The effects of the TRPV1 receptor antagonist SB-705498 on trigeminovascular sensitisation and neurotransmission

  • G. A. LambertEmail author
  • J. B. Davis
  • J. M. Appleby
  • B. A. Chizh
  • K. L. Hoskin
  • A. S. Zagami


This report examines the effect of the transient receptor potential vanilloid 1 receptor antagonist SB-705498 on neurotransmission and inflammation-induced sensitisation in the trigeminovascular sensory system. A single-neuron electrophysiological animal model for neurovascular head pain was used to evaluate dural and facial noxious inputs and the effects of SB-705498 administered by intravenous (i.v.) injection. Electrical and mechanical stimulation of the dura mater and the facial skin activated second-order neurons in the trigeminal nucleus caudalis of cats, with A-δ latencies. Intravenous injection of SB-705498 (2 mg kg−1) produced a slowly developing and long-lasting suppression of responses to dural and skin stimulation. Maximum suppression occurred by 1 h and reached 41% for dura and 24% for skin. Intravenous injection of drug vehicle did not produce significant suppression of responses to stimulation of either dura or skin. Intravenous injection of SB-705498 produced a brief and small rise in blood pressure and dural blood flow, which both returned to normal before suppression of the responses to stimulation became manifest. Application of “inflammatory soup” to the dura mater produced a pronounced increase in dural blood flow and induced a slowly developing increase in the responses of neurons to both electrical and mechanical stimulations of their facial and dural receptive fields. This sensitisation reached a maximum in 60–90 min, at which time responses had risen to approximately twice that of control levels seen before the application of inflammatory soup. Intravenous injection of SB-705498 subsequent to the development of sensitisation produced a slowly developing, prolonged and statistically significant reversal of the sensitisation induced by inflammatory soup. Maximum reversal of sensitisation to electrical stimulation occurred by 150–180 min, when responses had fallen to, or below, control levels. At 70–85 min following injection of SB-705498, the responses of previously sensitised neurons to mechanical stimulation of dura mater and facial receptive field had also returned to near control levels. SB-705498 was also able to prevent the development of sensitisation; application of inflammatory soup to the dura mater induced a slowly developing increase in the responses of neurons to electrical stimulation of the skin and dura mater in cats which had received an i.v. injection of vehicle for SB-705498 but not in cats which had received the active drug. Blood levels of SB-705498 were maximal immediately following i.v. injection and declined over the following 2 h. Significant brain levels of SB-705498 were maintained for up to 9 h. These results suggest that SB-705498 may be an effective suppressant and reversal agent of the sensitisation to sensory input which follows inflammation in the trigeminovascular sensory distribution but may not be particularly useful in blocking primary pain processes such as migraine headache. SB-705498 could thus potentially prevent, modify or reverse the cutaneous trigeminal allodynia seen in certain migraine conditions, especially “transformed” migraine.


TRPV1 receptor Sensitisation Dura mater 



Analysis of variance


Blood pressure


Cannabinoid 1


Calcitonin-gene-related peptide




Heart rate




Low threshold mechanoreceptor


Nociceptor specific


Receptive field


Transient receptor potential vanilloid 1


Wide dynamic range


  1. Aimar P, Pasti L, Carmignoto G, Merighi A (1998) Nitric oxide-producing islet cells modulate the release of sensory neuropeptides in the rat substantia gelatinosa. J Neurosci 18:10375–10388PubMedGoogle Scholar
  2. Amaya F, Oh-hashi K, Naruese Y, Iijima N, Ueda M, Shimosato G, Tominaga M, Tanaka Y, Tanaka M (2003) Local inflammation increases vanilloid receptor 1 expression within distinct groups of DRG neurons. Brain Res 963:190–196PubMedCrossRefGoogle Scholar
  3. Ashkenazi A, Young WB (2004) Dynamic mechanical (brush) allodynia in cluster headache. Headache 44:1010–1012PubMedCrossRefGoogle Scholar
  4. Bartsch T, Knight YE, Goadsby PJ (2004) Activation of 5-HT(1B/1D) receptor in the periaqueductal gray inhibits nociception. Ann Neurol 56:371–381PubMedCrossRefGoogle Scholar
  5. Biondi D (2006) Is migraine a neuropathic pain syndrome? Curr Pain Headache Rep 10:167–178PubMedCrossRefGoogle Scholar
  6. Brain SD, Cox HM (2006) Neuropeptides and their receptors: innovative science providing novel therapeutic targets. Br J Pharmacol 147:S202–S211PubMedCrossRefGoogle Scholar
  7. Burstein R, Jakubowski M (2003) Analgesic triptan action in an animal model of intractable pain: a race against the development of sensitization. Ann Neurol 55:27–36CrossRefGoogle Scholar
  8. Burstein R, Yamamura H, Malick A, Strassman AM (1998) Chemical stimulation of the intracranial dura induces enhanced responses to facial stimulation in brain stem trigeminal neurons. J Neurophysiol 79:964–982PubMedGoogle Scholar
  9. Burstein R, Yarnitsky D, Goor-Aryeh I, Ransil BJ, Bajwa ZH (2000) An association between migraine and cutaneous allodynia. Ann Neurol 47:614–624PubMedCrossRefGoogle Scholar
  10. Caterina MJ (2007) Transient receptor potential ion channels as participants in thermosensation and thermoregulation. Am J Physiol Regul Integr Comp Physiol 292:R64–76PubMedGoogle Scholar
  11. 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 325:151–153PubMedCrossRefGoogle Scholar
  12. Cooke L, Eliasziw M, Becker WJ (2007) Cutaneous allodynia in transformed migraine patients. Headache 47:531–539PubMedGoogle Scholar
  13. Cui M, Honore P, Zhong C, Gauvin D, Mikusa J, Hernandez G, Chandran P, Gomtsyan A, Brown B, Bayburt EK, Marsh K, Bianchi B, McDonald H, Niforatos W, Neelands TR, Moreland RB, Decker MW, Lee CH, Sullivan JP, Faltynek CR (2006) TRPV1 receptors in the CNS play a key role in broad-spectrum analgesia of TRPV1 antagonists. J Neurosci 26:9385–9393PubMedCrossRefGoogle Scholar
  14. Cumberbatch MJ, Williamson DJ, Mason GS, Hill RG, Hargreaves RJ (1999a) Dural vasodilation causes a sensitization of rat caudal trigeminal neurones in vivo that is blocked by a 5-HT1B/1D agonist. Br J Pharmacol 126:1478–1486CrossRefGoogle Scholar
  15. Cumberbatch MJ, Williamson DJ, Shepheard SL, Hill RG, Hargreaves RJ (1999b) Pre-clinical investigations into the central mechanisms of migraine. Cephalalgia 19:394–395Google Scholar
  16. Davis KD, Dostrovsky JO (1986) Activation of trigeminal brain-stem nociceptive neurons by dural artery stimulation. Pain 25:395–401PubMedCrossRefGoogle Scholar
  17. Davis J, Rami H, Stevens A (2005) SB-705498, a clinical candidate with antagonistic activity at TRPV1 receptors and efficacy in a range of preclinical pain models. Soc Neurosci Abstr Session 364:2Google Scholar
  18. Dodick D, Silberstein S (2006) Central sensitization theory of migraine: clinical implications. Headache 46:S182–S191PubMedCrossRefGoogle Scholar
  19. Durham PL (2004) CGRP-receptor antagonists—a fresh approach to migraine therapy? N Engl J Med 350:1073–1075PubMedCrossRefGoogle Scholar
  20. Edvinsson L, Juul R, Jansen I (1994) Perivascular neuropeptides (NPY, VIP, CGRP and SP) in human brain vessels after subarachnoid haemorrhage. Acta Neurol Scand 90:324–330PubMedCrossRefGoogle Scholar
  21. Ferrini F, Salio C, Vergnano AM, Merighi A (2007) Vanilloid receptor-1 (TRPV1)-dependent activation of inhibitory neurotransmission in spinal substantia gelatinosa neurons of mouse. Pain 129:195–209PubMedCrossRefGoogle Scholar
  22. Fischer MJM, Koulchitsky S, Messlinger K (2005) The nonpeptide calcitonin gene-related peptide receptor antagonist BIBN4096BS lowers the activity of neurons with meningeal input in the rat spinal trigeminal nucleus. J Neurosci 25:5877–5883PubMedCrossRefGoogle Scholar
  23. Goadsby PJ (2005) Can we develop neurally acting drugs for the treatment of migraine? Drug Discov 4:741–750CrossRefGoogle Scholar
  24. Gunthorpe MJ, Hannan SL, Smart D, Jerman JC, Arpino S, Smith GD, Brough S, Wright J, Egerton J, Lappin SC, Holland VA, Winborn K, Thompson M, Rami HK, Randall A, Davis JB (2007) Characterization of SB-705498, a potent and selective vanilloid receptor-1 (VR1/TRPV1) antagonist that inhibits the capsaicin-, acid-, and heat-mediated activation of the receptor. J Pharmacol Exp Ther 321:1183–1192PubMedCrossRefGoogle Scholar
  25. Guo A, Vulchanova L, Wang J, Li X, Elde R (1999) Immunocytochemical localization of the vanilloid receptor 1 (VR1): relationship to neuropeptides, the P2X3 purinoceptor and IB4 binding sites. Eur J NeuroSci 11:946–958PubMedCrossRefGoogle Scholar
  26. Hargreaves R (2007) New migraine and pain research. Headache 47:S26–S43PubMedCrossRefGoogle Scholar
  27. Ho TW, Mannix LK, Fan X, Assaid C, Furtek C, Jones CJ, Lines CR, Rapoport AM, On behalf of the MKPsg (2008) Randomized controlled trial of an oral CGRP receptor antagonist, MK-0974, in acute treatment of migraine. Neurology 70:1304–1312PubMedCrossRefGoogle Scholar
  28. Hoskin KL, Bulmer DCE, Lasalandra M, Goadsby PJ (1999) Fos expression in the trigeminocervical complex is reduced by NOS inhibition. Neurosci Lett 266:173–176PubMedCrossRefGoogle Scholar
  29. Hou M, Uddman R, Tajti J, Kanje M, Edvinsson L (2002) Capsaicin receptor immunoreactivity in the human trigeminal ganglion. Neurosci Lett 330:223–226PubMedCrossRefGoogle Scholar
  30. Hu JW, Sessle BJ (1984) Comparison of responses of cutaneous nociceptive and nonnociceptive brain stem neurons in trigeminal subnucleus caudalis (medullary dorsal horn) and subnucleus oralis to natural and electrical stimulation of tooth pulp. J Neurophysiol 52:39–53PubMedGoogle Scholar
  31. Jakubowski M, Levy D, Goor-Aryeh I, Collins B, Bajwa Z, Burstein R (2005) Terminating migraine with allodynia and ongoing central sensitization using parenteral administration of COX1/COX2 inhibitors. Headache 45:850–861PubMedCrossRefGoogle Scholar
  32. Jansen I, Uddman R, Ekman R, Olesen J, Ottosson A, Edvinsson L (1992) Distribution and effects of neuropeptide Y, vasoactive intestinal peptide, substance P, and calcitonin gene-related peptide in human middle meningeal arteries: comparison with cerebral and temporal arteries. Peptides 13:527–536PubMedCrossRefGoogle Scholar
  33. Jeftinija S, Liu F, Jeftinija K, Urban L (1992) Effect of capsaicin and resiniferatoxin on peptidergic neurons in cultured dorsal root ganglion. Regul Pept 39:123–135PubMedCrossRefGoogle Scholar
  34. Jennings EA, Vaughan CW, Christie MJ (2001) Cannabinoid actions on rat superficial medullary dorsal horn neurons in vitro. J Physiol 534:805–812PubMedCrossRefGoogle Scholar
  35. Jennings EA, Vaughan CW, Roberts LA, Christie MH (2003) The actions of anandamide on rat superficial medullary dorsal horn neurons in vitro. J Physiol 548:121–129PubMedCrossRefGoogle Scholar
  36. Keller JT, Marfurt CF (1991) Peptidergic and serotoninergic innervation of the rat dura mater. J Comp Neurol 309:515–534PubMedCrossRefGoogle Scholar
  37. Lambert GA, Zagami AS (2009) The mechanism of action of migraine triggers: an hypothesis. Headache 49:253–275PubMedCrossRefGoogle Scholar
  38. Lambert GA, Lowy AJ, Boers PM, Angus-Leppan H, Zagami AS (1992) The spinal cord processing of input from the superior sagittal sinus: pathway and modulation by ergot alkaloids. Brain Res 597:321–330PubMedCrossRefGoogle Scholar
  39. Lambert GA, Hoskin KL, Zagami AS (2004) Nitrergic and glutamatergic neuronal mechanisms at the trigeminovascular first-order synapse. Neuropharmacol 42:97–105Google Scholar
  40. Lambert GA, Hoskin KL, Zagami AS (2008) Cortico-NRM influences on trigeminovascular sensation. Cephalalgia 28:640–652PubMedCrossRefGoogle Scholar
  41. Lambert GA, Mallos G, Zagami AS (2009) Von Frey’s hairs—a review of their technology and use—a novel automated von Frey device for improved testing for hyperalgesia. J Neurosci Methods 177:420–426PubMedCrossRefGoogle Scholar
  42. Lance JW, Goadsby PJ (1999) Mechanism and management of headache. Butterworth Scientific, LondonGoogle Scholar
  43. Lance JW, Goadsby PJ (2005) Mechanism and management of headache. Butterworth Scientific, LondonGoogle Scholar
  44. Landy S, Rice K, Lobo B (2004) Central sensitisation and cutaneous allodynia in migraine: implications for treatment. CNS Drugs 18:337–342PubMedCrossRefGoogle Scholar
  45. Lappin SC, Randall AD, Gunthorpe MJ, Morisset V (2006) TRPV1 antagonist, SB-366791, inhibits glutamatergic synaptic transmission in rat spinal dorsal horn following peripheral inflammation. Eur J Pharmacol 540:73–81PubMedCrossRefGoogle Scholar
  46. Leong SK, Liu HP, Yeo JF (2000) Nitric oxide synthase and glutamate receptor immunoreactivity in the rat spinal trigeminal neurons expressing Fos protein after formalin injection. Brain Res 855:107–115PubMedCrossRefGoogle Scholar
  47. Liu-Chen L-Y, Mayberg MA, Moskowitz MA (1983) Immunohistochemical evidence for a substance P-containing trigeminovascular pathway to pial arteries in cats. Brain Res 168:162–166CrossRefGoogle Scholar
  48. MacDermott AB, Mayer ML, Westbrook GL, SS J, Baker JL (1986) NMDA-receptor activation increases cytoplasmic calcium concentration in cultured spinal cord neurons. Nature 321:519–522PubMedCrossRefGoogle Scholar
  49. Mandelbrod I, Feldman S, Werman R (1983) Mediobasal hypothalamic neurons are excited by the iontophoretic application of sodium. Brain Res 273:35–44PubMedCrossRefGoogle Scholar
  50. Mezey E, Toth ZE, Cortright DN, Arzubi MK, Krause JE, Elde R, Guo A, Blumberg PM, Szallasi A (2000) Distribution of mRNA for vanilloid receptor subtype 1 (VR1), and VR1-like immunoreactivity, in the central nervous system of the rat and human. PNAS 97:3655–3660PubMedCrossRefGoogle Scholar
  51. Michalicek J, Gordon V, Lambert GA (1996) Autoregulation in the middle meningeal artery. J Cereb Blood Flow Metab 16:507–516PubMedCrossRefGoogle Scholar
  52. Mitsikostas DD, Sanches del Rio M (2001) Receptor systems mediating c-fos expression within trigeminal nucleus caudalis in animal models of migraine. Brain Res Rev 35:20–35PubMedCrossRefGoogle Scholar
  53. Mitsikostas DD, del Rio MS, Waeber C, Huang ZH, Cutrer FM, Moskowitz MA (1999) Non-NMDA glutamate receptors modulate capsaicin induced c-fos expression within trigeminal nucleus caudalis. Br J Pharmacol 127:623–630PubMedCrossRefGoogle Scholar
  54. Nakamura A, Hayakawa T, Kuwahara S, Maeda S, Tanaka K, Seki M, Mimura O (2007) Morphological and immunohistochemical characterization of the trigeminal ganglion neurons innervating the cornea and upper eyelid of the rat. J Chem Neuroanat 34:95–101PubMedCrossRefGoogle Scholar
  55. Oshinsky ML, Pozo-Rosich P, Lua J, Hyman S, Silberstein SD (2004) Botulinum toxin type A blocks sensitization of neurons in the trigeminal nucleus caudalis. Cephalalgia 24:781Google Scholar
  56. Piper RD, Lambert GA, Duckworth JW (1991) Cortical blood flow changes during spreading depression in cats. Am J Physiol 261:H96–H102PubMedGoogle Scholar
  57. Price TJ, Flores CM (2007) Critical evaluation of the colocalization between calcitonin gene-related peptide, substance P, transient receptor potential vanilloid subfamily type 1 immunoreactivities, and isolectin B4 binding in primary afferent neurons of the rat and mouse. J Pain 8:263–272PubMedCrossRefGoogle Scholar
  58. Rami HK, Gunthorpe MJ (2004) The therapeutic potential of TRPV1 (VR1) antagonists: clinical answers await. Drug Discov Today Ther Strateg 1:97–104CrossRefGoogle Scholar
  59. Rami HK, Thompson M, Stemp G, Fell S, Jerman JC, Stevens AJ, Smart D, Sargent B, Sanderson D, Randall AD, Gunthorpe MJ, Davis JB (2006) Discovery of SB-705498: a potent, selective and orally bioavailable TRPV1 antagonist suitable for clinical development. Bioorg Med Chem Lett 16:3287–3291PubMedCrossRefGoogle Scholar
  60. Rigoni M, Trevisani M, Gazzieri D, Nadaletto R, Tognetto M, Creminon C, Davis JB, Campi B, Amadesi S, Geppetti P, Harrison S (2003) Neurogenic responses mediated by vanilloid receptor-1 (TRPV1) are blocked by the high affinity antagonist, iodo-resiniferatoxin. Br J Pharmacol 138:977–985PubMedCrossRefGoogle Scholar
  61. Scotland RS, Chauhan S, Davis C, De Felipe C, Hunt S, Kabir J, Kotsonis P, Oh U, Ahluwalia A (2004) Vanilloid receptor TRPV1, sensory C-fibers, and vascular autoregulation: a novel mechanism involved in myogenic constriction. Circ Res 95:1027–1034PubMedCrossRefGoogle Scholar
  62. Shimizu T, Toriumi H, Sato H, Shibata M, Nagata E, Gotoh K, Suzuki N (2007) Distribution and origin of TRPV1 receptor-containing nerve fibers in the dura mater of rat. Brain Res 1173:84–91PubMedCrossRefGoogle Scholar
  63. Siegel S, Castellan NJJ (1988) Nonparametric statistics for the behavioral sciences. McGraw-Hill, New YorkGoogle Scholar
  64. Smith D, Hill RG, Edvinsson L, Longmore J (2002) An immunocytochemical investigation of human trigeminal nucleus caudalis: CGRP, substance P and 5-HT1D-receptor immunoreactivities are expressed by trigeminal sensory fibres. Cephalalgia 22:424–431PubMedCrossRefGoogle Scholar
  65. Storer RJ, Goadsby PJ (1999) Trigeminovascular nociceptive transmission involves N-methyl-d-aspartate and non-N-methyl-d-aspartate glutamate receptors. Neurosci 90:1371–1376CrossRefGoogle Scholar
  66. Strassman A, Mason P, Moskowitz M, Maciewicz R (1986) Response of brainstem trigeminal neurons to electrical stimulation of the dura. Brain Res 379:242–250PubMedCrossRefGoogle Scholar
  67. Strassman AM, Raymond SA, Burstein R (1996) Sensitization of meningeal sensory neurons and the origin of headaches. Nature 384:560–563PubMedCrossRefGoogle Scholar
  68. Szallasi A, Cortright DN, Blum CA, Eid SR (2007) The vanilloid receptor TRPV1: 10 years from channel cloning to antagonist proof-of-concept. Nat Rev Drug Discov 6:357–372PubMedCrossRefGoogle Scholar
  69. Thalakoti S, Patil VV, Damodaram S, Vause CV, Langford LE, Freeman SE, Durham PL (2007) Neuron–glia signaling in trigeminal ganglion: implications for migraine pathology. Headache 47:1008–1023PubMedCrossRefGoogle Scholar
  70. Tohda C, Sasaki M, Konemura T, Sasamura T, Itoh M, Kuraishi Y (2001) Axonal transport of VR1 capsaicin receptor mRNA in primary afferents and its participation in inflammation-induced increase in capsaicin sensitivity. J Neurochem 76:1628–1635PubMedCrossRefGoogle Scholar
  71. Valtschanoff JG, Rustioni A, Guo A, Hwang SJ (2001) Vanilloid receptor VR1 is both presynaptic and postsynaptic in the superficial laminae of the rat dorsal horn. J Comp Neurol 436:225–235PubMedCrossRefGoogle Scholar
  72. Wang Y, Szabo T, Welter JD, Toth A, Tran R, Lee J, Kang SU, Suh Y-G, Blumberg PM, Lee J (2002) High affinity antagonists of the vanilloid receptor. Mol Pharmacol 62:947–956PubMedCrossRefGoogle Scholar
  73. Woolff CJ (1983) Evidence for a central component of post injury pain sensitivity. Nature 306:686–688CrossRefGoogle Scholar
  74. Xing J, Li J (2007) TRPV1 receptor mediates glutamatergic synaptic input to dorsolateral periaqueductal gray (dl-PAG) neurons. J Neurophysiol 97:503–511PubMedCrossRefGoogle Scholar
  75. Yarnitsky D, Goor-Aryeh I, Bajwa ZH, Ransil BI, Cutrer FM, Sottile A, Burstein R (2003) Possible parasympathetic contributions to peripheral and central sensitization during migraine. Headache 43:704–714PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • G. A. Lambert
    • 1
    • 3
    Email author
  • J. B. Davis
    • 2
  • J. M. Appleby
    • 2
  • B. A. Chizh
    • 2
  • K. L. Hoskin
    • 1
  • A. S. Zagami
    • 1
  1. 1.Institute of Neurological SciencesUniversity of New South Wales and Prince of Wales HospitalSydneyAustralia
  2. 2.Neurology CEDDHarlowUK
  3. 3.Institute of Neurological SciencesPrince of Wales Hospital Clinical SchoolSydneyAustralia

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