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. 1996 Jul;118(5):1317–1325. doi: 10.1111/j.1476-5381.1996.tb15539.x

Effect of CCK receptor antagonists on the antinociceptive, reinforcing and gut motility properties of morphine.

L Singh 1, R J Oles 1, M J Field 1, P Atwal 1, G N Woodruff 1, J C Hunter 1
PMCID: PMC1909600  PMID: 8818359

Abstract

1. The ability of a selective CCKA receptor antagonist PD 140548 and a selective CCKB receptor antagonist CI-988 (formerly PD 134308) to modulate the various in vivo properties of morphine was investigated in the rat. 2. PD 140548 dose-dependently (0.001-1.0 mg kg-1, i.p.) antagonised the development of conditioned place preference to morphine (2.0 mg kg-1, s.c.). In contrast, CI-988 (0.01-1.0 mg kg-1, i.p.) did not affect this morphine-induced behaviour. Neither of the CCK receptor antagonists blocked or generalised to the morphine (3.0 mg kg-1, i.p.) discriminative stimulus. 3. CI-988 (0.001-10.0 mg kg-1, s.c.) at doses of 0.05 and 0.1 mg kg-1 (s.c.), potentiated the antinociceptive action of a threshold dose of morphine (5.0 mg kg-1, i.p.) in a radiant heat model of acute nociception, the rat tail flick test. Furthermore, at 0.01 mg kg-1 it potentiated the antinociceptive action of morphine (3.0 mg kg-1) during the acute phase of the rat paw formalin test. And at doses of 0.01 and 0.1 mg kg-1 it also potentiated the antinociceptive action of morphine (1.0 mg kg-1) during the tonic phase of the formalin test. However, in both models, higher doses of CI-988 were ineffective. In contrast, PD 140548 (0.001-10 mg kg-1, s.c.) was only active at a dose of 1.0 mg kg-1 (s.c.) and only in the tonic phase of the formalin test. Neither CI-988 nor PD 140548 possessed any intrinsic antinociceptive action in either of the tests. Chronic treatment with CI-988 (0.01 mg kg-1, s.c.) prevented the development of tolerance to morphine antinociception (4 mg kg-1, s.c.) following a 6 day period of twice daily injections of morphine escalating from 1 to 16 mg kg-1 (i.p.). 4. Morphine dose-dependently (1-10 mg kg-1, s.c.) reduced the distance travelled by a charcoal meal in the rat intestine. Neither PD 140548 (0.01-1.0 mg kg-1, i.p.) nor CI-988 (0.01-1.0 mg kg-1, i.p.) potentiated or suppressed this inhibitory action of morphine. 5. In conclusion, the results of the present study indicate that CCKA and CCKB receptors modulate different properties of morphine. Thus, whilst a selective CCKA receptor antagonist blocked the rewarding properties of morphine, a selective CCKB receptor antagonist potentiated the antinociceptive action. However, neither compound displayed a potential for modulating the influence of morphine on gastro-intestinal motility. It is suggested that these findings may have important implications for development of CCK receptor antagonists as analgesic adjuncts to the therapeutic use of morphine.

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Selected References

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  1. Barbaz B. S., Hall N. R., Liebman J. M. Antagonism of morphine analgesia by CCK-8-S does not extend to all assays nor all opiate analgesics. Peptides. 1988 Nov-Dec;9(6):1295–1300. doi: 10.1016/0196-9781(88)90195-7. [DOI] [PubMed] [Google Scholar]
  2. Beinfeld M. C., Palkovits M. Distribution of cholecystokinin (CCK) in the rat lower brain stem nuclei. Brain Res. 1982 Apr 22;238(1):260–265. doi: 10.1016/0006-8993(82)90794-6. [DOI] [PubMed] [Google Scholar]
  3. Boden P. R., Higginbottom M., Hill D. R., Horwell D. C., Hughes J., Rees D. C., Roberts E., Singh L., Suman-Chauhan N., Woodruff G. N. Cholecystokinin dipeptoid antagonists: design, synthesis, and anxiolytic profile of some novel CCK-A and CCK-B selective and "mixed" CCK-A/CCK-B antagonists. J Med Chem. 1993 Mar 5;36(5):552–565. doi: 10.1021/jm00057a005. [DOI] [PubMed] [Google Scholar]
  4. Chang R. S., Chen T. B., Bock M. G., Freidinger R. M., Chen R., Rosegay A., Lotti V. J. Characterization of the binding of [3H]L-365,260: a new potent and selective brain cholecystokinin (CCK-B) and gastrin receptor antagonist radioligand. Mol Pharmacol. 1989 Jun;35(6):803–808. [PubMed] [Google Scholar]
  5. Chang R. S., Lotti V. J. Biochemical and pharmacological characterization of an extremely potent and selective nonpeptide cholecystokinin antagonist. Proc Natl Acad Sci U S A. 1986 Jul;83(13):4923–4926. doi: 10.1073/pnas.83.13.4923. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Crawley J. N. Subtype-selective cholecystokinin receptor antagonists block cholecystokinin modulation of dopamine-mediated behaviors in the rat mesolimbic pathway. J Neurosci. 1992 Sep;12(9):3380–3391. doi: 10.1523/JNEUROSCI.12-09-03380.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Dourish C. T., Hawley D., Iversen S. D. Enhancement of morphine analgesia and prevention of morphine tolerance in the rat by the cholecystokinin antagonist L-364,718. Eur J Pharmacol. 1988 Mar 15;147(3):469–472. doi: 10.1016/0014-2999(88)90183-5. [DOI] [PubMed] [Google Scholar]
  8. Dourish C. T., O'Neill M. F., Coughlan J., Kitchener S. J., Hawley D., Iversen S. D. The selective CCK-B receptor antagonist L-365,260 enhances morphine analgesia and prevents morphine tolerance in the rat. Eur J Pharmacol. 1990 Jan 25;176(1):35–44. doi: 10.1016/0014-2999(90)90129-t. [DOI] [PubMed] [Google Scholar]
  9. Faris P. L., Komisaruk B. R., Watkins L. R., Mayer D. J. Evidence for the neuropeptide cholecystokinin as an antagonist of opiate analgesia. Science. 1983 Jan 21;219(4582):310–312. doi: 10.1126/science.6294831. [DOI] [PubMed] [Google Scholar]
  10. Fuji K., Senba E., Fujii S., Nomura I., Wu J. Y., Ueda Y., Tohyama M. Distribution, ontogeny and projections of cholecystokinin-8, vasoactive intestinal polypeptide and gamma-aminobutyrate-containing neuron systems in the rat spinal cord: an immunohistochemical analysis. Neuroscience. 1985 Mar;14(3):881–894. doi: 10.1016/0306-4522(85)90151-4. [DOI] [PubMed] [Google Scholar]
  11. Gall C., Lauterborn J., Burks D., Seroogy K. Co-localization of enkephalin and cholecystokinin in discrete areas of rat brain. Brain Res. 1987 Feb 17;403(2):403–408. doi: 10.1016/0006-8993(87)90085-0. [DOI] [PubMed] [Google Scholar]
  12. Higgins G. A., Joharchi N., Wang Y., Corrigall W. A., Sellers E. M. The CCKA receptor antagonist devazepide does not modify opioid self-administration or drug discrimination: comparison with the dopamine antagonist haloperidol. Brain Res. 1994 Mar 21;640(1-2):246–254. doi: 10.1016/0006-8993(94)91880-5. [DOI] [PubMed] [Google Scholar]
  13. Higgins G. A., Nguyen P., Sellers E. M. Morphine place conditioning is differentially affected by CCKA and CCKB receptor antagonists. Brain Res. 1992 Feb 14;572(1-2):208–215. doi: 10.1016/0006-8993(92)90471-k. [DOI] [PubMed] [Google Scholar]
  14. Hill D. R., Campbell N. J., Shaw T. M., Woodruff G. N. Autoradiographic localization and biochemical characterization of peripheral type CCK receptors in rat CNS using highly selective nonpeptide CCK antagonists. J Neurosci. 1987 Sep;7(9):2967–2976. doi: 10.1523/JNEUROSCI.07-09-02967.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Hill D. R., Shaw T. M., Woodruff G. N. Binding sites for 125I-cholecystokinin in primate spinal cord are of the CCK-A subclass. Neurosci Lett. 1988 Jun 29;89(2):133–139. doi: 10.1016/0304-3940(88)90369-2. [DOI] [PubMed] [Google Scholar]
  16. Hill D. R., Woodruff G. N. Differentiation of central cholecystokinin receptor binding sites using the non-peptide antagonists MK-329 and L-365,260. Brain Res. 1990 Sep 3;526(2):276–283. doi: 10.1016/0006-8993(90)91232-6. [DOI] [PubMed] [Google Scholar]
  17. Hill R. G., Hughes J., Pittaway K. M. Antinociceptive action of cholecystokinin octapeptide (CCK 8) and related peptides in rats and mice: effects of naloxone and peptidase inhibitors. Neuropharmacology. 1987 Apr;26(4):289–300. doi: 10.1016/0028-3908(87)90180-8. [DOI] [PubMed] [Google Scholar]
  18. Hughes J., Boden P., Costall B., Domeney A., Kelly E., Horwell D. C., Hunter J. C., Pinnock R. D., Woodruff G. N. Development of a class of selective cholecystokinin type B receptor antagonists having potent anxiolytic activity. Proc Natl Acad Sci U S A. 1990 Sep;87(17):6728–6732. doi: 10.1073/pnas.87.17.6728. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Hunter J. C., Suman-Chauhan N., Meecham K. G., Dissanayake V. U., Hill D. R., Pritchard M. C., Kneen C. O., Horwell D. C., Hughes J., Woodruff G. N. [3H]PD 140376: a novel and highly selective antagonist radioligand for the cholecystokininB/gastrin receptor in guinea pig cerebral cortex and gastric mucosa. Mol Pharmacol. 1993 Apr;43(4):595–602. [PubMed] [Google Scholar]
  20. Hökfelt T., Rehfeld J. F., Skirboll L., Ivemark B., Goldstein M., Markey K. Evidence for coexistence of dopamine and CCK in meso-limbic neurones. Nature. 1980 Jun 12;285(5765):476–478. doi: 10.1038/285476a0. [DOI] [PubMed] [Google Scholar]
  21. Innis R. B., Snyder S. H. Distinct cholecystokinin receptors in brain and pancreas. Proc Natl Acad Sci U S A. 1980 Nov;77(11):6917–6921. doi: 10.1073/pnas.77.11.6917. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Jackson A., Tattersall D., Bentley G., Rycroft W., Bourson A., Hargreaves R., Tricklebank M., Iversen S. An investigation into the discriminative stimulus and reinforcing properties of the CCKB-receptor antagonist, L-365,260 in rats. Neuropeptides. 1994 May;26(5):343–353. doi: 10.1016/0143-4179(94)90119-8. [DOI] [PubMed] [Google Scholar]
  23. Kellstein D. E., Mayer D. J. Spinal co-administration of cholecystokinin antagonists with morphine prevents the development of opioid tolerance. Pain. 1991 Nov;47(2):221–229. doi: 10.1016/0304-3959(91)90208-F. [DOI] [PubMed] [Google Scholar]
  24. Lavigne G. J., Millington W. R., Mueller G. P. The CCK-A and CCK-B receptor antagonists, devazepide and L-365,260, enhance morphine antinociception only in non-acclimated rats exposed to a novel environment. Neuropeptides. 1992 Feb;21(2):119–129. doi: 10.1016/0143-4179(92)90522-x. [DOI] [PubMed] [Google Scholar]
  25. Ling G. S., MacLeod J. M., Lee S., Lockhart S. H., Pasternak G. W. Separation of morphine analgesia from physical dependence. Science. 1984 Oct 26;226(4673):462–464. doi: 10.1126/science.6541807. [DOI] [PubMed] [Google Scholar]
  26. Maldonado R., Derrien M., Noble F., Roques B. P. Association of the peptidase inhibitor RB 101 and a CCK-B antagonist strongly enhances antinociceptive responses. Neuroreport. 1993 Jul;4(7):947–950. doi: 10.1097/00001756-199307000-00028. [DOI] [PubMed] [Google Scholar]
  27. Marshall F. H., Barnes S., Hughes J., Woodruff G. N., Hunter J. C. Cholecystokinin modulates the release of dopamine from the anterior and posterior nucleus accumbens by two different mechanisms. J Neurochem. 1991 Mar;56(3):917–922. doi: 10.1111/j.1471-4159.1991.tb02009.x. [DOI] [PubMed] [Google Scholar]
  28. Moran T. H., Robinson P. H., Goldrich M. S., McHugh P. R. Two brain cholecystokinin receptors: implications for behavioral actions. Brain Res. 1986 Jan 1;362(1):175–179. doi: 10.1016/0006-8993(86)91413-7. [DOI] [PubMed] [Google Scholar]
  29. Noble F., Derrien M., Roques B. P. Modulation of opioid antinociception by CCK at the supraspinal level: evidence of regulatory mechanisms between CCK and enkephalin systems in the control of pain. Br J Pharmacol. 1993 Aug;109(4):1064–1070. doi: 10.1111/j.1476-5381.1993.tb13730.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Panerai A. E., Rovati L. C., Cocco E., Sacerdote P., Mantegazza P. Dissociation of tolerance and dependence to morphine: a possible role for cholecystokinin. Brain Res. 1987 Apr 28;410(1):52–60. doi: 10.1016/s0006-8993(87)80019-7. [DOI] [PubMed] [Google Scholar]
  31. Phillips A. G., LePiane F. G., Fibiger H. C. Dopaminergic mediation of reward produced by direct injection of enkephalin into the ventral tegmental area of the rat. Life Sci. 1983 Dec 19;33(25):2505–2511. doi: 10.1016/0024-3205(83)90159-5. [DOI] [PubMed] [Google Scholar]
  32. Pisegna J. R., de Weerth A., Huppi K., Wank S. A. Molecular cloning of the human brain and gastric cholecystokinin receptor: structure, functional expression and chromosomal localization. Biochem Biophys Res Commun. 1992 Nov 30;189(1):296–303. doi: 10.1016/0006-291x(92)91557-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Singh L., Field M. J., Vass C. A., Hughes J., Woodruff G. N. The antagonism of benzodiazepine withdrawal effects by the selective cholecystokininB receptor antagonist CI-988. Br J Pharmacol. 1992 Jan;105(1):8–10. doi: 10.1111/j.1476-5381.1992.tb14201.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Singh L., Lewis A. S., Field M. J., Hughes J., Woodruff G. N. Evidence for an involvement of the brain cholecystokinin B receptor in anxiety. Proc Natl Acad Sci U S A. 1991 Feb 15;88(4):1130–1133. doi: 10.1073/pnas.88.4.1130. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Spyraki C., Fibiger H. C., Phillips A. G. Attenuation of heroin reward in rats by disruption of the mesolimbic dopamine system. Psychopharmacology (Berl) 1983;79(2-3):278–283. doi: 10.1007/BF00427827. [DOI] [PubMed] [Google Scholar]
  36. Stanfa L. C., Dickenson A. H. Cholecystokinin as a factor in the enhanced potency of spinal morphine following carrageenin inflammation. Br J Pharmacol. 1993 Apr;108(4):967–973. doi: 10.1111/j.1476-5381.1993.tb13493.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Stanfa L. C., Sullivan A. F., Dickenson A. H. Alterations in neuronal excitability and the potency of spinal mu, delta and kappa opioids after carrageenan-induced inflammation. Pain. 1992 Sep;50(3):345–354. doi: 10.1016/0304-3959(92)90040-I. [DOI] [PubMed] [Google Scholar]
  38. Stengaard-Pedersen K., Larsson L. I. Localization and opiate receptor binding of enkephalin, CCK and ACTH/beta-endorphin in the rat central nervous system. Peptides. 1981;2 (Suppl 1):3–19. doi: 10.1016/0196-9781(81)90050-4. [DOI] [PubMed] [Google Scholar]
  39. Tricklebank M. D., Singh L., Oles R. J., Preston C., Iversen S. D. The behavioural effects of MK-801: a comparison with antagonists acting non-competitively and competitively at the NMDA receptor. Eur J Pharmacol. 1989 Aug 11;167(1):127–135. doi: 10.1016/0014-2999(89)90754-1. [DOI] [PubMed] [Google Scholar]
  40. Vaccarino F. J., Koob G. F. Microinjections of nanogram amounts of sulfated cholecystokinin octapeptide into the rat nucleus accumbens attenuates brain stimulation reward. Neurosci Lett. 1984 Nov 23;52(1-2):61–66. doi: 10.1016/0304-3940(84)90351-3. [DOI] [PubMed] [Google Scholar]
  41. Van Dijk A., Richards J. G., Trzeciak A., Gillessen D., Möhler H. Cholecystokinin receptors: biochemical demonstration and autoradiographical localization in rat brain and pancreas using [3H] cholecystokinin8 as radioligand. J Neurosci. 1984 Apr;4(4):1021–1033. doi: 10.1523/JNEUROSCI.04-04-01021.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Wank S. A., Pisegna J. R., de Weerth A. Brain and gastrointestinal cholecystokinin receptor family: structure and functional expression. Proc Natl Acad Sci U S A. 1992 Sep 15;89(18):8691–8695. doi: 10.1073/pnas.89.18.8691. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Watkins L. R., Kinscheck I. B., Kaufman E. F., Miller J., Frenk H., Mayer D. J. Cholecystokinin antagonists selectively potentiate analgesia induced by endogenous opiates. Brain Res. 1985 Feb 18;327(1-2):181–190. doi: 10.1016/0006-8993(85)91512-4. [DOI] [PubMed] [Google Scholar]
  44. Watkins L. R., Kinscheck I. B., Mayer D. J. Potentiation of morphine analgesia by the cholecystokinin antagonist proglumide. Brain Res. 1985 Feb 18;327(1-2):169–180. doi: 10.1016/0006-8993(85)91511-2. [DOI] [PubMed] [Google Scholar]
  45. White N. M., Packard M. G., Hiroi N. Place conditioning with dopamine D1 and D2 agonists injected peripherally or into nucleus accumbens. Psychopharmacology (Berl) 1991;103(2):271–276. doi: 10.1007/BF02244216. [DOI] [PubMed] [Google Scholar]
  46. Wiesenfeld-Hallin Z., Xu X. J., Hughes J., Horwell D. C., Hökfelt T. PD134308, a selective antagonist of cholecystokinin type B receptor, enhances the analgesic effect of morphine and synergistically interacts with intrathecal galanin to depress spinal nociceptive reflexes. Proc Natl Acad Sci U S A. 1990 Sep;87(18):7105–7109. doi: 10.1073/pnas.87.18.7105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Woodruff G. N., Hughes J. Cholecystokinin antagonists. Annu Rev Pharmacol Toxicol. 1991;31:469–501. doi: 10.1146/annurev.pa.31.040191.002345. [DOI] [PubMed] [Google Scholar]
  48. Zetler G. Ceruletide, ceruletide analogues and cholecystokinin octapeptide (CCK-8): effects on isolated intestinal preparations and gallbladders of guinea pigs and mice. Peptides. 1984 Jul-Aug;5(4):729–736. doi: 10.1016/0196-9781(84)90014-7. [DOI] [PubMed] [Google Scholar]

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