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. 1999 May;194(Pt 4):579–588. doi: 10.1046/j.1469-7580.1999.19440579.x

Stimulation of the middle meningeal artery leads to Fos expression in the trigeminocervical nucleus: a comparative study of monkey and cat

KAREN L HOSKIN 1 , ALESSANDRO S ZAGAMI 2 , PETER J GOADSBY 1 ,✉
PMCID: PMC1467956  PMID: 10445825

Abstract

The pain of a migraine attack is often described as unilateral, with a throbbing or pulsating quality. The middle meningeal artery (MMA) is the largest artery supplying the dura mater, is paired, and pain-producing in humans. This artery, or its branches, and other large intracranial extracerebral vessels have been implicated in the pathophysiology of migraine by theories suggesting neurogenic inflammation or cranial vasodilatation, or both, as explanations for the pain of migraine. Having previously studied in detail the distribution of the second order neurons that are involved in the transmission of nociceptive signals from intracranial venous sinuses, we sought to compare the distribution of second order neurons from a pain-producing intracranial artery in both monkey and cat. By electrically stimulating the middle meningeal artery in these species and using immunohistochemical detection of the proto-oncogene Fos as a marker of neuronal activation, we have mapped the sites of the central trigeminal neurons which may be involved in transmission of nociception from intracranial extracerebral arteries. Ten cats and 3 monkeys were anaesthetised with α-chloralose and the middle meningeal artery was isolated following a temporal craniotomy. The animals were maintained under stable anaesthesia for 24 h to allow Fos expression due to the initial surgery to dissipate. Following the rest period, the vessel was carefully lifted onto hook electrodes, and then left alone in control animals (cat n = 3), or stimulated (cat n = 6, monkey n = 3). Stimulation of the left middle meningeal artery evoked Fos expression in the trigeminocervical nucleus, consisting of the dorsal horn of the caudal medulla and upper 2 divisions of the cervical spinal cord, on both the ipsilateral and contralateral sides. Cats had larger amounts of Fos expressed on the ipsilateral than on the contralateral side. Fos expression in the caudal nucleus tractus solitarius and its caudal extension in lamina X of the spinal cord was seen bilaterally in response to middle meningeal artery stimulation. This study demonstrates a comparable anatomical distribution of Fos activation between cat and monkey and, when compared with previous studies, between this arterial structure and the superior sagittal sinus. These data add to the overall picture of the trigeminovascular innervation of the intracranial pain-producing vessels showing marked anatomical overlap which is consistent with the often poorly localised pain of migraine.

Keywords: Headache, migraine, Macaca nemestrina , trigeminal system

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Selected References

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  1. Apkarian A. V., Hodge C. J. Primate spinothalamic pathways: I. A quantitative study of the cells of origin of the spinothalamic pathway. J Comp Neurol. 1989 Oct 15;288(3):447–473. doi: 10.1002/cne.902880307. [DOI] [PubMed] [Google Scholar]
  2. Arbab M. A., Delgado T., Wiklund L., Svendgaard N. A. Brain stem terminations of the trigeminal and upper spinal ganglia innervation of the cerebrovascular system: WGA-HRP transganglionic study. J Cereb Blood Flow Metab. 1988 Feb;8(1):54–63. doi: 10.1038/jcbfm.1988.8. [DOI] [PubMed] [Google Scholar]
  3. Arbab M. A., Wiklund L., Svendgaard N. A. Origin and distribution of cerebral vascular innervation from superior cervical, trigeminal and spinal ganglia investigated with retrograde and anterograde WGA-HRP tracing in the rat. Neuroscience. 1986 Nov;19(3):695–708. doi: 10.1016/0306-4522(86)90293-9. [DOI] [PubMed] [Google Scholar]
  4. Bonaventure P., Voorn P., Luyten W. H., Leysen J. E. 5HT1B and 5HT1D receptor mRNA differential co-localization with peptide mRNA in the guinea pig trigeminal ganglion. Neuroreport. 1998 Mar 9;9(4):641–645. doi: 10.1097/00001756-199803090-00015. [DOI] [PubMed] [Google Scholar]
  5. Borges L. F., Moskowitz M. A. Do intracranial and extracranial trigeminal afferents represent divergent axon collaterals? Neurosci Lett. 1983 Mar 14;35(3):265–270. doi: 10.1016/0304-3940(83)90328-2. [DOI] [PubMed] [Google Scholar]
  6. Bullitt E., Lee C. L., Light A. R., Willcockson H. The effect of stimulus duration on noxious-stimulus induced c-fos expression in the rodent spinal cord. Brain Res. 1992 May 15;580(1-2):172–179. doi: 10.1016/0006-8993(92)90941-2. [DOI] [PubMed] [Google Scholar]
  7. Bullitt E. Somatotopy of spinal nociceptive processing. J Comp Neurol. 1991 Oct 8;312(2):279–290. doi: 10.1002/cne.903120210. [DOI] [PubMed] [Google Scholar]
  8. Burton H., Loewy A. D. Descending projections from the marginal cell layer and other regions of the monkey spinal cord. Brain Res. 1976 Nov 12;116(3):485–491. doi: 10.1016/0006-8993(76)90495-9. [DOI] [PubMed] [Google Scholar]
  9. CLARKE W. B., BOWSHER D. Terminal distribution of primary afferent trigeminal fibers in the rat. Exp Neurol. 1962 Nov;6:372–383. doi: 10.1016/0014-4886(62)90019-5. [DOI] [PubMed] [Google Scholar]
  10. DARIAN-SMITH I., PHILLIPS G., RYAN R. D. FUNCTIONAL ORGANIZATION IN THE TRIGEMINAL MAIN SENSORY AND ROSTRAL SPINAL NUCLEI OF THE CAT. J Physiol. 1963 Aug;168:129–146. doi: 10.1113/jphysiol.1963.sp007182. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. DARIAN-SMITH I., PROCTOR R., RYAN R. D. A SINGLE-NEURONE INVESTIGATION OF SOMATOTOPIC ORGANIZATION WITHIN THE CAT'S TRIGEMINAL BRAIN-STEM NUCLEI. J Physiol. 1963 Aug;168:147–157. doi: 10.1113/jphysiol.1963.sp007183. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Davis K. D., Dostrovsky J. O. Activation of trigeminal brain-stem nociceptive neurons by dural artery stimulation. Pain. 1986 Jun;25(3):395–401. doi: 10.1016/0304-3959(86)90244-7. [DOI] [PubMed] [Google Scholar]
  13. Dubbeldam J. L., Karten H. J. The trigeminal system in the pigeon (Columba livia). I. Projections of the gasserian ganglion. J Comp Neurol. 1978 Aug 15;180(4):661–678. doi: 10.1002/cne.901800402. [DOI] [PubMed] [Google Scholar]
  14. Edvinsson L., McCulloch J., Uddman R. Substance P: immunohistochemical localization and effect upon cat pial arteries in vitro and in situ. J Physiol. 1981 Sep;318:251–258. doi: 10.1113/jphysiol.1981.sp013862. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. FANG H. C. Cerebral arterial innervations in man. Arch Neurol. 1961 Jun;4:651–656. doi: 10.1001/archneur.1961.00450120065006. [DOI] [PubMed] [Google Scholar]
  16. FEINDEL W., PENFIELD W., McNAUGHTON F. The tentorial nerves and Iocalization of intracranial pain in man. Neurology. 1960 Jun;10:555–563. doi: 10.1212/wnl.10.6.555. [DOI] [PubMed] [Google Scholar]
  17. Fukuda H., Koga T. The Bötzinger complex as the pattern generator for retching and vomiting in the dog. Neurosci Res. 1991 Dec;12(4):471–485. doi: 10.1016/s0168-0102(09)80001-1. [DOI] [PubMed] [Google Scholar]
  18. Gallai V., Sarchielli P., Floridi A., Franceschini M., Codini M., Glioti G., Trequattrini A., Palumbo R. Vasoactive peptide levels in the plasma of young migraine patients with and without aura assessed both interictally and ictally. Cephalalgia. 1995 Oct;15(5):384–390. doi: 10.1046/j.1468-2982.1995.1505384.x. [DOI] [PubMed] [Google Scholar]
  19. Gibson S. J., Polak J. M., Bloom S. R., Wall P. D. The distribution of nine peptides in rat spinal cord with special emphasis on the substantia gelatinosa and on the area around the central canal (lamina X). J Comp Neurol. 1981 Sep 1;201(1):65–79. doi: 10.1002/cne.902010106. [DOI] [PubMed] [Google Scholar]
  20. Goadsby P. J., Edvinsson L., Ekman R. Release of vasoactive peptides in the extracerebral circulation of humans and the cat during activation of the trigeminovascular system. Ann Neurol. 1988 Feb;23(2):193–196. doi: 10.1002/ana.410230214. [DOI] [PubMed] [Google Scholar]
  21. Goadsby P. J., Edvinsson L., Ekman R. Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann Neurol. 1990 Aug;28(2):183–187. doi: 10.1002/ana.410280213. [DOI] [PubMed] [Google Scholar]
  22. Goadsby P. J., Edvinsson L. The trigeminovascular system and migraine: studies characterizing cerebrovascular and neuropeptide changes seen in humans and cats. Ann Neurol. 1993 Jan;33(1):48–56. doi: 10.1002/ana.410330109. [DOI] [PubMed] [Google Scholar]
  23. Goadsby P. J., Hoskin K. L. The distribution of trigeminovascular afferents in the nonhuman primate brain Macaca nemestrina: a c-fos immunocytochemical study. J Anat. 1997 Apr;190(Pt 3):367–375. doi: 10.1046/j.1469-7580.1997.19030367.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Grant G., Arvidsson J. Transganglionic degeneration in trigeminal primary sensory neurons. Brain Res. 1975 Sep 23;95(2-3):265–279. doi: 10.1016/0006-8993(75)90106-7. [DOI] [PubMed] [Google Scholar]
  25. Hammond D. L., Presley R., Gogas K. R., Basbaum A. I. Morphine or U-50,488 suppresses Fos protein-like immunoreactivity in the spinal cord and nucleus tractus solitarii evoked by a noxious visceral stimulus in the rat. J Comp Neurol. 1992 Jan 8;315(2):244–253. doi: 10.1002/cne.903150210. [DOI] [PubMed] [Google Scholar]
  26. Hoskin K. L., Kaube H., Goadsby P. J. Central activation of the trigeminovascular pathway in the cat is inhibited by dihydroergotamine. A c-Fos and electrophysiological study. Brain. 1996 Feb;119(Pt 1):249–256. doi: 10.1093/brain/119.1.249. [DOI] [PubMed] [Google Scholar]
  27. Hoskin K. L., Kaube H., Goadsby P. J. Sumatriptan can inhibit trigeminal afferents by an exclusively neural mechanism. Brain. 1996 Oct;119(Pt 5):1419–1428. doi: 10.1093/brain/119.5.1419. [DOI] [PubMed] [Google Scholar]
  28. Hu J. W., Dostrovsky J. O., Sessle B. J. Functional properties of neurons in cat trigeminal subnucleus caudalis (medullary dorsal horn). I. Responses to oral-facial noxious and nonnoxious stimuli and projections to thalamus and subnucleus oralis. J Neurophysiol. 1981 Feb;45(2):173–192. doi: 10.1152/jn.1981.45.2.173. [DOI] [PubMed] [Google Scholar]
  29. Ingvardsen B. K., Laursen H., Olsen U. B., Hansen A. J. Possible mechanism of c-fos expression in trigeminal nucleus caudalis following cortical spreading depression. Pain. 1997 Sep;72(3):407–415. doi: 10.1016/s0304-3959(97)00069-9. [DOI] [PubMed] [Google Scholar]
  30. Jacquin M. F., Semba K., Rhoades R. W., Egger M. D. Trigeminal primary afferents project bilaterally to dorsal horn and ipsilaterally to cerebellum, reticular formation, and cuneate, solitary, supratrigeminal and vagal nuclei. Brain Res. 1982 Aug 26;246(2):285–291. doi: 10.1016/0006-8993(82)91177-5. [DOI] [PubMed] [Google Scholar]
  31. Kaube H., Keay K. A., Hoskin K. L., Bandler R., Goadsby P. J. Expression of c-Fos-like immunoreactivity in the caudal medulla and upper cervical spinal cord following stimulation of the superior sagittal sinus in the cat. Brain Res. 1993 Nov 26;629(1):95–102. doi: 10.1016/0006-8993(93)90486-7. [DOI] [PubMed] [Google Scholar]
  32. Keller J. T., Marfurt C. F., Dimlich R. V., Tierney B. E. Sympathetic innervation of the supratentorial dura mater of the rat. J Comp Neurol. 1989 Dec 8;290(2):310–321. doi: 10.1002/cne.902900210. [DOI] [PubMed] [Google Scholar]
  33. Keller J. T., Marfurt C. F. Peptidergic and serotoninergic innervation of the rat dura mater. J Comp Neurol. 1991 Jul 22;309(4):515–534. doi: 10.1002/cne.903090408. [DOI] [PubMed] [Google Scholar]
  34. Keller J. T., Saunders M. C., Beduk A., Jollis J. G. Innervation of the posterior fossa dura of the cat. Brain Res Bull. 1985 Jan;14(1):97–102. doi: 10.1016/0361-9230(85)90181-9. [DOI] [PubMed] [Google Scholar]
  35. Kerber C. W., Newton T. H. The macro and microvasculature of the dura mater. Neuroradiology. 1973 Dec;6(4):175–179. doi: 10.1007/BF00335317. [DOI] [PubMed] [Google Scholar]
  36. Kerr F. W., Kruger L., Schwassmann H. O., Stern R. Somatotopic organization of mechanoreceptor units in the trigeminal nuclear complex of the macaque. J Comp Neurol. 1968 Oct;134(2):127–144. doi: 10.1002/cne.901340202. [DOI] [PubMed] [Google Scholar]
  37. Lambert G. A., Zagami A. S., Bogduk N., Lance J. W. Cervical spinal cord neurons receiving sensory input from the cranial vasculature. Cephalalgia. 1991 May;11(2):75–85. doi: 10.1046/j.1468-2982.1991.1102075.x. [DOI] [PubMed] [Google Scholar]
  38. Marfurt C. F. The central projections of trigeminal primary afferent neurons in the cat as determined by the tranganglionic transport of horseradish peroxidase. J Comp Neurol. 1981 Dec 20;203(4):785–798. doi: 10.1002/cne.902030414. [DOI] [PubMed] [Google Scholar]
  39. Martins I. P., Baeta E., Paiva T., Campos J., Gomes L. Headaches during intracranial endovascular procedures: a possible model of vascular headache. Headache. 1993 May;33(5):227–233. doi: 10.1111/j.1526-4610.1993.hed3305227.x. [DOI] [PubMed] [Google Scholar]
  40. Mayberg M. R., Zervas N. T., Moskowitz M. A. Trigeminal projections to supratentorial pial and dural blood vessels in cats demonstrated by horseradish peroxidase histochemistry. J Comp Neurol. 1984 Feb 10;223(1):46–56. doi: 10.1002/cne.902230105. [DOI] [PubMed] [Google Scholar]
  41. Mayberg M., Langer R. S., Zervas N. T., Moskowitz M. A. Perivascular meningeal projections from cat trigeminal ganglia: possible pathway for vascular headaches in man. Science. 1981 Jul 10;213(4504):228–230. doi: 10.1126/science.6166046. [DOI] [PubMed] [Google Scholar]
  42. Menétrey D., Gannon A., Levine J. D., Basbaum A. I. Expression of c-fos protein in interneurons and projection neurons of the rat spinal cord in response to noxious somatic, articular, and visceral stimulation. J Comp Neurol. 1989 Jul 8;285(2):177–195. doi: 10.1002/cne.902850203. [DOI] [PubMed] [Google Scholar]
  43. Moskowitz M. A., Cutrer F. M. SUMATRIPTAN: a receptor-targeted treatment for migraine. Annu Rev Med. 1993;44:145–154. doi: 10.1146/annurev.me.44.020193.001045. [DOI] [PubMed] [Google Scholar]
  44. Moskowitz M. A., Nozaki K., Kraig R. P. Neocortical spreading depression provokes the expression of c-fos protein-like immunoreactivity within trigeminal nucleus caudalis via trigeminovascular mechanisms. J Neurosci. 1993 Mar;13(3):1167–1177. doi: 10.1523/JNEUROSCI.13-03-01167.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Nichols F. T., 3rd, Mawad M., Mohr J. P., Hilal S., Adams R. J. Focal headache during balloon inflation in the vertebral and basilar arteries. Headache. 1993 Feb;33(2):87–89. doi: 10.1111/j.1526-4610.1993.hed3302087.x. [DOI] [PubMed] [Google Scholar]
  46. Nichols F. T., 3rd, Mawad M., Mohr J. P., Stein B., Hilal S., Michelsen W. J. Focal headache during balloon inflation in the internal carotid and middle cerebral arteries. Stroke. 1990 Apr;21(4):555–559. doi: 10.1161/01.str.21.4.555. [DOI] [PubMed] [Google Scholar]
  47. Nomura S., Yasui Y., Takada M., Mizuno N. Trigeminal primary afferent neurons projecting directly to the solitary nucleus in the cat: a transganglionic and retrograde horseradish peroxidase study. Neurosci Lett. 1984 Sep 7;50(1-3):257–262. doi: 10.1016/0304-3940(84)90495-6. [DOI] [PubMed] [Google Scholar]
  48. Nord S. G. Somatotopic organization in the spinal trigeminal nucleus, the dorsal column nuclei and related structures in the rat. J Comp Neurol. 1967 Aug;130(4):343–356. doi: 10.1002/cne.901300406. [DOI] [PubMed] [Google Scholar]
  49. Nozaki K., Boccalini P., Moskowitz M. A. Expression of c-fos-like immunoreactivity in brainstem after meningeal irritation by blood in the subarachnoid space. Neuroscience. 1992 Aug;49(3):669–680. doi: 10.1016/0306-4522(92)90235-t. [DOI] [PubMed] [Google Scholar]
  50. O'Connor T. P., van der Kooy D. Enrichment of a vasoactive neuropeptide (calcitonin gene related peptide) in the trigeminal sensory projection to the intracranial arteries. J Neurosci. 1988 Jul;8(7):2468–2476. doi: 10.1523/JNEUROSCI.08-07-02468.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. O'Connor T. P., van der Kooy D. Pattern of intracranial and extracranial projections of trigeminal ganglion cells. J Neurosci. 1986 Aug;6(8):2200–2207. doi: 10.1523/JNEUROSCI.06-08-02200.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Pfaller K., Arvidsson J. Central distribution of trigeminal and upper cervical primary afferents in the rat studied by anterograde transport of horseradish peroxidase conjugated to wheat germ agglutinin. J Comp Neurol. 1988 Feb 1;268(1):91–108. doi: 10.1002/cne.902680110. [DOI] [PubMed] [Google Scholar]
  53. REXED B. A cytoarchitectonic atlas of the spinal cord in the cat. J Comp Neurol. 1954 Apr;100(2):297–379. doi: 10.1002/cne.901000205. [DOI] [PubMed] [Google Scholar]
  54. Roland J., Bernard C., Bracard S., Czorny A., Floquet J., Race J. M., Forlodou P., Picard L. Microvascularization of the intracranial dura mater. Surg Radiol Anat. 1987;9(1):43–49. doi: 10.1007/BF02116853. [DOI] [PubMed] [Google Scholar]
  55. Ruskell G. L., Simons T. Trigeminal nerve pathways to the cerebral arteries in monkeys. J Anat. 1987 Dec;155:23–37. [PMC free article] [PubMed] [Google Scholar]
  56. Steiger H. J., Meakin C. J. The meningeal representation in the trigeminal ganglion--an experimental study in the cat. Headache. 1984 Nov;24(6):305–309. doi: 10.1111/j.1526-4610.1984.hed2406305.x. [DOI] [PubMed] [Google Scholar]
  57. Steiger H. J., Tew J. M., Jr, Keller J. T. The sensory representation of the dura mater in the trigeminal ganglion of the cat. Neurosci Lett. 1982 Aug 31;31(3):231–236. doi: 10.1016/0304-3940(82)90025-8. [DOI] [PubMed] [Google Scholar]
  58. Storer R. J., Butler P., Hoskin K. L., Goadsby P. J. A simple method, using 2-hydroxypropyl-beta-cyclodextrin, of administering alpha-chloralose at room temperature. J Neurosci Methods. 1997 Nov 7;77(1):49–53. doi: 10.1016/s0165-0270(97)00110-6. [DOI] [PubMed] [Google Scholar]
  59. Strassman A. M., Mineta Y., Vos B. P. Distribution of fos-like immunoreactivity in the medullary and upper cervical dorsal horn produced by stimulation of dural blood vessels in the rat. J Neurosci. 1994 Jun;14(6):3725–3735. doi: 10.1523/JNEUROSCI.14-06-03725.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Strassman A., Mason P., Moskowitz M., Maciewicz R. Response of brainstem trigeminal neurons to electrical stimulation of the dura. Brain Res. 1986 Aug 6;379(2):242–250. doi: 10.1016/0006-8993(86)90777-8. [DOI] [PubMed] [Google Scholar]
  61. TORVIK A. Afferent connections to the sensory trigeminal nuclei, the nucleus of the solitary tract and adjacent structures; an experimental study in the rat. J Comp Neurol. 1956 Nov;106(1):51–141. doi: 10.1002/cne.901060104. [DOI] [PubMed] [Google Scholar]
  62. Uddman R., Edvinsson L., Ekman R., Kingman T., McCulloch J. Innervation of the feline cerebral vasculature by nerve fibers containing calcitonin gene-related peptide: trigeminal origin and co-existence with substance P. Neurosci Lett. 1985 Nov 20;62(1):131–136. doi: 10.1016/0304-3940(85)90296-4. [DOI] [PubMed] [Google Scholar]
  63. WALL P. D., TAUB A. Four aspects of trigeminal nucleus and a paradox. J Neurophysiol. 1962 Jan;25:110–126. doi: 10.1152/jn.1962.25.1.110. [DOI] [PubMed] [Google Scholar]
  64. Wanaka A., Matsuyama T., Yoneda S., Kimura K., Kamada T., Girgis S., MacIntyre I., Emson P. C., Tohyama M. Origins and distribution of calcitonin gene-related peptide-containing nerves in the wall of the cerebral arteries of the guinea pig with special reference to the coexistence with substance P. Brain Res. 1986 Mar 26;369(1-2):185–192. doi: 10.1016/0006-8993(86)90527-5. [DOI] [PubMed] [Google Scholar]
  65. Westrum L. E., Canfield R. C., Black R. G. Transganglionic degeneration in the spinal trigeminal nucleus following removal of tooth pulps in adult cats. Brain Res. 1976 Jan 9;101(1):137–140. doi: 10.1016/0006-8993(76)90994-x. [DOI] [PubMed] [Google Scholar]
  66. Yamamoto K., Matsuyama T., Shiosaka S., Inagaki S., Senba E., Shimizu Y., Ishimoto I., Hayakawa T., Matsumoto M., Tohyama M. Overall distribution of substance P-containing nerves in the wall of the cerebral arteries of the guinea pig and its origins. J Comp Neurol. 1983 Apr 20;215(4):421–426. doi: 10.1002/cne.902150406. [DOI] [PubMed] [Google Scholar]

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