Skip to main content
NCBI home page
British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 1989 Nov;98(3):1039–1049. doi: 10.1111/j.1476-5381.1989.tb14636.x

Delta-opioid mediated inhibitions of acute and prolonged noxious-evoked responses in rat dorsal horn neurones.

A F Sullivan 1, A H Dickenson 1, B P Roques 1
PMCID: PMC1854772  PMID: 2556199

Abstract

1. The effects of a selective delta-opioid agonist Tyr-D-Ser(Otbu)-Gly-Phe-Leu-Thr (DSTBULET) were examined on the C- and A beta-evoked responses of convergent dorsal horn neurones in the halothane anaesthetized, intact rat. 2. Intrathecal DSTBULET produced selective dose-dependent inhibitions of electrically-evoked C fibre responses of both superficial and deep neurones. A near-complete inhibition of 83 +/- 5% followed 100 micrograms of DSTBULET and the ED50 was 9 micrograms (13.5 nmol). Inhibitions were antagonised by intrathecal naloxone and ICI 174,864 but were not antagonised by pretreatment with intrathecal beta-funaltrexamine at a dose that blocked mu-opioid effects. By contrast, DSTBULET produced excitations of electrically-evoked responses of cells recorded in a zone intermediate between the superficial and deep neurones. 3. DSTBULET (50 micrograms) was also tested on the more prolonged noxious neuronal response produced by subcutaneous formalin (5%, 50 microliters) into the receptive field. DSTBULET profoundly inhibited the response to formalin. Pretreatment with ICI 174,864 before DSTBULET antagonised the effects of the delta-agonist on the formalin response. 4. The full peptidase inhibitor kelatorphan, known to protect endogenous enkephalins, was also tested on the formalin response. The intrathecal administration of 50 micrograms kelatorphan has previously been shown to inhibit electrically-evoked C fibre resonses of dorsal horn neurones and to be antagonised by ICI 174,864. The same dose of kelatorphan inhibited the formalin response in the present study. 5. From this study it appears that the delta-opioid agonist DSTBULET can produce profound inhibitions of the responses of convergent neurones to nociceptive afferent inputs. Furthermore, activation of delta-opioid receptors either by DSTBULET, or by protection of endogenous enkephalins with kelatorphan, can inhibit a more prolonged chemically-evoked nociceptive input onto these dorsal horn neurones.

Full text

PDF
1039

Selected References

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

  1. Besson J. M., Chaouch A. Peripheral and spinal mechanisms of nociception. Physiol Rev. 1987 Jan;67(1):67–186. doi: 10.1152/physrev.1987.67.1.67. [DOI] [PubMed] [Google Scholar]
  2. Bourgoin S., Le Bars D., Artaud F., Clot A. M., Bouboutou R., Fournie-Zaluski M. C., Roques B. P., Hamon M., Cesselin F. Effects of kelatorphan and other peptidase inhibitors on the in vitro and in vivo release of methionine-enkephalin-like material from the rat spinal cord. J Pharmacol Exp Ther. 1986 Jul;238(1):360–366. [PubMed] [Google Scholar]
  3. Bourgoin S., Le Bars D., Clot A. M., Hamon M., Cesselin F. Spontaneous and evoked release of met-enkephalin-like material from the spinal cord of arthritic rats in vivo. Pain. 1988 Jan;32(1):107–114. doi: 10.1016/0304-3959(88)90029-2. [DOI] [PubMed] [Google Scholar]
  4. Brown A. G. The dorsal horn of the spinal cord. Q J Exp Physiol. 1982 Apr;67(2):193–212. doi: 10.1113/expphysiol.1982.sp002630. [DOI] [PubMed] [Google Scholar]
  5. Cesselin F., Le Bars D., Bourgoin S., Artaud F., Gozlan H., Clot A. M., Besson J. M., Hamon M. Spontaneous and evoked release of methionine-enkephalin-like material from the rat spinal cord in vivo. Brain Res. 1985 Jul 29;339(2):305–313. doi: 10.1016/0006-8993(85)90096-4. [DOI] [PubMed] [Google Scholar]
  6. Cotton R., Giles M. G., Miller L., Shaw J. S., Timms D. ICI 174864: a highly selective antagonist for the opioid delta-receptor. Eur J Pharmacol. 1984 Jan 27;97(3-4):331–332. doi: 10.1016/0014-2999(84)90470-9. [DOI] [PubMed] [Google Scholar]
  7. 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]
  8. Delay-Goyet P., Seguin C., Daugé V., Calenco G., Morgat J. L., Gacel G., Roques B. P. [3H]DSTBULET, a new linear hexapeptide with both an improved selectivity and a high affinity for delta-opioid receptors. NIDA Res Monogr. 1986;75:197–200. [PubMed] [Google Scholar]
  9. Delay-Goyet P., Zajac J. M., Rigaudy P., Foucaud B., Roques B. P. Comparative binding properties of linear and cyclic delta-selective enkephalin analogues: [3H]-[D-Thr2, Leu5] enkephalyl-Thr6 and [3H]-[D-Pen2, D-Pen5] enkephalin. FEBS Lett. 1985 Apr 22;183(2):439–443. doi: 10.1016/0014-5793(85)80827-9. [DOI] [PubMed] [Google Scholar]
  10. Dickenson A. H., Sullivan A. F. Electrophysiological studies on the effects of intrathecal morphine on nociceptive neurones in the rat dorsal horn. Pain. 1986 Feb;24(2):211–222. doi: 10.1016/0304-3959(86)90044-8. [DOI] [PubMed] [Google Scholar]
  11. Dickenson A. H., Sullivan A. F., Fournie-Zaluski M. C., Roques B. P. Prevention of degradation of endogenous enkephalins produces inhibition of nociceptive neurones in rat spinal cord. Brain Res. 1987 Apr 7;408(1-2):185–191. doi: 10.1016/0006-8993(87)90370-2. [DOI] [PubMed] [Google Scholar]
  12. Dickenson A. H., Sullivan A. F., Knox R., Zajac J. M., Roques B. P. Opioid receptor subtypes in the rat spinal cord: electrophysiological studies with mu- and delta-opioid receptor agonists in the control of nociception. Brain Res. 1987 Jun 9;413(1):36–44. doi: 10.1016/0006-8993(87)90151-x. [DOI] [PubMed] [Google Scholar]
  13. Dickenson A. H., Sullivan A. F. Subcutaneous formalin-induced activity of dorsal horn neurones in the rat: differential response to an intrathecal opiate administered pre or post formalin. Pain. 1987 Sep;30(3):349–360. doi: 10.1016/0304-3959(87)90023-6. [DOI] [PubMed] [Google Scholar]
  14. Dickenson A. H., Sullivan A., Feeney C., Fournie-Zaluski M. C., Roques B. P. Evidence that endogenous enkephalins produce delta-opiate receptor mediated neuronal inhibitions in rat dorsal horn. Neurosci Lett. 1986 Dec 12;72(2):179–182. doi: 10.1016/0304-3940(86)90076-5. [DOI] [PubMed] [Google Scholar]
  15. Duggan A. W., Hall J. G., Headley P. M. Enkephalins and dorsal horn neurones of the cat: effects on responses to noxious and innocuous skin stimuli. Br J Pharmacol. 1977 Nov;61(3):399–408. doi: 10.1111/j.1476-5381.1977.tb08432.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Duggan A. W., Hall J. G., Headley P. M. Morphine, enkephalin and the substantia gelatinosa. Nature. 1976 Dec 2;264(5585):456–458. doi: 10.1038/264456a0. [DOI] [PubMed] [Google Scholar]
  17. Duggan A. W., Johnson S. M., Morton C. R. Differing distributions of receptors for morphine and Met5-enkephalinamide in the dorsal horn of the cat. Brain Res. 1981 Dec 21;229(2):379–387. doi: 10.1016/0006-8993(81)91002-7. [DOI] [PubMed] [Google Scholar]
  18. Fleetwood-Walker S. M., Hope P. J., Mitchell R., el-Yassir N., Molony V. The influence of opioid receptor subtypes on the processing of nociceptive inputs in the spinal dorsal horn of the cat. Brain Res. 1988 Jun 7;451(1-2):213–226. doi: 10.1016/0006-8993(88)90766-4. [DOI] [PubMed] [Google Scholar]
  19. Fournie-Zaluski M. C., Chaillet P., Bouboutou R., Coulaud A., Cherot P., Waksman G., Costentin J., Roques B. P. Analgesic effects of kelatorphan, a new highly potent inhibitor of multiple enkephalin degrading enzymes. Eur J Pharmacol. 1984 Jul 20;102(3-4):525–528. doi: 10.1016/0014-2999(84)90575-2. [DOI] [PubMed] [Google Scholar]
  20. 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]
  21. Go V. L., Yaksh T. L. Release of substance P from the cat spinal cord. J Physiol. 1987 Oct;391:141–167. doi: 10.1113/jphysiol.1987.sp016731. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Gouardères C., Cros J., Quirion R. Autoradiographic localization of mu, delta and kappa opioid receptor binding sites in rat and guinea pig spinal cord. Neuropeptides. 1985 Jul;6(4):331–342. doi: 10.1016/0143-4179(85)90006-x. [DOI] [PubMed] [Google Scholar]
  23. Hentall I. D., Fields H. L. Actions of opiates, substance P, and serotonin on the excitability of primary afferent terminals and observations on interneuronal activity in the neonatal rat's dorsal horn in vitro. Neuroscience. 1983 Jul;9(3):521–528. doi: 10.1016/0306-4522(83)90170-7. [DOI] [PubMed] [Google Scholar]
  24. Heyman J. S., Mulvaney S. A., Mosberg H. I., Porreca F. Opioid delta-receptor involvement in supraspinal and spinal antinociception in mice. Brain Res. 1987 Sep 8;420(1):100–108. doi: 10.1016/0006-8993(87)90244-7. [DOI] [PubMed] [Google Scholar]
  25. Higashi H., Shinnick-Gallagher P., Gallagher J. P. Morphine enhances and depresses Ca2+-dependent responses in visceral primary afferent neurons. Brain Res. 1982 Nov 11;251(1):186–191. doi: 10.1016/0006-8993(82)91291-4. [DOI] [PubMed] [Google Scholar]
  26. Hirota N., Kuraishi Y., Hino Y., Sato Y., Satoh M., Takagi H. Met-enkephalin and morphine but not dynorphin inhibit noxious stimuli-induced release of substance P from rabbit dorsal horn in situ. Neuropharmacology. 1985 Jun;24(6):567–570. doi: 10.1016/0028-3908(85)90065-6. [DOI] [PubMed] [Google Scholar]
  27. Hunt S. P., Kelly J. S., Emson P. C. The electron microscopic localization of methionine-enkephalin within the superficial layers (I and II) of the spinal cord. Neuroscience. 1980;5(11):1871–1890. doi: 10.1016/0306-4522(80)90036-6. [DOI] [PubMed] [Google Scholar]
  28. Hylden J. L., Wilcox G. L. Pharmacological characterization of substance P-induced nociception in mice: modulation by opioid and noradrenergic agonists at the spinal level. J Pharmacol Exp Ther. 1983 Aug;226(2):398–404. [PubMed] [Google Scholar]
  29. Hökfelt T., Ljungdahl A., Terenius L., Elde R., Nilsson G. Immunohistochemical analysis of peptide pathways possibly related to pain and analgesia: enkephalin and substance P. Proc Natl Acad Sci U S A. 1977 Jul;74(7):3081–3085. doi: 10.1073/pnas.74.7.3081. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Jeftinija S. Enkephalins modulate excitatory synaptic transmission in the superficial dorsal horn by acting at mu-opioid receptor sites. Brain Res. 1988 Sep 20;460(2):260–268. doi: 10.1016/0006-8993(88)90371-x. [DOI] [PubMed] [Google Scholar]
  31. Kosterlitz H. W., Paterson S. J. Types of opioid receptors: relation to antinociception. Philos Trans R Soc Lond B Biol Sci. 1985 Feb 19;308(1136):291–297. doi: 10.1098/rstb.1985.0029. [DOI] [PubMed] [Google Scholar]
  32. Kuraishi Y., Hirota N., Satoh M., Takagi H. Antinociceptive effects of intrathecal opioids, noradrenaline and serotonin in rats: mechanical and thermal algesic tests. Brain Res. 1985 Feb 4;326(1):168–171. doi: 10.1016/0006-8993(85)91398-8. [DOI] [PubMed] [Google Scholar]
  33. LaMotte C. C., de Lanerolle N. C. Ultrastructure of chemically defined neuron systems in the dorsal horn of the monkey. II. Methionine-enkephalin immunoreactivity. Brain Res. 1983 Sep 5;274(1):51–63. doi: 10.1016/0006-8993(83)90520-6. [DOI] [PubMed] [Google Scholar]
  34. Mauborgne A., Lutz O., Legrand J. C., Hamon M., Cesselin F. Opposite effects of delta and mu opioid receptor agonists on the in vitro release of substance P-like material from the rat spinal cord. J Neurochem. 1987 Feb;48(2):529–537. doi: 10.1111/j.1471-4159.1987.tb04125.x. [DOI] [PubMed] [Google Scholar]
  35. Maurer R., Cortés R., Probst A., Palacios J. M. Multiple opiate receptor in human brain: an autoradiographic investigation. Life Sci. 1983;33 (Suppl 1):231–234. doi: 10.1016/0024-3205(83)90485-x. [DOI] [PubMed] [Google Scholar]
  36. McQuay H. J., Sullivan A. F., Smallman K., Dickenson A. H. Intrathecal opioids, potency and lipophilicity. Pain. 1989 Jan;36(1):111–115. doi: 10.1016/0304-3959(89)90118-8. [DOI] [PubMed] [Google Scholar]
  37. Morris B. J., Herz A. Distinct distribution of opioid receptor types in rat lumbar spinal cord. Naunyn Schmiedebergs Arch Pharmacol. 1987 Aug;336(2):240–243. doi: 10.1007/BF00165811. [DOI] [PubMed] [Google Scholar]
  38. Mosberg H. I., Hurst R., Hruby V. J., Gee K., Yamamura H. I., Galligan J. J., Burks T. F. Bis-penicillamine enkephalins possess highly improved specificity toward delta opioid receptors. Proc Natl Acad Sci U S A. 1983 Oct;80(19):5871–5874. doi: 10.1073/pnas.80.19.5871. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Neumaier J. F., Mailheau S., Chavkin C. Opioid receptor-mediated responses in the dentate gyrus and CA1 region of the rat hippocampus. J Pharmacol Exp Ther. 1988 Feb;244(2):564–570. [PubMed] [Google Scholar]
  40. Pohl M., Mauborgne A., Bourgoin S., Benoliel J. J., Hamon M., Cesselin F. Neonatal capsaicin treatment abolishes the modulations by opioids of substance P release from rat spinal cord slices. Neurosci Lett. 1989 Jan 2;96(1):102–107. doi: 10.1016/0304-3940(89)90250-4. [DOI] [PubMed] [Google Scholar]
  41. Porreca F., Mosberg H. I., Hurst R., Hruby V. J., Burks T. F. Roles of mu, delta and kappa opioid receptors in spinal and supraspinal mediation of gastrointestinal transit effects and hot-plate analgesia in the mouse. J Pharmacol Exp Ther. 1984 Aug;230(2):341–348. [PubMed] [Google Scholar]
  42. Portoghese P. S., Larson D. L., Sayre L. M., Fries D. S., Takemori A. E. A novel opioid receptor site directed alkylating agent with irreversible narcotic antagonistic and reversible agonistic activities. J Med Chem. 1980 Mar;23(3):233–234. doi: 10.1021/jm00177a002. [DOI] [PubMed] [Google Scholar]
  43. Quirion R., Zajac J. M., Morgat J. L., Roques B. P. Autoradiographic distribution of mu and delta opiate receptors in rat brain using highly selective ligands. Life Sci. 1983;33 (Suppl 1):227–230. doi: 10.1016/0024-3205(83)90484-8. [DOI] [PubMed] [Google Scholar]
  44. Randić M., Miletić V. Depressant actions of methionine-enkephalin and somatostatin in cat dorsal horn neurones activated by noxious stimuli. Brain Res. 1978 Aug 18;152(1):196–202. doi: 10.1016/0006-8993(78)90148-8. [DOI] [PubMed] [Google Scholar]
  45. Rodriguez R. E., Leighton G., Hill R. G., Hughes J. In vivo evidence for spinal delta-opiate receptor operated antinociception. Neuropeptides. 1986 Oct;8(3):221–241. doi: 10.1016/0143-4179(86)90050-8. [DOI] [PubMed] [Google Scholar]
  46. Rothman R. B., Westfall T. C. Morphine allosterically modulates the binding of [3H]leucine enkephalin to a particulate fraction of rat brain. Mol Pharmacol. 1982 May;21(3):538–547. [PubMed] [Google Scholar]
  47. Russell R. D., Leslie J. B., Su Y. F., Watkins W. D., Chang K. J. Continuous intrathecal opioid analgesia: tolerance and cross-tolerance of mu and delta spinal opioid receptors. J Pharmacol Exp Ther. 1987 Jan;240(1):150–158. [PubMed] [Google Scholar]
  48. Sastry B. R., Goh J. W. Actions of morphine and met-enkephalin-amide on nociceptor driven neurones in substantia gelatinosa and deeper dorsal horn. Neuropharmacology. 1983 Jan;22(1):119–122. doi: 10.1016/0028-3908(83)90270-8. [DOI] [PubMed] [Google Scholar]
  49. Sastry B. R. Presynaptic effects of morphine and methionine-enkephalin in feline spinal cord. Neuropharmacology. 1979 Apr;18(4):367–375. doi: 10.1016/0028-3908(79)90144-8. [DOI] [PubMed] [Google Scholar]
  50. Satoh M., Kawajiri S. I., Ukai Y., Yamamoto M. Selective and non-selective inhibition by enkephalins and noradrenaline of nociceptive response of lamina V type neurons in the spinal dorsal horn of the rabbit. Brain Res. 1979 Nov 16;177(2):384–387. doi: 10.1016/0006-8993(79)90791-1. [DOI] [PubMed] [Google Scholar]
  51. Schmauss C., Yaksh T. L. In vivo studies on spinal opiate receptor systems mediating antinociception. II. Pharmacological profiles suggesting a differential association of mu, delta and kappa receptors with visceral chemical and cutaneous thermal stimuli in the rat. J Pharmacol Exp Ther. 1984 Jan;228(1):1–12. [PubMed] [Google Scholar]
  52. Schoffelmeer A. N., Rice K. C., Heijna M. H., Hogenboom F., Mulder A. H. Fentanyl isothiocyanate reveals the existence of physically associated mu- and delta-opioid receptors mediating inhibition of adenylate cyclase in rat neostriatum. Eur J Pharmacol. 1988 Apr 27;149(1-2):179–182. doi: 10.1016/0014-2999(88)90060-x. [DOI] [PubMed] [Google Scholar]
  53. Shaw J. S., Rourke J. D., Burns K. M. Differential sensitivity of antinociceptive tests to opioid agonists and partial agonists. Br J Pharmacol. 1988 Oct;95(2):578–584. doi: 10.1111/j.1476-5381.1988.tb11679.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Tung A. S., Yaksh T. L. In vivo evidence for multiple opiate receptors mediating analgesia in the rat spinal cord. Brain Res. 1982 Sep 9;247(1):75–83. doi: 10.1016/0006-8993(82)91029-0. [DOI] [PubMed] [Google Scholar]
  55. Ueda H., Fukushima N., Kitao T., Ge M., Takagi H. Low doses of naloxone produce analgesia in the mouse brain by blocking presynaptic autoinhibition of enkephalin release. Neurosci Lett. 1986 Apr 24;65(3):247–252. doi: 10.1016/0304-3940(86)90269-7. [DOI] [PubMed] [Google Scholar]
  56. Waksman G., Hamel E., Fournié-Zaluski M. C., Roques B. P. Autoradiographic comparison of the distribution of the neutral endopeptidase "enkephalinase" and of mu and delta opioid receptors in rat brain. Proc Natl Acad Sci U S A. 1986 Mar;83(5):1523–1527. doi: 10.1073/pnas.83.5.1523. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Werz M. A., Grega D. S., MacDonald R. L. Actions of mu, delta and kappa opioid agonists and antagonists on mouse primary afferent neurons in culture. J Pharmacol Exp Ther. 1987 Oct;243(1):258–263. [PubMed] [Google Scholar]
  58. Wiesenfeld-Hallin Z., Duranti R. Intrathecal cholecystokinin interacts with morphine but not substance P in modulating the nociceptive flexion reflex in the rat. Peptides. 1987 Jan-Feb;8(1):153–158. doi: 10.1016/0196-9781(87)90179-3. [DOI] [PubMed] [Google Scholar]
  59. Willcockson W. S., Chung J. M., Hori Y., Lee K. H., Willis W. D. Effects of iontophoretically released peptides on primate spinothalamic tract cells. J Neurosci. 1984 Mar;4(3):741–750. doi: 10.1523/JNEUROSCI.04-03-00741.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Willcockson W. S., Kim J., Shin H. K., Chung J. M., Willis W. D. Actions of opioids on primate spinothalamic tract neurons. J Neurosci. 1986 Sep;6(9):2509–2520. doi: 10.1523/JNEUROSCI.06-09-02509.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Woolf C. J., Fitzgerald M. Lamina-specific alteration of C-fibre evoked activity by morphine in the dorsal horn of the rat spinal cord. Neurosci Lett. 1981 Aug 7;25(1):37–41. doi: 10.1016/0304-3940(81)90097-5. [DOI] [PubMed] [Google Scholar]
  62. Yaksh T. L. In vivo studies on spinal opiate receptor systems mediating antinociception. I. Mu and delta receptor profiles in the primate. J Pharmacol Exp Ther. 1983 Aug;226(2):303–316. [PubMed] [Google Scholar]
  63. Zajac J. M., Gacel G., Petit F., Dodey P., Rossignol P., Roques B. P. Deltakephalin, Tyr-D-Thr-Gly-Phe-Leu-Thr: a new highly potent and fully specific agonist for opiate delta-receptors. Biochem Biophys Res Commun. 1983 Mar 16;111(2):390–397. doi: 10.1016/0006-291x(83)90318-2. [DOI] [PubMed] [Google Scholar]
  64. Zajac J. M., Lombard M. C., Peschanski M., Besson J. M., Roques B. P. Autoradiographic study of mu and delta opioid binding sites and neutral endopeptidase-24.11 in rat after dorsal root rhizotomy. Brain Res. 1989 Jan 16;477(1-2):400–403. doi: 10.1016/0006-8993(89)91436-4. [DOI] [PubMed] [Google Scholar]
  65. Zieglgänsberger W., French E. D., Siggins G. R., Bloom F. E. Opioid peptides may excite hippocampal pyramidal neurons by inhibiting adjacent inhibitory interneurons. Science. 1979 Jul 27;205(4404):415–417. doi: 10.1126/science.451610. [DOI] [PubMed] [Google Scholar]

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

RESOURCES