Psychopharmacology

, Volume 111, Issue 4, pp 457–464 | Cite as

Reduction of morphine dependence and potentiation of analgesia by chronic co-administration of nifedipine

  • Lucyna Antkiewicz-Michaluk
  • Jerzy Michaluk
  • Irena Romańska
  • Jerzy Vetulani
Original Investigations

Abstract

Nifedipine, 5 mg/kg IP, potentiated the morphine-induced analgesia measured in the hot-plate, but not in the tail-flick test. Further experiments were carried out using the hot-plate test only. Pretreatment with nifedipine partially restores the analgesic action of morphine in morphine-tolerant rats. Co-administration of nifedipine with morphine in a chronic experiment did not prevent the loss of morphine efficiency (an increase in latency of 44% was not significant) and did not prevent the debilitating effect of chronic morphine administration reflected by an inhibition of the body weight gain, but prevented naloxone-induced withdrawal syndrome (quantified by counting head shakes) in the test carried out 24 h after the injection of nifedipine, when the drug did not affect morphine analgesia. Chronic treatment with either morphine or nifedipine did not produce a significant increase in the density of [3H] naloxone or [3H]prazosin binding sites in the cortex and in the rest of the brain (measured 24 h after the last dose), but the combined treatment resulted in a significant increase in the cortical [3H]prazosin binding site density. The present results suggest that opiate tolerance and physical dependence may be separated by coadministration of nifedipine and suggest that the combined chronic treatment with morphine and nifedipine may increase the efficacy of morphine during chronic treatment and prevent development of abstinence.

Key words

Morphine analgesia Morphine tolerance Morphine dependence Nifedipine Calcium channel antagonist Chronic treatment 

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References

  1. Antkiewicz-Michaluk L, Michaluk J, Marona-Lewicka D, Vetulani J (1988) The effect of morphine dependence and abstinence on opioid receptors in cerebral cortex and spinal cord of the rat. Pol J Pharmacol Pharm 40:11–16PubMedGoogle Scholar
  2. Antikiewicz-Michaluk L, Michaluk J, Romanska I, Vetulani J (1990) Cortical dihydropyridine binding sites and a behavioral syndrome in morphine-abstinent rats. Eur J Pharmacol 180:129–135CrossRefPubMedGoogle Scholar
  3. Antkiewicz-Michaluk L, Michaluk J, Romanska I, Vetulani J (1991) Role of calcium channels in effects of antidepressant drugs on responsiveness to pain. Psychopharmacology 105:269–274Google Scholar
  4. Ayesta FJ (1991) Tolerance and physical dependence: physiological manifestations of chronic exposure to opioids. In: Almeida OXF, Shippenberg TS (eds) Neurobiology of opioids. Springer, Berlin Hidelberg New York, pp 387–405Google Scholar
  5. Baeyens JM, Esposito E, Ossowska G, Samanin R (1987) Effects of peripheral and central administration of calcium channel blockers in the naloxone-precipitated abstinence syndrome in morphine-dependent rats. Eur J Pharmacol 137:9–13CrossRefPubMedGoogle Scholar
  6. Bongianni F, Carla V, Moroni F, Pellegrini-Giampietro DE (1986) Calcium channel inhibitors suppress the morphine-withdrawal syndrome in rats. Br J Pharmacol 88:561–567PubMedGoogle Scholar
  7. Bozarth MA (1983) Opiate reward mechanisms mapped by intracranial self administration. In: Smith JE, Lane JD (eds) The neurobiology of opiate reward processes. Elsevier, New York, pp 551–555Google Scholar
  8. Bozarth MA, Wise RA (1984) Anatomically distinct opiate receptor fields mediate reward and physical dependence. Science 224:516–517Google Scholar
  9. Bray GA (1960) A simple efficient liquid scintillator for counting solutions in a liquid scintillation counter. Anal Biochem 1:279–285CrossRefGoogle Scholar
  10. Caro G, Barrios M, Baeyens JM (1988) Dose-dependent and stereoselective antagonism by diltiazem of naloxone-precipitated morphine abstinence after acute morphine dependence in vivo and in vitro. Life Sci 43:1523–1527CrossRefPubMedGoogle Scholar
  11. Chapman DB, Way EL (1980) Metal ion interactions with opiates. Annu Rev Pharmacol Toxicol 20:553–579CrossRefPubMedGoogle Scholar
  12. Charney DS, Riodan CE, Kleber HD, Murburg M, Braverman P, Sternberg DE, Heninger GR, Redmond DE (1982) Clonidine and naltrexone. A safe, effective and rapid treatment of abrupt withdrawal from methadone therapy. Arch Gen Psychiatry 39:1327–1333PubMedGoogle Scholar
  13. Christie MJ, Williams JT, North RA (1987) Cellular mechanisms of opioid tolerance: studies in single brain neurons. Mol Pharmacol 32:633–638PubMedGoogle Scholar
  14. Contreras E, Tamayo L, Amigo M (1988) Calcium channel antagonists increase morphine-induced analgesia and antagonize morphine tolerance. Eur J Pharmacol 148:463–466CrossRefPubMedGoogle Scholar
  15. Gold MS, Redmond DE Jr, Kleber HD (1978) Clonidine blocks acute opiate-withdrawal symptoms. Lancet ii:599–602CrossRefGoogle Scholar
  16. Hoffmeister F, Tettenborn D (1986) Calcium agonists and antagonists of dihydropyridine type: antinociceptive effects, interference with opiate-μ-receptor agonists and neuropharmacological action in rodents. Psychopharmacology 90:299–307PubMedGoogle Scholar
  17. Hölt V, Dum J, Blasig J, Schubert P, Herz A (1975) Comparison of in vivo and in vitro parameters of opiate receptor binding in naive and tolerant/dependent rats. Life Sci 16:1823–1828CrossRefPubMedGoogle Scholar
  18. Jacquet YF, Lajtha A (1976) The periaqueductal gray: site of morphine analgesia and tolerance as shown by 2-way cross tolerance between systematic and intracerebral injections. Brain Res 103:501–513CrossRefPubMedGoogle Scholar
  19. Janicki PK, Siembab D, Paulo EA, Krzaścik P (1988) Single-dose kinetics of nifedipine in rat plasma and brain. Pharmacology 36:183–187PubMedGoogle Scholar
  20. Kavaliers M (1987) Stimulatory influences of calcium channel antagonists on stress-induced opioid analgesia and locomotor activity. Brain Res 408:403–407CrossRefPubMedGoogle Scholar
  21. Koob GF, Bloom FE (1988) Cellular and molecular mechanisms of drug dependence. Science 242:715–723Google Scholar
  22. Louie AK, Way EL (1991) Overview of opioid tolerance and physical dependence. In: Almeida OXF, Shippenberg TS (eds) Neurobiology of opioids. Springer, Berlin Heidelberg, New York, pp 417–439Google Scholar
  23. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275PubMedGoogle Scholar
  24. Mayer DJ, Liebeskind JC (1974) Pain reduction by focal electrical stimulation of the brain: an anatomical and behavioral analysis. Brain Res 68:73–93CrossRefPubMedGoogle Scholar
  25. Ohnishi T, Saito K, Maeda S, Matsumoto K, Sakuda M, Inoki R (1990) Intracerebroventricular treatment of mice with pertussis toxin induces hyperalgesia and enhances3H-nitrendipine binding to synaptic membranes: similarity with morphine tolerance. Naunyn-Schmiedeberg's Arch Pharmacol 341:123–127CrossRefGoogle Scholar
  26. Pellegrini-Giampietro DE, Bacciottini L, Carla V, Moroni F (1988) Morphine withdrawal in cortical slices: suppression by Ca2+-channel inhibitors of abstinence-induced [3H]-noradrenaline release, Br J Pharmacol 93:535–540PubMedGoogle Scholar
  27. Pert A, Yaksh T (1975) Localization of the antinociceptive action of morphine in primate brain. Pharmacol Biochem Behav 3:133–138CrossRefPubMedGoogle Scholar
  28. Ramaswamy S, Rajasekaran M, Bapna JS (1986) Role of calcium in prolactin analgesia. Arch Int Pharmacodyn Ther 283:56–60PubMedGoogle Scholar
  29. Ramkumar V, El-Fakahany E (1988) Prolonged morphine treatment increases rat brain dihydropyridine binding sites: possible involvement in development of morphine dependence. Eur J Pharmocol 146:73–83CrossRefGoogle Scholar
  30. Schulz R (1991) Aspect of opioid tolerance and dependence in peripheral nerve tissues. In: Almeida OXF, Shippenberg TS (eds) Neurobiology of opioids, Springer, Berlin Heidelberg, New York, pp 407–415Google Scholar
  31. Schurr A, Rigor BM, Ho BT, Dafny N (1981) Periaqueductal gray neurons response to microiontophoretically injected morphine in naive and morphine-dependent rats. Brain Res Bull 6:473–478CrossRefPubMedGoogle Scholar
  32. Shippenberg TS, Bals-Kubik R (1991) Motivational effects of opioids: Neurochemical and neuroanatomical substrates. In: Almeida OXF, Shippenberg TS (eds) Neurobiology of opioids. Springer, Berlin Heidelberg, New York, pp 330–350Google Scholar
  33. Thirugnanasambantham P, Viswanathan S, Ramaswamy S, Krishnamurthy V, Mythirayee Cl, Ramachandran S, Kameswaran L (1988) Involvement of calcium in flavonoid analgesia. Eur J Pharmacol 152:367–369CrossRefPubMedGoogle Scholar
  34. Urca G, Nahin RL, Liebeskind JC (1979) Development of tolerance to the effects of morphine: association between analgesia and electrical activity in the periaqueductal gray matter. Brain Res 176:202–207CrossRefPubMedGoogle Scholar
  35. Valeri P, Martinelli B, Morrone LA, Severini C (1990) Reproducible withdrawal contractions of isolated guinea-pig ileum after brief morphine exposure: effects of clonidine and nifedipine. J Pharm Pharmacol 42:115–120PubMedGoogle Scholar
  36. Vetulani J, Bednarczyk B (1977) Depression by clonidine of shaking behaviour elicited by nalorphine in morphine-dependent rats. J Pharm Pharmacol 29:567–569PubMedGoogle Scholar
  37. Von Bormann B, Boldt J, Sturm G, Kling D, Weidler B, Lohmann E, Hempelmann G (1985) Calciumantagonisten in der Analgesie. Additive Analgesie durch Nimodipin während kardiochirurgischer Eingriffe. Anaesthetist 34:429–435Google Scholar
  38. Whittaker VP, Barker LA (1972) The subcellular fractionation of brain tissue with special reference to the preparation of synaptosomes and their component organelles. In: Fried R (ed) Methods of Neurochemistry, vol 2. Dekker, New York, pp 1–52Google Scholar
  39. Wilcox RE, Mikula JA, Levitt RA (1979) Periaqueductal gray naloxone microinjections in morphine-dependent rats: hyperalgesia without “classical” withdrawal. Neuropharmacology 18:639–641CrossRefPubMedGoogle Scholar
  40. Woolfe G, MacDonald AD (1944) The evaluation of the analgesic action of pethidine hydrochloride. J Pharmacol Exp Ther 80:300–307Google Scholar
  41. Yaksh TL (1978a) Opiate receptors for behavioral analgesia resemble those related to the depression of spinal nociceptive neurons. Science 199:1231–1233Google Scholar
  42. Yaksh TL (1978b) Narcotic analgetics: CNS sites and mechanisms as revealed by intracerebral injection techniques. Pain 4:299–359CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 1993

Authors and Affiliations

  • Lucyna Antkiewicz-Michaluk
    • 1
  • Jerzy Michaluk
    • 1
  • Irena Romańska
    • 1
  • Jerzy Vetulani
    • 1
  1. 1.Polish Academy of SciencesInstitute of PharmacologyKrakówPoland

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