Summary
The discovery of the selective kappa opioid receptor agonist, U-50488H, has provided a tool for the study of the mechanisms and function of the kappa receptor-effector. We have investigated the interactions of this compound with calcium in several biochemical and functional studies to assess the involvement of calcium mechanisms in the kappa receptor-linked effector. In rat brain synaptosomes, U-50488H attenuated the uptake of 45Ca++ induced by K+ (40 mM) depolarization. This effect was concentration-related (U-50488H 10-5 to 10-7M), was apparent in short (8-second) but not longer (1-minute) term incubations, and did not occur in the presence of a non-polarizing concentration (5.6 mM) of K+. Naloxone (10-7M) did not block this effect of U-50488H (10-6M), and higher concentrations (10-5M) alone blocked calcium uptake. We have found that the binding of the depolarizing amino acid analog, kainic acid, is enhanced by CaC12. U-50488H (10-4 to 10-6M) blocks this enhancement of 3H-kainic acid binding in vitro and also blocks the in vivo effects of kainic acid. In mice, intravenous injection of kainic acid causes scratching, convulsions, and death, depending on the dose administered. U-50488H blocks all of these effects (ED50=4.5 mg/kg for antagonism of convulsions induced by 27.5 mg/kg kainic acid). The convulsions induced by intracerebroventricularly administered kainic acid are also blocked by U-50488H as are those induced by similarly administered Bay K 8644, a calcium channel activator. All of these anticonvulsant effects of U-50488H were antagonized by naltrexone. Together these data indicate that the kappa agonist U-50488H has functionally relevant interactions with depolarization-related Ca++ mechanisms in the central nervous system.
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References
Cherubini, E. and North, R. A., Mu and kappa opioids inhibit transmitter release by different mechanisms, Proc. Nat. Acad. Sci. 82: 1860–1863 (1985).
Drejer, J., Benveniste, H., Diemer, N. H. and Schousboe, A., Cellular origin of ischemia-induced glutamate release from brain tissue in vivo and in vitro, J. Neurochem. 45: 145–151 (1985).
Greenmyre, J. T., Young, A. B. and Penny, J. B., Quantitative autoradiography of L-glutamate binding to rat brain, Neurosci. Lett. 37: 155–160 (1983).
Gripenberg, J., Heinonen, E. and Jansson, S. E., Uptake of radiocalcium by nerve endings isolated from rat brain: Pharmacological studies, Br. J. Pharmac. 71: 273–278 (1980).
Harris, R. A., Fenner, D. and Leslie, S. W., Calcium uptake by isolated nerve endings: Evidence for a rapid component mediated by the breakdown of phosphatidylinositol, Life Sci. 32: 2661–2666 (1983).
James, I. F. and Goldstein, A., Site-directed alkylation of multiple opioid receptors. I. Binding selectivity, Mol. Pharmacol. 25: 337–342 (1984).
Lahti, R. A., VonVoigtlander, P. F. and Barsuhn, C., Properties of a selective kappa agonist, U-50488H, Life Sci. 31: 2257–2260 (1982).
Lahti, R. A., Mickelson, M. M., McCall, J. M. and VonVoigtlander, P. F., (3H)-U-69593, A highly selective ligand for the K receptor, European J. Pharmacol. 109: 281–284 (1985).
London, E. D. and Coyle, J. T., Specific binding of (3H)-kainic acid to receptor sites in rat brain, Mol. Pharmacol. 15: 492–505 (1979).
Martin, W. R., Eades, C. G., Thompson, J. A., Huppler, R. E. and Gilbert, P. E., The effects of morphine-and nalorphine-like drugs in the nondependent and morphine-dependent chronic spinal dog, J. Pharmacol. Exp. Ther. 197: 517–532 (1976).
Meldrum, B., Evans, M., Griffiths, T. and Simon, R., Ischemic brain damage: The role of excitatory activity and of calcium entry, Br. J. Anaesth. 57: 44–46 (1985).
Mena, E. E., Whittemore, S. R., Monaghan, D. T. and Cotman, C. W., Ionic Regulation of glutamate binding sites, Life Sciences 35: 2427–2433 (1984).
Nicoletti, F., Meek, J. L., Iadarola, M. J., Chuang, D. M., Roth, B. L. and Costa, E., Coupling of inositol phospholipid metabolism with excitatory amino acid recognition sites in rat hippocampus, J. Neurochem. 46: 40–46 (1986).
Rhoads, D. L., Yamasaki, Y. and Way, E. L., Opioids reduce human red blood cell deformability, Alcohol and Drug Res. 6: 229 (1985).
Schramm, M., Thomas, G., Toward, R. and Franckowiak, G., Novel dihydropyridines with positive inotropic action through activation of Ca++ channels, Nature 303: 535–537 (1983).
Shelton, R. C., Grebbe, J. A. and Freed, W. J., Calcium channel agonistinduced murine seizures, Soc. Neurosci. Abstr. 11: 924 (1985).
Simon, J. R., Contrera, J. F. and Kuhar, M. J., Binding of (3H)-kainic acid, an analogue of L-glutamic acid, to brain membranes, J. Neurochem. 26: 141–147 (1976).
Simon, R., Swan, J. H., Griffiths, T. and Meldrum, B., Blockade of N-methyl-D-asparate receptors may protect against ischemic damage in the brain, Science 226: 850–852 (1984).
Sladeczek, F., Pin, J.-P., Recasens, M., Bockaert, J. and Weiss, S., Glutamate stimulates inositol phosphate formation in striatal neurones, Nature 317: 717–719 (1985).
Szmuszkovicz, J and VonVoigtlander, P. F., Benzeneacetamide amines: Structurally novel non-mu opioids, J. Med. Chem. 25: 1125–1126 (1982).
Tang, A. H., Protection from cerebral ischemia by U-50488H, a specific kappa opioid analgesic agent, Life Sci. 16: 1475–1482 (1985).
Tortella, F. C., Robles, L. and Holaday, J. W., Seizure-specific, dose-and time-dependent anticonvulsant profile for U-50488H, a novel kappa opioid agonist in rats, Soc. Neuro. Abstr. 10: 408 (1984).
VonVoigtlander, P. F. and Lewis, R. A., U-50488H, a selective kappa opioid agonist: Comparison to other reputed kappa agonists, Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 6: 467–470 (1982).
VonVoigtlander, P. F., Lahti, R. A. and Ludens, J. H., U-50488H: A selective and structurally novel non-mu (kappa) opioid agonist, J. Pharmacol. Exp. Ther. 224: 7–12 (1983).
VonVoigtlander, P. F., Lewis, R. A. and Neff, G. L., Kappa opioid analgesia is dependent on serotonergic mechanisms, J. Pharmacol. Exp. Ther. 231: 270–274 (1984).
Werz, M. A. and MacDonald, R. L., Dynorphin and neoendorphin peptides decrease dorsal root ganglion neuron calcium-dependent action potential duration, J. Pharmacol. Exp. Ther. 234: 49–56 (1985).
Yamasaki, Y. and Way, E. L., Possible inhibition of calcium pump of rat erythrocyte ghosts by K agonists, Life Sci. 33: 723–726 (1983).
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© 1987 Plenum Press, New York
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VonVoigtlander, P.F., Ochoa, M.C., Lewis, R.A. (1987). Biochemical and Functional Interactions of a Selective Kappa Opioid Agonist with Calcium. In: Ehrlich, Y.H., Lenox, R.H., Kornecki, E., Berry, W.O. (eds) Molecular Mechanisms of Neuronal Responsiveness. Advances in Experimental Medicine and Biology, vol 221. Springer, Boston, MA. https://doi.org/10.1007/978-1-4684-7618-7_24
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