurosci Lett 108:1–5PubMedGoogle Scholar
  148. O'Brien C, Woolf CJ, Fitzgerald M, Lindsay RM, Molander C (1989) Differences in the chemical expression of rat primary afferent neurons which innervate skin, muscle or joint. Neuroscience 32:493–502PubMedGoogle Scholar
  149. Ogawa T, Kanazawa I, Kimura S (1985) Regional distribution of substance P, neurokinin alpha and neurokinin beta in rat spinal cord, nerve roots and dorsal root ganglia, and the effects of dorsal root section or spinal transection. Brain Res 359:152–157PubMedGoogle Scholar
  150. Oku R, Satoh M, Fujii N, Otaka A, Yajima H, Takagi H (1987) Calcitonin gene-related peptide promotes mechanical nociception by potentiating release of substance P from the spinal dorsal horn in rats. Brain Res 403:350–354PubMedGoogle Scholar
  151. Oliver KR, Kane SA, Salvatore CA, Mallee JJ, Kinsey AM, Koblan KS, Keyvan-Fouladi N, Heavens RP, Wainwright A, Jacobson M, Dickerson IM, Hill RG (2001) Cloning, characterization and central nervous system distribution of receptor activity modifying proteins in the rat. Eur J Neurosci 14:618–628PubMedGoogle Scholar
  152. Ouyang K, Zheng H, Qin X, Zhang C, Yang D, Wang X, Wu C, Zhou Z, Cheng H (2005) Ca2+ sparks and secretion in dorsal root ganglion neurons. Proc Natl Acad Sci USA 102:12259–12264PubMedGoogle Scholar
  153. Park YH, Shin CY, Lee TS, Huh IH, Sohn UD (2000) The role of nitric oxide and prostaglandin E2 on the hyperalgesia induced by excitatory amino acids in rats. J Pharm Pharmacol 52:431–436PubMedGoogle Scholar
  154. Parsons AM, Seybold VS (1997) Calcitonin gene-related peptide induces the formation of second messengers in primary cultures of neonatal rat spinal cord. Synapse 26:235–242PubMedGoogle Scholar
  155. Parsons AM, el-Fakahany EE, Seybold VS (1995) Tachykinins alter inositol phosphate formation, but not cyclic AMP levels, in primary cultures of neonatal rat spinal neurons through activation of neurokinin receptors. Neuroscience 68:855–865PubMedGoogle Scholar
  156. Parsons AM, Honda CN, Jia YP, Budai D, Xu XJ, Wiesenfeld-Hallin Z, Seybold VS (1996) Spinal NK1 receptors contribute to the increased excitability of the nociceptive flexor reflex during persistent peripheral inflammation. Brain Res 739:263–275PubMedGoogle Scholar
  157. Perry MJ, Lawson SN (1998) Differences in expression of oligosaccharides, neuropeptides, carbonic anhydrase and neurofilament in rat primary afferent neurons retrogradely labelled via skin, muscle or visceral nerves. Neuroscience 85:293–310PubMedGoogle Scholar
  158. Picard P, Boucher S, Regoli D, Gitter BD, Howbert JJ, Couture R (1993) Use of non-peptide tachykinin receptor antagonists to substantiate the involvement of NK1 and NK2 receptors in a spinal nociceptive reflex in the rat. Eur J Pharmacol 232:255–261PubMedGoogle Scholar
  159. Pitcher GM, Henry JL (1999) Mediation and modulation by eicosanoids of responses of spinal dorsal horn neurons to glutamate and substance P receptor agonists: results with indomethacin in the rat in vivo. Neuroscience 93:1109–1121PubMedGoogle Scholar
  160. Pitcher GM, Henry JL (2001) Meloxicam selectively depresses the afterdischarge of rat spinal dorsal horn neurones in response to noxious stimulation. Neurosci Lett 305:45–48PubMedGoogle Scholar
  161. Pokabla MJ, Dickerson IM, Papka RE (2002) Calcitonin gene-related peptide-receptor component protein expression in the uterine cervix, lumbosacral spinal cord, and dorsal root ganglia. Peptides 23:507–514PubMedGoogle Scholar
  162. Poyner D (1995) Pharmacology of receptors for calcitonin gene-related peptide and amylin. Trends Pharmacol Sci 16:424–428PubMedGoogle Scholar
  163. Quartu M, Floris A, Del Fiacco M (1990) Substance P- and calcitonin gene-related peptide-like immunoreactive pericellular baskets in human trigeminal ganglion. Basic Appl Histochem 34:177–181PubMedGoogle Scholar
  164. Randic M, Miletic V (1977) Effects of substance P in cat dorsal horn neurons activated by noxious stimuli. Brain Res 128:164–169PubMedGoogle Scholar
  165. Randić M, Urbán L (1987) Slow excitatory transmission in rat spinal dorsal horn and the effects of capsaicin. Acta Physiol Hung 69:375–392PubMedGoogle Scholar
  166. Randic M, Hecimovic H, Ryu PD (1990) Substance P modulates glutamate-induced currents in acutely isolated rat spinal dorsal horn neurones. Neurosci Lett 117:74–80PubMedGoogle Scholar
  167. Rao A, Luo C, Hogan PG (1997) Transcription factors of the NFAT family: regulation and function. Annu Rev Immunol 15:707–747PubMedGoogle Scholar
  168. Ren K, Iadarola MJ, Dubner R (1996) An isobolographic analysis of the effects of N-methyl-d-aspartate and NK1 tachykinin receptor antagonists on inflammatory hyperalgesia in the rat. Br J Pharmacol 117:196–202PubMedGoogle Scholar
  169. Rojas A, Su J, Yang L, Lee M, Cui N, Zhang X, Fountain D, Jiang C (2008) Modulation of the heteromeric Kir4.1–Kir5.1 channel by multiple neurotransmitters via Galphaq-coupled receptors. J Cell Physiol 214:84–95PubMedGoogle Scholar
  170. Rosenfeld MG, Mermod JJ, Amara SG, Swanson LW, Sawchenko PE, Rivier J, Vale WW, Evans RM (1983) Production of a novel neuropeptide encoded by the calcitonin gene via tissue-specific RNA processing. Nature 304:129–135PubMedGoogle Scholar
  171. Ruda MA, Iadarola MJ, Cohen LV, Young WS 3rd (1988) In situ hybridization histochemistry and immunohistochemistry reveal an increase in spinal dynorphin biosynthesis in rat model of peripheral inflammation and hyperalgesia. Proc Natl Acad Sci USA 85:622–626PubMedGoogle Scholar
  172. Rusin KI, Ryu PD, Randic M (1992) Modulation of excitatory amino acid responses in rat dorsal horn neurons by tachykinins. J Neurophysiol 68:265–286PubMedGoogle Scholar
  173. Rusin KI, Bleakman D, Chard PS, Randic M, Miller RJ (1993) Tachykinins potentiate N-methyl-d-aspartate responses in acutely isolated neurons from the dorsal horn. J Neurochem 60: 952–960PubMedGoogle Scholar
  174. Ryu PD, Gerber G, Murase K, Randic M (1988a) Calcitonin gene-related peptide enhances calcium current of rat dorsal root ganglion neurons and spinal excitatory synaptic transmission. Neurosci Lett 89:305–312PubMedGoogle Scholar
  175. Ryu PD, Gerber G, Murase K, Randic M (1988b) Actions of calcitonin gene-related peptide on rat spinal dorsal horn neurons. Brain Res 441:357–361PubMedGoogle Scholar
  176. Salmon AM, Damaj I, Sekine S, Picciotto MR, Marubio L, Changeux JP (1999) Modulation of morphine analgesia in alphaCGRP mutant mice. Neuroreport 10:849–854PubMedGoogle Scholar
  177. Samad TA, Moore KA, Sapirstein A, Billet S, Allchorne A, Poole S, Bonventre JV, Woolf CJ (2001) Interleukin-1 beta-mediated induction of Cox-2 in the CNS contributes to inflammatory pain hypersensitivity. Nature 410:471–475PubMedGoogle Scholar
  178. Schaible HG, Jarrott B, Hope PJ, Duggan AW (1990) Release of immunoreactive substance P in the spinal cord during development of acute arthritis in the knee joint of the cat: a study with antibody microprobes. Brain Res 529:214–223PubMedGoogle Scholar
  179. Schaible HG, Hope PJ, Lang CW, Duggan AW (1992) Calcitonin gene-related peptide causes intraspinal spreading of substance P released by peripheral stimulation. Eur J Neurosci 4:750–757PubMedGoogle Scholar
  180. Schaible HG, Freudenberger U, Neugebauer V, Stiller RU (1994) Intraspinal release of immunoreactive calcitonin gene-related peptide during development of inflammation in the joint in vivo – a study with antibody microprobes in cat and rat. Neuroscience 62:1293–1305PubMedGoogle Scholar
  181. Sculptoreanu A, de Groat WC (2007) Neurokinins enhance excitability in capsaicin-responsive DRG neurons. Exp Neurol 205:92–100PubMedGoogle Scholar
  182. Segond von Banchet G, Pastor A, Biskup C, Schlegel C, Benndorf K, Schaible HG (2002) Localization of functional calcitonin gene-related peptide binding sites in a subpopulation of cultured dorsal root ganglion neurons. Neuroscience 110:131–145PubMedGoogle Scholar
  183. Seibert K, Zhang Y, Leahy K, Hauser S, Masferrer J, Perkins W, Lee L, Isakson P (1994) Pharmacological and biochemical demonstration of the role of cyclooxygenase 2 in inflammation and pain. Proc Natl Acad Sci USA 91:12013–12017PubMedGoogle Scholar
  184. Seybold VS, Abrahams LG (1995) Characterization and regulation of neurokinin1 receptors in primary cultures of rat neonatal spinal neurons. Neuroscience 69:1263–1273PubMedGoogle Scholar
  185. Seybold V, Elde R (1980) Immunohistochemical studies of peptidergic neurons in the dorsal horn of the spinal cord. J Histochem Cytochem 28:367–370PubMedGoogle Scholar
  186. Seybold VS, Hylden JLK, Wilcox GL (1982) Intrathecal substance P and somatostatin in rats: Behaviors indicative of sensation. Peptides 3:49–54PubMedGoogle Scholar
  187. Seybold VS, Grkovic I, Portbury AL, Ding YQ, Shigemoto R, Mizuno N, Furness JB, Southwell BR (1997) Relationship of NK3 receptor-immunoreactivity to subpopulations of neurons in rat spinal cord. J Comp Neurol 381:439–448PubMedGoogle Scholar
  188. Seybold VS, Jia YP, Abrahams LG (2003a) Cyclo-oxygenase-2 contributes to central sensitization in rats with peripheral inflammation. Pain 105:47–55PubMedGoogle Scholar
  189. Seybold VS, McCarson KE, Mermelstein PG, Groth RD, Abrahams LG (2003b) Calcitonin gene-related peptide regulates expression of neurokinin1 receptors by rat spinal neurons. J Neurosci 23:1816–1824PubMedGoogle Scholar
  190. Seybold VS, Coicou LG, Groth RD, Mermelstein PG (2006) Substance P initiates NFAT-dependent gene expression in spinal neurons. J Neurochem 97:397–407PubMedGoogle Scholar
  191. Shaywitz AJ, Greenberg ME (1999) CREB: a stimulus-induced transcription factor activated by a diverse array of extracellular signals. Annu Rev Biochem 68:821–861PubMedGoogle Scholar
  192. Shieh PB, Hu SC, Bobb K, Timmusk T, Ghosh A (1998) Identification of a signaling pathway involved in calcium regulation of BDNF expression. Neuron 20:727–740PubMedGoogle Scholar
  193. Shinder V, Devor M (1994) Structural basis of neuron-to-neuron cross-excitation in dorsal root ganglia. J Neurocytol 23:515–531PubMedGoogle Scholar
  194. Sluka KA, Milton MA, Willis WD, Westlund KN (1997) Differential roles of neurokinin 1 and neurokinin 2 receptors in the development and maintenance of heat hyperalgesia induced by acute inflammation. Br J Pharmacol 120:1263–1273PubMedGoogle Scholar
  195. Sorkin LS, Moore JH (1996) Evoked release of amino acids and prostanoids in spinal cords of anesthetized rats: changes during peripheral inflammation and hyperalgesia. Am J Ther 3:268–275PubMedGoogle Scholar
  196. Southwell BR, Woodman HL, Murphy R, Royal SJ, Furness JB (1996) Characterisation of substance P-induced endocytosis of NK1 receptors on enteric neurons. Histochem Cell Biol 106:563–571PubMedGoogle Scholar
  197. Southwell BR, Seybold VS, Woodman HL, Jenkinson KM, Furness JB (1998) Quantitation of neurokinin 1 receptor internalization and recycling in guinea-pig myenteric neurons. Neuroscience 87:925–931PubMedGoogle Scholar
  198. Spike RC, Puskár Z, Andrew D, Todd AJ (2003) A quantitative and morphological study of projection neurons in lamina I of the rat lumbar spinal cord. Eur J Neurosci 18:2433–2448PubMedGoogle Scholar
  199. Strack S, Wadzinski BE, Ebner FF (1996) Localization of the calcium/calmodulin-dependent protein phosphatase, calcineurin, in the hindbrain and spinal cord of the rat. J Comp Neurol 375:66–76PubMedGoogle Scholar
  200. Stucky CL, Galeazza MT, Seybold VS (1993) Time-dependent changes in Bolton-Hunter-labeled 125I-substance P binding in rat spinal cord following unilateral adjuvant-induced peripheral inflammation. Neuroscience 57:397–409PubMedGoogle Scholar
  201. Sugiura Y, Lee CL, Perl ER (1986) Central projections of identified, unmyelinated (C) afferent fibers innervating mammalian skin. Science 234:358–361PubMedGoogle Scholar
  202. Sun RQ, Lawand NB, Willis WD (2003) The role of calcitonin gene-related peptide (CGRP) in the generation and maintenance of mechanical allodynia and hyperalgesia in rats after intradermal injection of capsaicin. Pain 104:201–208PubMedGoogle Scholar
  203. Sun RQ, Tu YJ, Lawand NB, Yan JY, Lin Q, Willis WD (2004) Calcitonin gene-related peptide receptor activation produces PKA- and PKC-dependent mechanical hyperalgesia and central sensitization. J Neurophysiol 92:2859–2866PubMedGoogle Scholar
  204. Svensson CI, Hua XY, Protter AA, Powell HC, Yaksh TL (2003) Spinal p38 MAP kinase is necessary for NMDA-induced spinal PGE(2) release and thermal hyperalgesia. Neuroreport 14:1153–1157PubMedGoogle Scholar
  205. Sweeney MI, Sawynok J (1986) Evidence that substance P may be a modulator rather than a transmitter of noxious mechanical stimulation. Can J Physiol Pharmacol 64:1324–1327PubMedGoogle Scholar
  206. Taiwo YO, Levine JD (1986) Indomethacin blocks central nociceptive effects of PGF2 alpha. Brain Res 373:81–84PubMedGoogle Scholar
  207. Takano K, Yasufuku-Takano J, Kozasa T, Singer WD, Nakajima S, Nakajima Y (1996) Gq/11 and PLC-beta 1 mediate the substance P-induced inhibition of an inward rectifier K+ channel in brain neurons. J Neurophysiol 76:2131–2136PubMedGoogle Scholar
  208. Takeda Y, Krause JE (1991) Pharmacological and molecular biological studies on the diversity of rat tachykinin NK-2 receptor subtypes in rat CNS, duodenum, vas deferens, and urinary bladder. Ann N Y Acad Sci 632:479–482PubMedGoogle Scholar
  209. Takeda Y, Blount P, Sachais BS, Hershey AD, Raddatz R, Krause JE (1992) Ligand binding kinetics of substance P and neurokinin A receptors stably expressed in Chinese hamster ovary cells and evidence for differential stimulation of inositol 1,4,5-trisphosphate and cyclic AMP second messenger responses. J Neurochem 59:740–745PubMedGoogle Scholar
  210. Tao X, Finkbeiner S, Arnold DB, Shaywitz AJ, Greenberg ME (1998) Ca2+ influx regulates BDNF transcription by a CREB family transcription factor-dependent mechanism. Neuron 20:709–726PubMedGoogle Scholar
  211. Todd AJ, Puskar Z, Spike RC, Hughes C, Watt C, Forrest L (2002) Projection neurons in lamina I of rat spinal cord with the neurokinin 1 receptor are selectively innervated by substance p-containing afferents and respond to noxious stimulation. J Neurosci 22:4103–4113PubMedGoogle Scholar
  212. Trafton JA, Abbadie C, Basbaum AI (2001) Differential contribution of substance P and neurokinin A to spinal cord neurokinin-1 receptor signaling in the rat. J Neurosci 21:3656–3664PubMedGoogle Scholar
  213. Tschopp FA, Tobler PH, Fischer JA (1985) Calcitonin gene-related peptide and its binding sites in the human central nervous system and pituitary. Proc Natl Acad Sci USA 82:248–252PubMedGoogle Scholar
  214. Tsuchida K, Shigemoto R, Yokota Y, Nakanishi S (1990) Tissue distribution and quantitation of the mRNAs for three rat tachykinin receptors. Eur J Biochem 193:751–757PubMedGoogle Scholar
  215. Tuchscherer MM, Seybold VS (1989) A quantitative study of the coexistence of peptides in varicosities within the superficial laminae of the dorsal horn of the rat spinal cord. J Neurosci 9:195–205PubMedGoogle Scholar
  216. Tzabazis AZ, Pirc G, Votta-Velis E, Wilson SP, Laurito CE, Yeomans DC (2007) Antihyperalgesic effect of a recombinant herpes virus encoding antisense for calcitonin gene-related peptide. Anesthesiology 106:1079–1080Google Scholar
  217. Uda R, Horiguchi S, Ito S, Hyodo M, Hayaishi O (1990) Nociceptive effects induced by intrathecal administration of prostaglandin D2, E2, or F to conscious mice. Brain Res 510:26–32PubMedGoogle Scholar
  218. Ulrich-Lai YM, Flores CM, Harding-Rose CA, Goodis HE, Hargreaves KM (2001) Capsaicin-evoked release of immunoreactive calcitonin gene-related peptide from rat trigeminal ganglion: evidence for intraganglionic neurotransmission. Pain 91:219–226PubMedGoogle Scholar
  219. Urban AL and Fox AJ (2000) NK1 receptor antagonists – are they really without effect in the pain clinic? Trends Pharmacol Sci 12:462–464Google Scholar
  220. Urban L, Thompson SWN, Dray A (1994) Modulation of spinal excitability: co-operation between neurokinin and excitatory amino acid neurotransmitters. Trends Neurosci 17:432–438PubMedGoogle Scholar
  221. Vasko MR, Campbell WB, Waite KJ (1994) Prostaglandin E2 enhances bradykinin-stimulated release of neuropeptides from rat sensory neurons in culture. J Neurosci 14:4987–4997PubMedGoogle Scholar
  222. Verhage M, McMahon HT, Ghijsen WE, Boomsma F, Scholten G, Wiegant VM, Nicholls DG (1991) Differential release of amino acids, neuropeptides, and catecholamines from isolated nerve terminals. Neuron 6:517–524PubMedGoogle Scholar
  223. Villar MJ, Cortés R, Theodorsson E, Wiesenfeld-Hallin Z, Schalling M, Fahrenkrug J, Emson PC, Hökfelt T (1989) Neuropeptide expression in rat dorsal root ganglion cells and spinal cord after peripheral nerve injury with special reference to galanin. Neuroscience 33:587–604PubMedGoogle Scholar
  224. Wall PD, Woolf CJ (1984) Muscle but not cutaneous C-afferent input produces prolonged increases in the excitability of the flexion reflex in the rat. J Physiol 356:443–458PubMedGoogle Scholar
  225. Warden MK, Young WS 3rd (1988) Distribution of cells containing mRNAs encoding substance P and neurokinin B in the rat central nervous system. J Comp Neurol 272:90–113PubMedGoogle Scholar
  226. Watling KJ, Guard S, Krause JE, Takeda Y, Quirion R, Zarnegar R, Pain D, Franks R (1993) On the presence of NK2 receptor subtypes in peripheral and central tissues. Regul Pept 46:311–313PubMedGoogle Scholar
  227. Watson A, Latchman D (1995) The cyclic AMP response element in the calcitonin/calcitonin gene-related peptide gene promoter is necessary but not sufficient for its activation by nerve growth factor. J Biol Chem 270:9655–9660PubMedGoogle Scholar
  228. Wiesenfeld-Hallin Z, Hokflet T, Lundberg JM, Forssmann WG, Reinecke M, Tschopp FA, Fischer JA (1984) Immunoreactive calcitonin gene-related peptide and substance P coexist in sensory neurons to the spinal cord and interact in spinal behavioral responses of the rat. Neurosci Lett 52:199–204PubMedGoogle Scholar
  229. Womack MD, MacDermott AB, Jessell TM (1988) Sensory transmitters regulate intracellular calcium in dorsal horn neurons. Nature 334:351–353. Erratum in: Nature (1988) 335:744Google Scholar
  230. Woolf CJ, King AE (1990) Dynamic alterations in the cutaneous mechanoreceptive fields of dorsal horn neurons in the rat spinal cord. J Neurosci 10:2717–2726PubMedGoogle Scholar
  231. Wright DM, Roberts MH (1980) Responses of spinal neurones to a substance P analogue, noxious pinch and bradykinin. Eur J Pharmacol 64:165–167PubMedGoogle Scholar
  232. Yaksh TL, Jessell TM, Gamse R, Mudge AW, Leeman SE (1980) Intrathecal morphine inhibits substance P release from mammalian spinal cord in vivo. Nature 286:155–157PubMedGoogle Scholar
  233. Yaksh TL, Dirig DM, Conway CM, Svensson C, Luo ZD, Isakson PC (2001) The acute antihyperalgesic action of nonsteroidal, anti-inflammatory drugs and release of spinal prostaglandin E2 is mediated by the inhibition of constitutive spinal cyclooxygenase-2 (COX-2) but not COX-1. J Neurosci 21:5847–5853PubMedGoogle Scholar
  234. Yamamoto T, Sakashita Y (1998) COX-2 inhibitor prevents the development of hyperalgesia induced by intrathecal NMDA or AMPA. Neuroreport 9:3869–3873PubMedGoogle Scholar
  235. Yamamoto T, Yaksh TL (1991) Stereospecific effects of a nonpeptidic NK1 selective antagonist, CP-96,345: antinociception in the absence of motor dysfunction. Life Sci 49:1955–1963PubMedGoogle Scholar
  236. Yashpal K, Dam TV, Quirion R (1990) Quantitative autoradiographic distribution of multiple neurokinin binding sites in rat spinal cord. Brain Res 506:259–266PubMedGoogle Scholar
  237. Yashpal K, Dam TV, Quirion R (1991) Effects of dorsal rhizotomy on neurokinin receptor sub-types in the rat spinal cord: a quantitative autoradiographic study. Brain Res 552:240–247PubMedGoogle Scholar
  238. Yashpal K, Radhakrishnan V, Coderre TJ, Henry JL (1993) CP-96,345, but not its stereoisomer, CP-96,344, blocks the nociceptive responses to intrathecally administered substance P and to noxious thermal and chemical stimuli in the rat. Neuroscience 52:1039–1047PubMedGoogle Scholar
  239. Zaratin P, Angelici O, Clarke GD, Schmid G, Raiteri M, Carità F, Bonanno G (2000) NK3 receptor blockade prevents hyperalgesia and the associated spinal cord substance P release in monoarthritic rats. Neuropharmacology 39:141–149PubMedGoogle Scholar
  240. Zhang X, Ji RR, Arvidsson J, Lundberg JM, Bartfai T, Bedecs K, Hökfelt T (1996) Expression of peptides, nitric oxide synthase and NPY receptor in trigeminal and nodose ganglia after nerve lesions. Exp Brain Res 111:393–404PubMedGoogle Scholar
  241. Zhang L, Hoff AO, Wimalawansa SJ, Cote GJ, Gagel RF, Westlund KN (2001) Arthritic calcitonin/alpha calcitonin gene-related peptide knockout mice have reduced nociceptive hypersensitivity. Pain 89:265–273PubMedGoogle Scholar
  242. Zhang Z, Winborn CS, Marquez de Prado B, Russo AF (2007) Sensitization of calcitonin gene-related peptide receptors by receptor activity-modifying protein-1 in the trigeminal ganglion. J Neurosci 27:2693–2703PubMedGoogle Scholar
  243. Zhuo H, Helke CJ (1993) Neurokinin B peptide-2 neurons project from the hypothalamus to the thoracolumbar spinal cord of the rat. Neuroscience 52:1019–1028PubMedGoogle Scholar

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© Springer-Verlag Berlin Heidelberg 2009

Authors and Affiliations

  1. 1.Department of NeuroscienceUniversity of MinnesotaMinneapolisUSA

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