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. 1986 Mar-Apr;59(2):159–168.

Is prostaglandin E the neural mediator of the febrile response? The case against a proven obligatory role.

D Mitchell, H P Laburn, K E Cooper, R F Hellon, W I Cranston, Y Townsend
PMCID: PMC2590132  PMID: 3739373

Abstract

We have reviewed the evidence in favor of a prostaglandin mediator of the thermal responses in fever and found that PGE injected into the hypothalamus does not always cause fever, that cerebrospinal fluid concentrations of PGE are not reliable reflections of hypothalamic events, and that antipyretic drugs may act in ways other than inhibiting PGE synthesis. Fever is not blocked by prostaglandin antagonists, nor by ablation of PGE-sensitive areas of the brain. There is poor correlation between the effects of pyrogens and of PGE on cerebral neurons. There is evidence that at least one prostanoid other than prostaglandin is a mediator of fever, but the prostanoid has not been identified yet. We conclude that PGE may contribute to the neural responses in fever but is not essential.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Abdel-Halim M. S., Sjöquist B., Anggård E. Inhibition of prostaglandin synthesis in rat brain. Acta Pharmacol Toxicol (Copenh) 1978 Oct;43(4):266–272. doi: 10.1111/j.1600-0773.1978.tb02264.x. [DOI] [PubMed] [Google Scholar]
  2. Bernheim H. A., Gilbert T. M., Stitt J. T. Prostaglandin E levels in third ventricular cerebrospinal fluid of rabbits during fever and changes in body temperature. J Physiol. 1980 Apr;301:69–78. doi: 10.1113/jphysiol.1980.sp013189. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Clark W. G., Cumby H. R. Antagonism by antipyretics of the hyperthermic effect of a prostaglandin precursor, sodium arachidonate, in the cat. J Physiol. 1976 Jun;257(3):581–595. doi: 10.1113/jphysiol.1976.sp011386. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Clark W. G., Cumby H. R. Effects of prostaglandin antagonist SC-19220 on body temperature and on hyperthermic responses to prostaglandin E-1 and leukocytic pyrogen in the cat. Prostaglandins. 1975 Mar;9(3):361–368. doi: 10.1016/0090-6980(75)90140-9. [DOI] [PubMed] [Google Scholar]
  5. Clark W. G., Lipton J. M. Hyperthermic effect of prostacyclin injected into the third cerebral ventricle of the cat. Brain Res Bull. 1979 Jan-Feb;4(1):15–16. doi: 10.1016/0361-9230(79)90052-2. [DOI] [PubMed] [Google Scholar]
  6. Clark W. G. Mechanisms of antipyretic action. Gen Pharmacol. 1979;10(2):71–77. doi: 10.1016/0306-3623(79)90038-7. [DOI] [PubMed] [Google Scholar]
  7. Coceani F., Bishai I., Dinarello C. A., Fitzpatrick F. A. Prostaglandin E2 and thromboxane B2 in cerebrospinal fluid of afebrile and febrile cat. Am J Physiol. 1983 Jun;244(6):R785–R793. doi: 10.1152/ajpregu.1983.244.6.R785. [DOI] [PubMed] [Google Scholar]
  8. Cooper K. E., Veale W. L. The effect of injecting an inert oil into the cerebral ventricular system upon fever produced by intravenous leucocyte pyrogen. Can J Physiol Pharmacol. 1972 Nov;50(11):1066–1071. doi: 10.1139/y72-154. [DOI] [PubMed] [Google Scholar]
  9. Cranston W. I., Duff G. W., Hellon R. F., Mitchell D., Townsend Y. Evidence that brain prostaglandin synthesis is not essential in fever. J Physiol. 1976 Jul;259(1):239–249. doi: 10.1113/jphysiol.1976.sp011464. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Cranston W. I., Hellon R. F., Mitchell D. A dissociation between fever and prostaglandin concentration in cerebrospinal fluid. J Physiol. 1975 Dec;253(2):583–592. doi: 10.1113/jphysiol.1975.sp011208. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Cranston W. I., Hellon R. F., Mitchell D., Townsend Y. Intraventricular injections of drugs which inhibit phospholipase A2 suppress fever in rabbits. J Physiol. 1983 Jun;339:97–105. doi: 10.1113/jphysiol.1983.sp014705. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Cranston W. I., Hellon R. F., Townsend Y. Suppression of fever in rabbits by a protein synthesis inhibitor, anisomycin. J Physiol. 1980 Aug;305:337–344. doi: 10.1113/jphysiol.1980.sp013367. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Crawford I. L., Kennedy J. I., Lipton J. M., Ojeda S. R. Effects of central administation of probenecid on fevers produced by leukocytic pyrogen and PGE2 in the rabbit. J Physiol. 1979 Feb;287:519–533. doi: 10.1113/jphysiol.1979.sp012674. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Dinarello C. A., Bernheim H. A. Ability of human leukocytic pyrogen to stimulate brain prostaglandin synthesis in vitro. J Neurochem. 1981 Sep;37(3):702–708. doi: 10.1111/j.1471-4159.1982.tb12544.x. [DOI] [PubMed] [Google Scholar]
  15. Dinarello C. A. Interleukin-1 and the pathogenesis of the acute-phase response. N Engl J Med. 1984 Nov 29;311(22):1413–1418. doi: 10.1056/NEJM198411293112205. [DOI] [PubMed] [Google Scholar]
  16. Feldberg W., Gupta K. P., Milton A. S., Wendlandt S. Effect of pyrogen and antipyretics on prostaglandin acitvity in cisternal c.s.f. of unanaesthetized cats. J Physiol. 1973 Oct;234(2):279–303. doi: 10.1113/jphysiol.1973.sp010346. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Feldberg W., Gupta K. P. Pyrogen fever and prostaglandin-like activity in cerebrospinal fluid. J Physiol. 1973 Jan;228(1):41–53. doi: 10.1113/jphysiol.1973.sp010071. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Flower R. J. Drugs which inhibit prostaglandin biosynthesis. Pharmacol Rev. 1974 Mar;26(1):33–67. [PubMed] [Google Scholar]
  19. Hales J. R., Bennett J. W., Baird J. A., Fawcett A. A. Thermoregulatory effects of prostaglandins E 1 , E 2 , F 1 and F 2 in the sheep. Pflugers Arch. 1973 Mar 21;339(2):125–133. doi: 10.1007/BF00587179. [DOI] [PubMed] [Google Scholar]
  20. Harrisberg C. J., Laburn H., Mitchell D. Intraventricular microinjections of a stable analogue of prostaglandin endoperoxide cause fever in rabbits. J Physiol. 1979 Jun;291:29–35. doi: 10.1113/jphysiol.1979.sp012797. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Hawkins M., Lipton J. M. Analogs of endoperoxide precursors of prostaglandins: failure to affect body temperature when injected into primary and secondary central temperature controls. Prostaglandins. 1977 Feb;13(2):209–218. doi: 10.1016/0090-6980(77)90002-8. [DOI] [PubMed] [Google Scholar]
  22. Jell R. M., Sweatman P. Prostaglandin-sensitive neurones in cat hypothalamus: relation to thermoregulation and to biogenic amines. Can J Physiol Pharmacol. 1977 Jun;55(3):560–567. doi: 10.1139/y77-078. [DOI] [PubMed] [Google Scholar]
  23. Kandasamy S. B., Kirlin W. G., Kaul P. N. Prostacyclin-induced hypothermia: involvement of central histamine H2-receptors. Life Sci. 1981 Jun 1;28(22):2553–2560. doi: 10.1016/0024-3205(81)90598-1. [DOI] [PubMed] [Google Scholar]
  24. Kantor H. S., Hampton M. Indomethacin in submicromolar concentrations inhibits cyclic AMP-dependent protein kinase. Nature. 1978 Dec 21;276(5690):841–842. doi: 10.1038/276841a0. [DOI] [PubMed] [Google Scholar]
  25. Laburn H., Mitchell D., Rosendorff C. Effects of prostaglandin antagonism on sodium arachidonate fever in rabbits. J Physiol. 1977 May;267(2):559–570. doi: 10.1113/jphysiol.1977.sp011826. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Laburn H., Mitchell D., Stephen J. Effects of intracerebroventricular floctafenine and indomethacin on body temperature in febrile rabbits. Br J Pharmacol. 1980;71(2):525–528. doi: 10.1111/j.1476-5381.1980.tb10967.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Leksell L. G. Effects on fluid balance induced by non-febrile intracerebroventricular infusions of PGE2, PGF2alpha, and arachidonic acid in the goat. Acta Physiol Scand. 1978 Oct;104(2):225–231. doi: 10.1111/j.1748-1716.1978.tb06270.x. [DOI] [PubMed] [Google Scholar]
  28. Milton A. S., Wendlandt S. Effects on body temperature of prostaglandins of the A, E and F series on injection into the third ventricle of unanaesthetized cats and rabbits. J Physiol. 1971 Oct;218(2):325–336. doi: 10.1113/jphysiol.1971.sp009620. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Mitchell D., Laburn H. P. Pathophysiology of temperature regulation. Physiologist. 1985 Dec;28(6):507–517. [PubMed] [Google Scholar]
  30. Nakayama T., Hori T. Effects of anesthetic and pyrogen on thermally sensitive neurons in the brainstem. J Appl Physiol. 1973 Mar;34(3):351–355. doi: 10.1152/jappl.1973.34.3.351. [DOI] [PubMed] [Google Scholar]
  31. Philipp-Dormston W. K. Prostaglandins as possible mediators of fever genesis in man. Zentralbl Bakteriol Orig A. 1976 Dec;236(4):415–421. [PubMed] [Google Scholar]
  32. Philipp-Dormston W. K., Siegert R. Prostaglandins of the E and F series in rabbit cerebrospinal fluid during fever induced by Newcastle disease virus, E. coli-endotoxin, or endogenous pyrogen. Med Microbiol Immunol. 1974 Jun 19;159(4):279–284. doi: 10.1007/BF02123737. [DOI] [PubMed] [Google Scholar]
  33. Pittman Q. J., Veale W. L., Cooper K. E. Absence of fever following intrahypothalamic injections of prostaglandins in sheep. Neuropharmacology. 1977 Nov;16(11):743–749. doi: 10.1016/0028-3908(77)90132-0. [DOI] [PubMed] [Google Scholar]
  34. Pittman Q. J., Veale W. L., Cooper K. E. Temperature responses of lambs after centrally injected prostaglandins and pyrogens. Am J Physiol. 1975 Apr;228(4):1034–1038. doi: 10.1152/ajplegacy.1975.228.4.1034. [DOI] [PubMed] [Google Scholar]
  35. Rosendorff C., Mooney J. J. Central nervous system sites of action of a purified leucocyte pyrogen. Am J Physiol. 1971 Mar;220(3):597–603. doi: 10.1152/ajplegacy.1971.220.3.597. [DOI] [PubMed] [Google Scholar]
  36. Ruwe W. D., Myers R. D. The role of protein synthesis in the hypothalamic mechanism mediating pyrogen fever. Brain Res Bull. 1980 Nov-Dec;5(6):735–743. doi: 10.1016/0361-9230(80)90213-0. [DOI] [PubMed] [Google Scholar]
  37. Sakata Y. Effects of pyrogen on the medullary temperature-responsive neurone of rabbits. Jpn J Physiol. 1979;29(5):585–596. doi: 10.2170/jjphysiol.29.585. [DOI] [PubMed] [Google Scholar]
  38. Sakata Y., Morimoto A., Takase Y., Murakami N. Direct effects of endogenous pyrogen on medullary temperature-responsive neurons in rabbits. Jpn J Physiol. 1981;31(2):247–257. doi: 10.2170/jjphysiol.31.247. [DOI] [PubMed] [Google Scholar]
  39. Sanner J. H. Substances that inhibit the actions of prostaglandins. Arch Intern Med. 1974 Jan;133(1):133–146. [PubMed] [Google Scholar]
  40. Saxena P. N., Beg M. M., Singhal K. C., Ahmad M. Prostaglandin-like activity in the cerebrospinal fluid of febrile patients. Indian J Med Res. 1979 Sep;70:495–498. [PubMed] [Google Scholar]
  41. Saxena P. N. Role of prostaglandins in mediation of pyrogen fever. Indian J Med Res. 1979 Sep;70:499–503. [PubMed] [Google Scholar]
  42. Schoener E. P., Wang S. C. Leukocytic pyrogen and sodium acetylsalicylate on hypothalamic neurons in the cat. Am J Physiol. 1975 Jul;229(1):185–190. doi: 10.1152/ajplegacy.1975.229.1.185. [DOI] [PubMed] [Google Scholar]
  43. Skarnes R. C., Brown S. K., Hull S. S., McCracken J. A. Role of prostaglandin E in the biphasic fever response to endotoxin. J Exp Med. 1981 Oct 1;154(4):1212–1224. doi: 10.1084/jem.154.4.1212. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Spagnuolo C., Galli C., Omini C., Folco G. C. Antipyretic action of mepacrine without blockade of prostaglandin (PG) synthesis in the C.N.S. Pharmacol Res Commun. 1978 Sep;10(8):779–786. doi: 10.1016/s0031-6989(78)80047-2. [DOI] [PubMed] [Google Scholar]
  45. Splawiński J. A., Reichenberg K., Vetulani J., Marchaj J., Kaluza J. Hyperthermic effect of intraventricular injections of arachidonic acid and prostaglandin E2 in the rat. Pol J Pharmacol Pharm. 1974 Jan-Apr;26(1):101–107. [PubMed] [Google Scholar]
  46. Spławiński J. A., Wojtaszek B., Swies J. Endotoxin fever in rats: is it triggered by a decrease in breakdown of prostaglandin E2? Neuropharmacology. 1979 Feb;18(2):111–115. doi: 10.1016/0028-3908(79)90050-9. [DOI] [PubMed] [Google Scholar]
  47. Stitt J. T., Hardy J. D. Microelectrophoresis of PGE1 onto single units in the rabbit hypothalamus. Am J Physiol. 1975 Jul;229(1):240–245. doi: 10.1152/ajplegacy.1975.229.1.240. [DOI] [PubMed] [Google Scholar]
  48. Stitt J. T. Prosaglandin E1 fever induced in rabbits. J Physiol. 1973 Jul;232(1):163–179. doi: 10.1113/jphysiol.1973.sp010262. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Székely M., Komáromi I. Endotoxin and prostaglandin fever of newborn guinea pigs at different ambient temperatures. Acta Physiol Acad Sci Hung. 1978;51(3):293–298. [PubMed] [Google Scholar]
  50. Vane J. R. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nat New Biol. 1971 Jun 23;231(25):232–235. doi: 10.1038/newbio231232a0. [DOI] [PubMed] [Google Scholar]
  51. Veale W. L., Cooper K. E. Prostaglandin in cerebrospinal fluid following perfusion of hypothalamic tissue. J Appl Physiol. 1974 Dec;37(6):942–945. doi: 10.1152/jappl.1974.37.6.942. [DOI] [PubMed] [Google Scholar]
  52. Williams J. W., Rudy T. A., Yaksh T. L., Viswanathan C. T. An extensive exploration of the rat brain for sites mediating prostaglandin-induced hyperthermia. Brain Res. 1977 Jan 21;120(2):251–262. doi: 10.1016/0006-8993(77)90904-0. [DOI] [PubMed] [Google Scholar]

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