Summary
The study was aimed at elucidating the possible participation of l-type Ca2+ channel in the acute analgesic effect of an opiate and the development of tolerance to this action. Sufentanil, a selective p agonist, and two dihydropyridines, the Ca2+ antagonist nimodipine and the Ca2+ agonist Bay K 8644, were selected. The tail-flick test was used to assess the nociceptive threshold. In naive rats, nimodipine (200 μg/kg) potentiated the analgesic effect of sufentanil reducing the ED50 from 0.26 to 0.08 μg/kg. Similar results were observed with its (−)-enantiomer Bay N 5248, while the (+) enantiomer Bay N 5247 was ineffective. Tolerance to the opiate was induced by chronic subcutaneous administration of sufentanil with minipumps (2 μg/h, 7 days). In these conditions the dose-response curve to sufentanil was displaced to the right and the ED50 was increased to 1.49 μg/kg. In tolerant rats, nimodipine preserved its potentiating ability and prevented the displacement to the right of the sufentanil dose response-curve (ED50 = 0.48 μg/kg). When nimodipine was pumped (1 μg/h, 7 days) concurrently with sufentanil, the development of tolerance to the opioid was not disturbed. However, the expression of tolerance was abolished and even the effect of acutely administered sufentanil was markedly potentiated (ED50 = 0.03 μg/kg). Similar experiments were performed with Bay K 8644. In naive rats, Bay K 8644 at a low dose (20 μg/kg) that behaves as a calcium agonist, antagonized the analgesic effect of sufentanil (ED50 = 0.58 μg/kg), whereas at a high dose (200 μg/kg) it potentiated this action (ED50 = 0.15 μg/kg). In tolerant rats, Bay K 8644 (20 μg/kg) preserved its antagonizing ability inducing a displacement to the right of the sufentanildose-response curve (ED50 = 4.2 μg/kg). When Bay K 8644 was pumped (1 μg/h, 7 days) concurrently with sufentanil, it enhanced the expression of tolerance to the opiate (ED50 = 3.8 μg/kg). These results suggest that the calcium fluxes through the l-type channel in neurones are functionally linked to the activation of the μ opiate receptor: the blockade of the channel increased the potency of sufentanil, whereas its activation reduced the potency of the opiate. In chronic experiments, DHPs concurrently administered with sufentanil did not affect the development of tolerance to the opiate. However, nimodipine prevented the expression of this phenomenon. Even more, the animals became hypersensitive to the opiate suggesting that the adaptative mechanisms induced by chronic opiate could be affected by chronic nimodipine.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Attali B, Saya D, Nah S-Y, Vogel Z (1989) K-Opiate agonists inhibit Ca2+ influx in rat spinal cord-dorsal root ganglion cocultures. J Biol Chem 264:347–353
Ayesta FJ, Flórez J (1989) Development of tolerance to the respiratory actions of sufentanil: route-dependent and differential tolerance. J Pharmacol Exp Ther 250:371–378
Baeyens JM, Espósito E, Ossowska A, 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 137:9–14
Bechem M, Hebisch S, Schramm M (1988) Calcium agonists: new, sensitive probes for calcium channels. Trends Pharmacol Sci 9:257–260
Ben-Sreti MM, González JP, Sewell RDE (1983) Effects of elevated calcium and calcium antagonists on 6,7-benzomorphan-induced analgesia. Eur J Pharmacol 90:385–391
Benedek G, Szikszay M (1984) Potentiation of thermoregulatory and analgesic effects of morphine by calcium antagonists. Pharmacol Res Commun 16:1009–1018
Bongianni F, Carla V, Moroni F, Pellegrini-Giampietro DE (1986) Calcium channel inhibitors suppress the morphine-withdrawal syndrome in rats. Br J Pharmacol 88:561–567
Bourson A, Moser PC, Gower AJ, Mir AK (1989) Central and peripheral effects of the dihydropyridine calcium channel activator Bay K 8644 in the rat. Eur J Pharmacol 160:339–347
Cardenas HL, Ross DH (1976) Calcium depletion of synaptosomes after morphine treatment. Br J Pharmacol 57: 521–526
Chapman DB, Way EL (1980) Metal ion interactions with opiates. Ann Rev Pharmacol Toxicol 20:553–579
Contreras E, Tamayo L, Amigo M (1988) Calcium channel antagonists-increase morphine-induced analgesia and antagonize morphine tolerance. Eur J Pharmacol 148:463–466
D'Amour FE, Smith DL (1941) A method for determining loss of pain sensation. J Pharmacol Exp Ther 72:74–79
Del Pozo E, Caro G, Baeyens JM (1987) Analgesic effect of calcium channel blockers in mice. Eur J Pharmacol 137:155–160
Dougall JG, Leff P (1987) Pharmacological analysis of the calcium-dependence of μ-receptor agonism. Br J Pharmacol 92:723–731
Finney DJ (1964) Statistical method in biological assay. Griffen, London
Gandhi VC, Ross DH (1988) The effect of k agonist U50–488H on 3H-nimodipine receptor binding in rat brain regions. Eur J Pharmacol 150:51–57
Gengo P, Skattebol A, Moron JF, Gallant S, Hawthorn M, Triggle DJ (1988) Regulation by chronic drug administration of neuronal and cardiac calcium channel, beta-adrenoceptor and muscarinic receptor levels. Biochem Pharmacol 37:627–633
Guerrero-Munoz F, Guerrero ML, Way EL (1979a) Effects of morphine in calcium uptake by lysed synaptosomes. J Pharmacol Exp Ther 211:370–374
Guerrero-Muñoz F, Cerreta KV, Guerrero ML, Way EL (1979b) Effect of morphine on synaptosomal Ca2+ uptake. J Pharmacol Exp Ther 209:132–136
Guerrero-Muñoz F, Adames C, Fearon Z, Way EL (1981) Calcium opiate antagonism in the periaqueductal grey (PGA) region. Eur J Pharmacol 76:417–420
Guerrero-Muñoz F, Fearon Z (1982) Opioids/opiates analgesic response modified by calcium. Life Sci 31:1237–1240
Harris RA, Loh HH, Way EL (1975) Effects of divalent cations, cation chelators and an ionophore on morphine analgesia and tolerance. J Pharmacol Exp Ther 195:88–498
Harris RA, Yamamoto H, Loh HH, Way EL (1977) Discrete changes in brain calcium with morphine analgesia, tolerance/dependence and abstinence. Life Sci 20:501–506
Hoffmeister F, Tettenborn D (1986) Calcium agonists and antagonists of dihydropyridine type: Antinociceptive effects, interference with opiate-μ-receptor agonists and neuropharmacological actions in rodents. Psychopharmacology 90:299–307
Inoki R, Ohnishi T, Saito K, Maeda S, Matsumoto K, Sakuda M (1989) Chronic morphine administration and in vivo pertussis toxin treatment induce hyperalgesia and enhance 3H-nitrendipine binding. Progr Clin Biol Res 328:469–472
Iwamoto EJ, Harris RA, Loh HH, Way EL (1978) Antinociceptive ] response after microinjection of morphine or lanthanum in discrete brain sites. J Pharmacol Exp Ther 206:46–55
Kakunaga T, Kaneto H, Kano K (1966) Pharmacological studies on analgesics. VII. Significance of the calcium ion in morphine analgesia. J Pharmacol Exp Ther 153:134–141
Kamikubo K, Niwa M, Fujimura H, Miura K (1983) Morphine inhibits depolarization-dependent calcium uptake by synaptosomes. Eur J Pharmacol 95:149–150
Litchfield JT, Wilcoxon F (1949) A simplified method for evaluating dose-effect experiments. J Pharmacol Exp Ther 96:99–113
Lux F, Welch SP, Brase DA, Dewey WL (1988) Interaction of morphine with intrathecally administered calcium and calcium antagonists: Evidence for supraspinal endogenous opioid mediation of intrathecal calcium-induced antinociception in mice. J Pharmacol Exp Ther 246:500–507
McFadzeam I, Docherty RJ (1989) Noradrenaline- and enkephalin-induced inhibition of voltage-sensitive calcium currents in NG108–15 hybrid cells. Eur J Neurosci 1:141–147
Michiels M, Hendriks R, Heykants J (1983) Radioimmunoassay of the new opiate analgesics alfentanil and sufentanil. Preliminary pharmacokinetic profile in man. J Pharm Pharmacol 35:86–93
Miller RJ (1987) Multiple calcium channels and neuronal function. Science 235:46–52
North RA (1984) Opiates and nerve cell membranes. In: Hughes J, Collier HOJ, Rance MJ, Tyers MB (eds) Opioids: Past, Present and Future. Taylor and Francis, 53—60
North RA, Williams JT (1985) On the potassium conductance increased by opioids in rat locus coeruleus neurons. J Physiol 364:265- 280
Ramkumar V, El-Fakahany EE (1984) Increase in 3H-nitrendipine binding sites on the brain in morphine tolerant mice. Eur J Pharmacol 102: 371–372
Ramkumar V, El-Fakahany EE (1988) Prolonged morphine treatment increases rat brain dihydropyridine binding sites: possible involvement in development of morphine dependence. Eur J Pharmacol 146:73–83
Rämsch K-D, Graefe KH, Sherling D, Sommer J, Ziegler R (1986) Pharmacokinetics and metabolism of calcium-blocking agents: nifedipine, nitrendipine and nimodipine. Am J Nephrol 6:73–80
Tallarida RJ, Murray RB (1987) Manual of pharmacologic calculations with computer programs. Springer, New York Heidelberg Berlin Tokyo
Toru T, Konno F, Takayanagi I, Hirobe M (1989) Kappa-receptor mechanisms in synaptosomal Ca uptake. Gen Pharmacol 20:249- 252
Tsunoo A, Yoshii M, Narahasi T (1986) Block of calcium channels by enkephalin and somatostatin in neuroblastoma-glyoma hybrid NG 108–15 cells. Proc Natl Acad Sci USA 83:9832–9835
Werz MA, Macdonald RL (1983) Opioid peptides selective for muand delta-opiate receptors reduce calcium-dependent action potential duration by increasing potassium conductance. Neurosci Lett 42:173 -178
Yamamoto H, Harris RA, Loh HH, Way EL (1978) Effects of acute and chronic morphine treatments in calcium localization and binding in brain. J Pharmacol Exp Ther 205:255–264
Author information
Authors and Affiliations
Additional information
This work was supported by grants from Universidad de Cantabria-Caja Cantabria (1988) and Bayer AG, Wuppertal, FRG
Predoctoral Fellow: Fondo de Investigaciones Sanitarias de la Seguridad Social.
Send offprint requests to: M. A. Hurlé at the above address
Rights and permissions
About this article
Cite this article
Dierssen, M., Flórez, J. & Hurlé, M.A. Calcium channel modulation by dihydropyridines modifies sufentanil-induced antinociception in acute and tolerant conditions. Naunyn-Schmiedeberg's Arch Pharmacol 342, 559–565 (1990). https://doi.org/10.1007/BF00169046
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00169046