Prostagladin system in the spinal cord: a neuroanatomical study in the pathophysiological states

  • K. Matsumura
  • H. S. Sharma
  • C. Cao
  • Yu. Watanabe
  • K. Yamagata
  • M. Ozaki
  • K. Takeuchi
  • T. Gordh
  • J. Westman
  • Y. Watanabe


Prostaglandins (PGs) exert a wide range of biological actions in various types of tissues in the body. The nervous system is not an exception. A large number of studies have implicated PGs as playing essential roles in a variety of physiological and pathological responses in the nervous system (Shimizu and Wolfe, 1990; Bazan et al., 1995). In the brain, regional distributions of the sites of PG biosynthesis and PG actions have been clarified to some extent, although not completely (Watanabe et al., 1983; Yamashita et al., 1983; Watanabe et al., 1988; Watanabe et al., 1989; Matsumura et al., 1990; Tsubokura et al., 1991; Breder et al., 1992; Matsumura et al., 1992; Sugimoto et al., 1994; Breder et al., 1995; Cao et al., 1995; Matsumura et al., 1995; Breder and Saper, 1996; Cao et al., 1996; Takechi et al., 1996; Cao et al., 1997; Matsumura et al., 1997). In contrast, in the spinal cord, little is known as to where PGs are bio- synthesized and where they act. Such information is of importance for a better understanding of the mechanism of PG-related disorders in the spinal cord and for proper clinical treatment. In this chapter, we would like to overview the functions and location of PG system in the spinal cord. In the first part, biochemical aspects of PG system are shortly summarized. The second part surveys the literature concerning the patho-physiological roles of PGs in the spinal cord. In the third part, our recent experimental results on the location of the PG system in the spinal cord are presented.


Spinal Cord Spinal Cord Injury Dorsal Root Ganglion Nucleus Tractus Solitarius Primary Sensory Neuron 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Barkai AI, Bazan NG (1989) Arachidonic acid metabolism in the nervous system. Physiological and Pathological significance. Ann NY Acad Sci 559: 1–353Google Scholar
  2. Bazan NG, Rodriguez de Turco EB, Allan G (1995) Mediators of injury in neurotrauma: intraceilular signal transduction and gene expression. J Neurotrauma 12: 791–814PubMedCrossRefGoogle Scholar
  3. Beiche F, Scheuerer S, Brune K, Geisslinger G, Goppelt-Struebe M (1996) lip-regulation of cyclooxygenase-2 mRNA in the rat spinal cord following peripheral inflammation. FEBS Lett 390: 165–169PubMedCrossRefGoogle Scholar
  4. Birrell GJ, McQueen DS (1993) The effects of capsaicin, bradykinin, PGE2 and cicaprost on the discharge of articular sensory receptors in vitro. Brain Res 611: 103–107PubMedCrossRefGoogle Scholar
  5. Birrell GJ, McQueen DS, Iggo A, Colernan RA, Grubb BD (1991) PGI2-induced activation and sensitization of articular mechanonociceptors. Neurosci Lett 124: 5–8PubMedCrossRefGoogle Scholar
  6. Breder CD, Dewitt D, Kraig RP (1995) Characterization of inducible cyclooxygenase in rat brain. J Comp Neurol 355: 296–315PubMedCrossRefGoogle Scholar
  7. Breuer CD, Saper CB (1996) Expression of inducible cyciooxygenase mRNA in the mouse brain after systemic administration of bacterial lipopolysaccharide. Brain Res 713: 64–69CrossRefGoogle Scholar
  8. Breder CD, Smith WL, Raz A, Masferrer J, Seibert K. Needleman P, Saper CB (1992) Distribution and characterization of cyclooxygenase immunoreactivity in the ovine brain. J Cornp Neurol 322: 409–438CrossRefGoogle Scholar
  9. Cao C, Matsumura K, Yamagata K, Watanabe Y (1995) Induction by Iipopolysaccharide of cyclooxygenase-2 mRNA in rat brain; its possible role in the febrile response. Brain Res 697: 187–19PubMedCrossRefGoogle Scholar
  10. Cao C, Matsumura K, Yamagata K, Watanabe Y (1996) Endothelial cells of the rat brain vasculacture express cyclooxygenase-2 mRNA in response to systemic interieukin-1β: a possible site of prostaglandin synthesis responsible for fever. Brain Res 733: 263–272PubMedCrossRefGoogle Scholar
  11. Cao C, Matsumura K, Yamagata K, Watanabe Y (1997) Involvement of cyclooxygenase-2 in LPS-induced fever and its regulation in the brain. Am J Physiol 272: R1712-R1725Google Scholar
  12. Chahl LA, Iggo A (1977) The effects of bradykinin and prostaglandin Ein1 on rat cutaneous afferent nerve activity. Br J Pharmacol 59: 343–347PubMedCrossRefGoogle Scholar
  13. Coleman RA, Smith WL, Narumiya S (1994) International union of pharmacology classification of prostanoid receptors: properties, distribution, and structure of the receptors and their subtypes. Pharmacol Rev 46: 205–229PubMedGoogle Scholar
  14. Collier JG, Karim SMM, Robinson B, Somers K (1972) Action of prostaglandin A2, B j, E2 and F on superficial hand veins of man. Br J Pharmacol 44: 374–375Google Scholar
  15. Demeduik P, Saunders RD. Clendenon NR, Means ED, Anderson DK, Horrocks LA (1985) Changes in lipid metabolism in traumatised spinal cord. Prog Brain Res 63: 211–226CrossRefGoogle Scholar
  16. England S, Bevan S, Docherty RJ (1996) PGE2 modulates the tetrodotoxin-resistant sodium current in neonatal rat dorsal root ganglion neurones via the cyclic AMP-protein kinase A cascade. J Physiol 495: 429–440PubMedGoogle Scholar
  17. Faden AI, Lemke M, Demeduik P (1988) Effects of BW755C, a mixed cyelo-oxygenase-lipoxygenase inhibitor, following traumatic spinal cord injury in rats. Brain Res 463: 63–68PubMedCrossRefGoogle Scholar
  18. Ferreira SH (1972) Prostaglandins. aspirin-like drugs and analgesia. Nature 240: 200–203Google Scholar
  19. Ferreira SH, Moncada S, Vane JR (1973) Prostaglandins and the mechanism of analggesia produced by aspirin-like drugs. Br j Pharmacol 49: 86–97PubMedCrossRefGoogle Scholar
  20. Ferreira SH, Nakamura M, Castro MSA (1978) The hyperalgesic effects of prostacyclin and prostaglandin E2. Prostaglandin 16: 31–37Google Scholar
  21. Glaser KB, Mobilio D, Chang JY, Senko N (1993) Phospholipase A2 enzymes: regulation and inhibition. Trends Pharmacol Sci 14: 92–98PubMedCrossRefGoogle Scholar
  22. Gold MS, Reichling DB, Shuster MJ, Levine JD (1996) Hyperalgesic agents increase a tetrodotoxin-resistant Na+current in nociceptors. Proc Natl Acad Sci USA 93: 1108–1312PubMedCrossRefGoogle Scholar
  23. Gold MS, Shuster MJ, Levine JD (1996) Role of a Ca2+-dependent slow afterhyperpolar-ization in prostaglandin E2-induced sensitization of cultured rat sensory neurons. Neurosci Lett 205: 161–164PubMedCrossRefGoogle Scholar
  24. Goppelt-Struebe M (1995) Regulation of prostaglandin endoperoxide synthase (cyclooxygenase) isozyme expression. Prostaglandins Leukot. Essent Fatty Acids 52: 213–222PubMedCrossRefGoogle Scholar
  25. Hingigen CM, Vasko MR (1994) Prostacyclin enhances the evoked-release of substance P and calcitonin gene-related peptide from rat sensory neurons. Brain Res 655: 51–60CrossRefGoogle Scholar
  26. Hirata M, Hayashi Y, Ushikubi F, Yokota Y, Kageyama R, Nakanishi S, Narumiya S (1991) Cloning and expression ofcDNA forahumanthromboxane A2 receptor. Nature 349: 617–62PubMedCrossRefGoogle Scholar
  27. Hsu CY, Halushka PV, Hogan EL, Banik NL, Lee WA, Perot PL (1985) Alterations of thromboxane and prostacyclin levels in experimental spinal cord injury. Neurology 35:1003–1009PubMedCrossRefGoogle Scholar
  28. Khasar SG, Levine JD (1996) Neonatal capsaicin attenuates mechanical nociception in the rat. Neurosci Lett 205: 141–143PubMedCrossRefGoogle Scholar
  29. Malmberg AB, Yaksh TL (1992) Antinociceptive actions of spinal nonsteroidal anti-inflammatory agents on the formalin test in the rat. J Pharmacol Exp Ther 263: 136–146PubMedGoogle Scholar
  30. Malmberg AB, Yaksh TL (1994) Capsaicin-evoked prostaglandin E2 release in spinal cord slices: relative effect of cyclooxygenase inhibitors. Eur J Pharmacol 271; 293–299PubMedCrossRefGoogle Scholar
  31. Matmberg 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: 2768–2776Google Scholar
  32. Matsumura K, Cao C, Watanabe Yu, Watanabe Y (1998) Prostaglandin system in the brain: sites of biosynthesis and sites of action under normal and hyperthermic conditions. Prog Brain Res 115: 275–295PubMedCrossRefGoogle Scholar
  33. Matsumura K, Watanabe Yu, 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: 292–298Google Scholar
  34. Matsumura K, Watanabe Yu, Onoe H, Watanabe Y (1995) Prostacyclin recpetor in the brain and central terminals of the primary sensory neurons: an autoradiographic study using a stable prostacyclin analogue l3H]iloprost. Neuroscience 65: 493–503PubMedCrossRefGoogle Scholar
  35. Matsumura K, Watanabe Yu, Onoe H, Watanabe Y, Hayaishi O (1990) High density of prostaglandin E2 binding sites in the anterior wall of the 3rd ventricle: a possible site of its hyperthermic action. Brain Res 533: 147–151PubMedCrossRefGoogle Scholar
  36. Mense S (1981) Sensitization of group IV muscle receptors to bradykinin by 5-hydroxy-tryptaminse and prostagiandin E2. Brain Res 225: 95–105PubMedCrossRefGoogle Scholar
  37. Minami T, Nishihara I, Uda R, Ito S, Hyodo M, Hayaishi O (1994) Characterization of EP-receptor subtypes involved in allodynia and hyperalgesia induced by intrathecal administration of prostaglandin E2 to mice. Br J Pharmacol 112: 735–740PubMedCrossRefGoogle Scholar
  38. Minami T, Uda R, Horiguchi S, Ito S, Hyodo M, Hayaishi O (1994) Allodynia evoked by intrathecal administration of prostaglandin E2 to conscious mice. Pain 57: 217–223PubMedCrossRefGoogle Scholar
  39. Minami T, Uda R, Horiguchi S, Ito S, Hyodo M, Hayaishi O (1992) Allodynia evoked by intrathecal administration of prostaglandin F to conscious mice. Pain 50: 223–229PubMedCrossRefGoogle Scholar
  40. Oida H, Namba T, Sugimoto Y, Ushikubi F, Ohishi H, Ichikawa A, Narumiya S (1995) In situ hybridization of prostacyclin receptor mRNA expression in various mouse organs. Br J Pharmacol 116: 2828–2837PubMedCrossRefGoogle Scholar
  41. Sharma HS, Olsson Y, Nyberg F, Dey PK (1993a) Prostaglandins modulate alterations of microvascular permeability, blood flow, edema and serotonin levels following spinal cord injury. An experimental study in the rat. Neuroscience 57: 443–449Google Scholar
  42. Sharma HS, Olsson Y, Cervós-Navarro, J (1993b) Early perifocal cell changes and edema in traumatic injury of the spinal cord are reduced by indomethacin, an inhibitor of prostaglandin synthesis. Experimental study in the rat. Acta Neuropathol (Berl) 85: 145–153Google Scholar
  43. Sharma HS, Olsson Y, Persson S, Nyberg F (1995) Trauma-induced opening of the the blood-spinal cord barrier is reduced by indomethacin, an inhibitor of prostaglandin biosynthesis. Experimental observations in the rat using [131I]-sodium, Evans blue and lanthanum as tracers. Restorat Neurol Neurosci 7: 207–215Google Scholar
  44. Shimizu T, Wolfe LS (1990) Arachidonic acid cascade and signal transduction. J Neurochem 55: 1–15PubMedCrossRefGoogle Scholar
  45. Shohami E, Shapiro Y, Cotev S (1988) Experimental closed head injury in rats: prostaglandin production in a noninjured zone. Neurosurgery 22: 859–863PubMedCrossRefGoogle Scholar
  46. Smith WL, Marnett LJ, DeWitt DL (1991) Prostaglandin and thromboxane biosynthesis. Pharmacol Ther 49: 153–179PubMedCrossRefGoogle Scholar
  47. Sugimoto Y, Shigemoto R, Namba T, Negishi M, Mizuno N, Narumiya S, Ichikawa A (1994) Distriburion of the mRNA for the prostaglandin E receptor subtype EP3 in the mouse nervous system. Neuroscience 62: 919–928PubMedCrossRefGoogle Scholar
  48. Taiwo YO, Bjerknes LK, Goetzl EJ, Levine JD (1989) Mediation of primary afferent peripheral hyperalgesia by the cAMP second messenger system. Neuroscience 32: 577–580PubMedCrossRefGoogle Scholar
  49. Taiwo YO, Levince JD (1988) Prostagiandin inhibit endogenous pain control mechanisms by blocking transmission at spinal noradrenergic synapses. J Neurosci 8: 1346–1349PubMedGoogle Scholar
  50. Taiwo YO, Levine JD (1990) Effects of cyclooxygenase products of arachidonic acid metabolism on cutaneous nociceptive threshold in the rat. Brain Res 537: 372–374PubMedCrossRefGoogle Scholar
  51. Takechi H, Matsumura K, Watanabe Y, Kato K, Noyori R, Suzuki M, Watanabe Y (J 996) A novel subtype of the prostaglandin receptor expressed in the central nervous system. J Biol Chem 271: 5901–5906Google Scholar
  52. Takeuchi K, Abe T, Takahashi N, Abe K (1993) Molecular cloning and intrarenai localization of rat prostagiandin E2 receptor EP3 subtype. Biochem Biophys Res Commun 194: 885–891PubMedCrossRefGoogle Scholar
  53. Tsubokura S, Watanabe Y, Ehara H, Imamura K, Sugimoto O, Kagamiyama H, Yamamoto S, Hayaishi O (1991) Localization of prostaglandin endoperoxide synthase in neurons and glia of monkey brain. Brain Res 543: 15–24PubMedCrossRefGoogle Scholar
  54. 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: 26–32PubMedCrossRefGoogle Scholar
  55. Undem B.T, Weinreich D (1993) Electrophysiological properties and chemosensitivity of guinea pig nodose ganglion neurons in vitro. J Auton Nerv Syst 44: 17–34PubMedCrossRefGoogle Scholar
  56. Ushikubi F, Hirata M, Narumiya S (1995) Molecular biology of prostanoid receptors; an overview. J Lipid Mediat 12: 343–359CrossRefGoogle Scholar
  57. Vane JR (1971) Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nature 231: 232–235Google Scholar
  58. 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
  59. Watanabe Yu, Watanabe Y, Hamada K, Bommelaer-Bayt M-C, Dray F, Kaneko T, Yumoto N, Hayaishi O (1989) Distinct localization of prostaglandin D2, E2, and F203B1 binding sites in monkey brain. Brain Res 478: 143–148PubMedCrossRefGoogle Scholar
  60. Watanabe Yu, Watanabe Y, Hayaishi O (1988) Quantitative autoradiographic localization of prostaglandin E2 binding sites in monkey diencephalon. J Neurosci 8: 2003–2010PubMedGoogle Scholar
  61. Watanabe Y, Yamashita A, Tokumoto H, Hayaishi O (1983) Localization of prostaglandin D2 binding protein and NADP-linked 15-hydroxyprostaglandin D2 dehydrogenase in the Purkinje cells of miniature pig cerebellum. Proc Natl Acad Sci USA 80: 4542–4545PubMedCrossRefGoogle Scholar
  62. Winkler T, Sharma HS, Ståerg E, Olsson Y (1993) Indomethacin, an inhibitor of prostaglandin synthesis attenuates alteration in spinal cord evoked potentials and edema formation after trauma to the spinal cord. An experimental study in the rat. Neuroscience 52: 1057–1067Google Scholar
  63. Yamagata K, Andreasson KI, Kaufmann WE, Barnes CA, Worley PF (1993) Expression of a mitogen-inducible cyclooxygenase in brain neurons: regulation by synaptic activity and glucocorticoids. Neuron 11: 371–386PubMedCrossRefGoogle Scholar
  64. Yamamoto T, Nozaki-Taguchi N (1996) Analysis of the effects of cyclooxygenase (COX)-1 and COX-2 in spinal nociceptive transmission using indomethacin, a non-selective COX inhibitor, and NS-398, a COX-2 selective inhibitor. Brain Res 739: 104–110PubMedCrossRefGoogle Scholar
  65. Yamashita A, Watanabe Y, Hayaishi O (1983) Autoradiographic localization of a binding protein(s) specific for prostaglandin D2 in rat brain. Proc Natl Acad Sci USA 80: 6114–6118PubMedCrossRefGoogle Scholar
  66. Yang LC, Marsala M, Yaksh TL (1996) Characterization of time course of spinal amino acids, citruline and PGE2 release after carrageenan/kaolin-induced knee joint inflammation: a chronic microdialysis study. Pain 67: 345–354PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Wien 1998

Authors and Affiliations

  • K. Matsumura
    • 1
    • 2
  • H. S. Sharma
    • 3
  • C. Cao
    • 2
  • Yu. Watanabe
    • 1
    • 2
  • K. Yamagata
    • 5
  • M. Ozaki
    • 2
  • K. Takeuchi
    • 6
  • T. Gordh
    • 4
  • J. Westman
    • 3
  • Y. Watanabe
    • 1
    • 2
  1. 1.Subfemtomol Biorecognition ProjectJapan Science and Technology CorporationJapan
  2. 2.Department of NeuroscienceOsaka Bioscience InstituteSuita, OsakaJapan
  3. 3.Laboratory of Neuroanatomy, Department of AnatomyBiomedical CentreSweden
  4. 4.Department of AnaesthesiologyUniversity Hospital, Uppsala UniversityUppsalaSweden
  5. 5.Deptartment of Molecular NeurobiologyTokyo Metropolitan Institute for NeurosciencesFuchu-shi, TokyoJapan
  6. 6.The 2nd Department of Internal MedicineTohoku University, School of MedicineSendai, MiyagiJapan

Personalised recommendations