Skip to main content
NCBI home page
British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 1983 Feb;78(2):307–319. doi: 10.1111/j.1476-5381.1983.tb09396.x

The antinociceptive action of etorphine in the dorsal horn is due to a direct spinal action and not to activation of descending inhibition.

S L Clark, R W Ryall
PMCID: PMC2044707  PMID: 6338986

Abstract

1--Etorphine, microinjected into the brainstem or administered intravenously, inhibited the firing of dorsal horn neurones to noxious heat in spinal or non-spinal anaesthetized cats and in decerebrate, non-anaesthetized cats with intact spinal cords. 2--Small doses of etorphine sometimes caused facilitation, especially when the cord was intact, but this was invariably followed by inhibition at higher doses. 3--The ED50 for inhibition (mean 3.9 micrograms/kg) after microinjection into nucleus raphe magnus, nucleus reticularis magnocellularis or the lateral tegmental field was similar at all sites in anaesthetized, non-spinal cats. 4--The ED50 for microinjection was not increased by spinal transection in anaesthetized cats (mean ED50, 2.6 micrograms/kg) and was similar to the ED50 in decerebrate, non-anaesthetized cats. 5--Intravenous administration was 2 to 3 times more effective than microinjection and the time course of inhibition was faster after intravenous administration than after microinjection. 6--It is concluded that etorphine inhibits dorsal horn neurones after microinjection or intravenous administration by a direct action on the spinal cord and not by activating a descending inhibition. After microinjection it rapidly enters the general circulation and subsequently distributes into the spinal cord. 7--It is also concluded that naloxone readily gains entry to the circulation from the brain because microinjection antagonized the effects of systemic etorphine on dorsal horn neurones in spinal cats.

Full text

PDF
307

Selected References

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

  1. Azami J., Llewelyn M. B., Roberts M. H. The contribution of nucleus reticularis paragigantocellularis and nucleus raphe magnus to the analgesia produced by systemically administered morphine, investigated with the microinjection technique. Pain. 1982 Mar;12(3):229–246. doi: 10.1016/0304-3959(82)90155-5. [DOI] [PubMed] [Google Scholar]
  2. Basbaum A. I., Clanton C. H., Fields H. L. Three bulbospinal pathways from the rostral medulla of the cat: an autoradiographic study of pain modulating systems. J Comp Neurol. 1978 Mar 15;178(2):209–224. doi: 10.1002/cne.901780203. [DOI] [PubMed] [Google Scholar]
  3. Belcher G., Ryall R. W. Differential excitatory and inhibitory effects of opiates on non-nociceptive and nociceptive neurones in the spinal cord of the cat. Brain Res. 1978 Apr 28;145(2):303–314. doi: 10.1016/0006-8993(78)90864-8. [DOI] [PubMed] [Google Scholar]
  4. Belcher G., Ryall R. W., Schaffner R. The differential effects of 5-hydroxytryptamine, noradrenaline and raphe stimulation on nociceptive and non-nociceptive dorsal horn interneurones in the cat. Brain Res. 1978 Aug 4;151(2):307–321. doi: 10.1016/0006-8993(78)90887-9. [DOI] [PubMed] [Google Scholar]
  5. Bennett G. J., Mayer D. J. Inhibition of spinal cord interneurons by narcotic microinjection and focal electrical stimulation in the periaqueductal central gray matter. Brain Res. 1979 Aug 24;172(2):243–257. doi: 10.1016/0006-8993(79)90536-5. [DOI] [PubMed] [Google Scholar]
  6. Blane G. F., Boura A. L., Fitzgerald A. E., Lister R. E. Actions of etorphine hydrochloride, (M99): a potent morphine-like agent. Br J Pharmacol Chemother. 1967 May;30(1):11–22. doi: 10.1111/j.1476-5381.1967.tb02108.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Bradley P. B., Dray A. Morphine and neurotransmitter substances: Microiontophoretic study in the rat brain stem. Br J Pharmacol. 1974 Jan;50(1):47–55. doi: 10.1111/j.1476-5381.1974.tb09591.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Bramwell G. J., Bradley P. B. Actions and interactions of narcotic agonists and antagonists on brain stem neurones. Brain Res. 1974 Jun 14;73(1):167–170. doi: 10.1016/0006-8993(74)91017-8. [DOI] [PubMed] [Google Scholar]
  9. Calvillo O., Henry J. L., Neuman R. S. Effects of morphine and naloxone on dorsal horn neurones in the cat. Can J Physiol Pharmacol. 1974 Dec;52(6):1207–1211. doi: 10.1139/y74-158. [DOI] [PubMed] [Google Scholar]
  10. Carstens E., Klumpp D., Zimmermann M. Differential inhibitory effects of medial and lateral midbrain stimulation on spinal neuronal discharges to noxious skin heating in the cat. J Neurophysiol. 1980 Feb;43(2):332–342. doi: 10.1152/jn.1980.43.2.332. [DOI] [PubMed] [Google Scholar]
  11. Davies J., Dray A. Pharmacological and electrophysiological studies of morphine and enkephalin on rat supraspinal neurones and cat spinal neurones. Br J Pharmacol. 1978 May;63(1):87–96. doi: 10.1111/j.1476-5381.1978.tb07778.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Dickenson A. H., Oliveras J. L., Besson J. M. Role of the nucleus raphe magnus in opiate analgesia as studied by the microinjection technique in the rat. Brain Res. 1979 Jul 6;170(1):95–111. doi: 10.1016/0006-8993(79)90943-0. [DOI] [PubMed] [Google Scholar]
  13. Duggan A. W., Griersmith B. T. Inhibition of the spinal transmission of nociceptive information by supraspinal stimulation in the cat. Pain. 1979 Apr;6(2):149–161. doi: 10.1016/0304-3959(79)90122-2. [DOI] [PubMed] [Google Scholar]
  14. Duggan A. W., Griersmith B. T., North R. A. Morphine and supraspinal inhibition of spinal neurones: evidence that morphine decreases tonic descending inhibition in the anaesthetized cat. Br J Pharmacol. 1980 Jul;69(3):461–466. doi: 10.1111/j.1476-5381.1980.tb07035.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Duggan A. W., Hall J. G., Headley P. M. Suppression of transmission of nociceptive impulses by morphine: selective effects of morphine administered in the region of the substantia gelatinosa. Br J Pharmacol. 1977 Sep;61(1):65–76. [PMC free article] [PubMed] [Google Scholar]
  16. Engberg I., Lundberg A., Ryall R. W. Reticulospinal inhibition of interneurones. J Physiol. 1968 Jan;194(1):225–236. doi: 10.1113/jphysiol.1968.sp008403. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Fields H. L., Basbaum A. I., Clanton C. H., Anderson S. D. Nucleus raphe magnus inhibition of spinal cord dorsal horn neurons. Brain Res. 1977 May 13;126(3):441–453. doi: 10.1016/0006-8993(77)90596-0. [DOI] [PubMed] [Google Scholar]
  18. Guilbaud G., Oliveras J. L., Giesler G., Besson J. M. Effects induced by stimulation of the centralis inferior nucleus of the raphe on dorsal horn interneurons in cat's spinal cord. Brain Res. 1977 May 6;126(2):355–360. doi: 10.1016/0006-8993(77)90732-6. [DOI] [PubMed] [Google Scholar]
  19. Hanaoka K., Ohtani M., Toyooka H., Dohi S., Ghazisaidi K., Taub A., Kitahata L. M. The relative contribution of direct and supraspinal descending effects upon spinal mechanisms of morphine analgesia. J Pharmacol Exp Ther. 1978 Nov;207(2):476–484. [PubMed] [Google Scholar]
  20. Jacquet Y. F., Lajtha A. The periaqueductal gray: site of morphine analgesia and tolerance as shown by 2-way cross tolerance between systemic and intracerebral injections. Brain Res. 1976 Feb 27;103(3):501–513. doi: 10.1016/0006-8993(76)90448-0. [DOI] [PubMed] [Google Scholar]
  21. Johnston S. E., Davies J. Descending inhibitions from the nucleus raphe magnus and adjacent reticular formation to the dorsal horn of the rat are not antagonized by bicuculline or strychnine. Neurosci Lett. 1981 Oct;26(1):43–47. doi: 10.1016/0304-3940(81)90423-7. [DOI] [PubMed] [Google Scholar]
  22. Kitahata L. M., Kosaka Y., Taub A., Bonikos K., Hoffert M. Lamina-specific suppression of dorsal-horn unit activity by morphine sulfate. Anesthesiology. 1974 Jul;41(1):39–48. doi: 10.1097/00000542-197407000-00008. [DOI] [PubMed] [Google Scholar]
  23. Le Bars D., Dickenson A. H., Besson J. M. Microinjection of morphine within nucleus raphe magnus and dorsal horn neurone activities related to nociception in the rat. Brain Res. 1980 May 12;189(2):467–481. doi: 10.1016/0006-8993(80)90106-7. [DOI] [PubMed] [Google Scholar]
  24. Le Bars D., Guilbaud G., Chitour D., Besson J. M. Does systemic morphine increase descending inhibitory controls of dorsal horn neurones involved in nociception? Brain Res. 1980 Nov 24;202(1):223–228. doi: 10.1016/0006-8993(80)90659-9. [DOI] [PubMed] [Google Scholar]
  25. Le Bars D., Menétrey D., Conseiller C., Besson J. M. Depressive effects of morphine upon lamina V cells activities in the dorsal horn of the spinal cat. Brain Res. 1975 Nov 14;98(2):261–277. doi: 10.1016/0006-8993(75)90005-0. [DOI] [PubMed] [Google Scholar]
  26. Levy R. A., Proudfit H. K. Analgesia produced by microinjection of baclofen and morphine at brain stem sites. Eur J Pharmacol. 1979 Jul 15;57(1):43–55. doi: 10.1016/0014-2999(79)90102-x. [DOI] [PubMed] [Google Scholar]
  27. Lewis V. A., Gebhart G. F. Evaluation of the periaqueductal central gray (PAG) as a morphine-specific locus of action and examination of morphine-induced and stimulation-produced analgesia at coincident PAG loci. Brain Res. 1977 Mar 25;124(2):283–303. doi: 10.1016/0006-8993(77)90886-1. [DOI] [PubMed] [Google Scholar]
  28. Lynn B. Heat pain sensitivity of human skin after mild heat injury and its lack of dependence of the local blood flow. Pain. 1980 Apr;8(2):189–196. doi: 10.1016/0304-3959(88)90006-1. [DOI] [PubMed] [Google Scholar]
  29. Lynn B. The heat sensitization of polymodal nociceptors in the rabbit and its independence of the local blood flow. J Physiol. 1979 Feb;287:493–507. doi: 10.1113/jphysiol.1979.sp012672. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Misra A. L., Pontani R. B., Vadlamani N. L., Mulé S. J. Physiological disposition and biotransformation of [allyl-1', 3' - 14C naloxone in the rat and some comparative observations on nalorphine. J Pharmacol Exp Ther. 1976 Feb;196(2):257–268. [PubMed] [Google Scholar]
  31. Ossenberg F. W., Peignoux M., Bourdiau D., Benhamou J. P. Pentobarbital pharmacokinetics in the normal and in the hepatectomized rat. J Pharmacol Exp Ther. 1975 Jul;194(1):111–116. [PubMed] [Google Scholar]
  32. Pert A., Yaksh T. Sites of morphine induced analgesia in the primate brain: relation to pain pathways. Brain Res. 1974 Nov 8;80(1):135–140. doi: 10.1016/0006-8993(74)90731-8. [DOI] [PubMed] [Google Scholar]
  33. Rosenfeld J. P., Stocco S. Differential effects of systemic versus intracranial injection of opiates on central, orofacial and lower body nociception: somatotypy in bulbar analgesia systems. Pain. 1980 Dec;9(3):307–318. doi: 10.1016/0304-3959(80)90045-7. [DOI] [PubMed] [Google Scholar]
  34. Wang J. K., Nauss L. A., Thomas J. E. Pain relief by intrathecally applied morphine in man. Anesthesiology. 1979 Feb;50(2):149–151. doi: 10.1097/00000542-197902000-00013. [DOI] [PubMed] [Google Scholar]
  35. Willer J. C., Bussel B. Evidence for a direct spinal mechanism in morphine-induced inhibition of nociceptive reflexes in humans. Brain Res. 1980 Apr 7;187(1):212–215. doi: 10.1016/0006-8993(80)90507-7. [DOI] [PubMed] [Google Scholar]
  36. Willis W. D., Haber L. H., Martin R. F. Inhibition of spinothalamic tract cells and interneurons by brain stem stimulation in the monkey. J Neurophysiol. 1977 Jul;40(4):968–981. doi: 10.1152/jn.1977.40.4.968. [DOI] [PubMed] [Google Scholar]
  37. Yaksh T. L. Inhibition by etorphine of the discharge of dorsal horn neurons: effects on the neuronal response to both high- and low-threshold sensory input in the decerebrate spinal cat. Exp Neurol. 1978 May 15;60(1):23–40. doi: 10.1016/0014-4886(78)90166-8. [DOI] [PubMed] [Google Scholar]
  38. Yaksh T. L., Rudy T. A. Studies on the direct spinal action of narcotics in the production of analgesia in the rat. J Pharmacol Exp Ther. 1977 Aug;202(2):411–428. [PubMed] [Google Scholar]
  39. Zorman G., Hentall I. D., Adams J. E., Fields H. L. Naloxone-reversible analgesia produced by microstimulation in the rat medulla. Brain Res. 1981 Aug 24;219(1):137–148. doi: 10.1016/0006-8993(81)90273-0. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Pharmacology are provided here courtesy of The British Pharmacological Society

RESOURCES