Abstract
To investigate the role of glutamate in the locus coeruleus (LC) during opioid withdrawal, rats were continuously infused with morphine (a μ-opioid receptor agonist, 26 nmol/µl/h) or butorphanol (a μ/δ/κ-mixed opioid receptor agonist, 26 nmol/µl/h) intracerebroventricularly (i.c.v.) via osmotic minipumps for 3 days. A direct LC injection of glutamate (1 or 10 nmol/5 µl) or naloxone (an opioid receptor antagonist, 24 nmol/5 µl) induced withdrawal signs in morphine- or butorphanol-dependent animals. However, these agents failed to precipitate any withdrawal signs in saline-treated control animals. On the other hand, the expression of withdrawal signs precipitated by the administration of glutamate or naloxone in opioid-dependent animals was completely blocked by concomitant infusion with 1 or 10 nmol/µl/h of an inhibitor of adenosine 3′,5′-cyclic monophosphate (cAMP)-dependent protein kinase and protein kinase C, H-7 [1-(5-isoquinolinesulfonyl)-2-methylpiperazine]. In animals that had been infused with opioids in the same manner, i.c.v. injection of naloxone (48 nmol/5 µl) precipitated withdrawal signs and increased extracellular fluid levels of glutamate in the LC of morphine- or butorphanol-dependent rats measured by in vivo microdialysis method. However, concomitant infusion with H-7 inhibited the increases of glutamate levels in the LC. These results strongly suggest that an expeditious release of glutamate in the LC region plays an important role in the expression of physical dependence on opioids. Furthermore, the action on glutamate release might be increased by the enhancement of cAMP-dependent protein kinase and/or protein kinase C activity.
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References
Aghajanian GK. Tolerance of locus coeruleus neurons to morphine and suppression of withdrawal response by clonidine. Nature 276:186–188;1978.
Aghajanian GK, Kogan JH, Moghaddam B. Opiate withdrawal increases glutamate and aspartate efflux in the locus coeruleus: An in vivo microdialysis study. Brain Res 636:126–130;1994.
Akaoka H, Aston-Jones G. Opiate withdrawal-induced hyperactivity of locus coeruleus neurons is substantially mediated by augmented excitatory amino acid input. J Neurosci 11:3830–3839;1991.
Aston-Jones G, Ennis M, Pieribone VA, Nickell WT, Shipley MT. The brain nucleus locus coeruleus: Restricted afferent control of a broad efferent network. Science 234:734–737;1986.
Atweh SF, Kuhar MJ. Autoradiographic localization of opioid receptors in rat brain. II. The brain stem. Brain Res 129:1–12;1977.
Chen L, Huang LM. Sustained potentiation of NMDA receptor-mediated glutamate response through activation of protein kinase C by a μ opioid. Neuron 7:319–326;1991.
Dahlstrom A, Fuxe L. Evidence for the existence of monoamine-containing neurons in the central nervous system. I. Demonstration of monoamines in the cell bodies of brain stem neurons. Acta Physiol Scand 62, Suppl. 232 (1):1–55;1964.
Ellison DW, Beal MF, Martin JB. Amino acid neurotransmitters in postmortem human brain analyzed by high performance liquid chromatography with electrochemical detection. J Neurosci Methods 19:305–315;1987.
Ennis M, Aston-Jones G. Activation of locus coeruleus from nucleus paragigantocellularis: A new excitatory amino acid pathway in brain. J Neurosci 8:3644–3657;1988.
Esposito E, Kruszzewska A, Ossowska G, Samanin R. Noradrenergic and behavioural effects of naloxone injected in the locus coeruleus of morphine-dependent rats and their control by clonidine. Psychopharmacology 93:393–396;1987.
Feng YZ, Zhang T, Rockhold RW, Ho IK. Increased locus coeruleus glutamate levels are associated with naloxone-precipitated withdrawal from butorphanol in the rat. Neurochem Res 20:745–751;1995.
Feng YZ, Zhang T, Tokuyama S, Zhu H, Rockhold RW, Ho IK. μ- and δ-opioid receptor antagonists precipitate similar withdrawal phenomena in butorphanol and morphine dependence. Neurochem Res 21:63–71;1996.
Garland LG, Bonser RW, Thompson NT. Protein kinase C inhibitors are not selective. Trends Pharmacol Sci 8:334;1987.
Gucker S, Bidlack JM. Protein kinase C activation increases the rate and magnitude of agonist-induced δ-opioid receptor down-regulation in NG108-15 cells. Mol Pharmacol 42:656–665;1992.
Hidaka H, Inagaki M, Kawamoto S, Sasaki Y. Isoquinolinesulfonamides, novel and potent inhibitors of cyclic nucleotide protein kinase and protein kinase C. Biochemistry 23:5036–5041;1984.
Honore T, Davies SN, Drejer J, Fletcher EJ, Jacobsen P, Lodge D, Nielsen FE. Quinoxalinediones: Potent competitive non-NMDA glutamate receptor antagonist. Science 241:701–703;1988.
Jaw SP, Hoskins B, Ho IK. Involvement of δ-opioid receptors in physical dependence on butorphanol. Eur J Pharmacol 240:67–72;1993.
Jaw SP, Makimura M, Hoskins B, Ho IK. Effect of nor-binaltorphimine on butorphanol dependence. Eur J Pharmacol 239:133–140;1993.
Johnson JW, Ascher P. Glycine potentiates the NMDA response in cultured mouse brain neurons. Nature 325:529–531;1987.
Kogan JH, Nestler EJ, Aghajanian GK. Elevated basal firing rates and enhanced responses to 8-Br-cAMP in locus coeruleus in brain slices from opiate-dependent rats. Eur J Pharmacol 211:47–53;1992.
Lodge D, Collingridge G. The pharmacology of excitatory amino acids: A TIPS special report. Trends Pharmacol Sci (Elsevier Trends Journals, Cambridge, UK), 1991.
Maldonado R, Stinus L, Gold LH, Koob GF. Role of different brain structures in the expression of the morphine physical withdrawal syndrome. J Pharmacol Exp Ther 261:669–677;1992.
Nestler EJ, Hope BT, Widnell KL. Drug addiction: A model for molecular basis of neural plasticity. Neuron 11:995–1006;1993.
Nestler EJ, Tallman JF. Chronic morphine treatment increases cyclic AMP-dependent protein kinase activity in the rat locus coeruleus. Mol Pharmacol 33:127–132;1988.
Paxinos G, Watson C. The rat brain in stereotaxic coordinates. 2nd ed. Orlando, FL, Academic Press, 1986.
Rasmussen K, Aghajanian GK. Withdrawal-induced activation of locus coeruleus neurons in opiate-dependent rats: Attenuation by lesions of the nucleus paragigantocellularis. Brain Res 505:346–350;1989.
Rasmussen K, Beitner-Johnson DB, Krystal JH. Opiate withdrawal and the rat locus coeruleus: Behavioral, electrophysiological and biochemical correlates. J Neurosci 10:2308–2317;1990.
Redmond DE Jr, Huang YH, Snyder DR, Maas JW. Behavioral effects of stimulation of the nucleus locus coeruleus in the stump-tailed monkey(Macaca arctoides). Brain Res 116:502–510;1976.
Redmond DE Jr, Krystal JH. Multiple mechanisms of withdrawal from opioid drugs. Annu Rev Neurosci 7:443–478;1984.
Schoepp DD, Conn PJ. Metabotropic glutamate receptors in brain function and pathology. Trends Pharmacol Sci 14:13–20;1993.
Tanganelli S, Antonelli T, Morari M, Bianchi C, Beani L. Glutamate antagonists prevent morphine withdrawal in mice and guinea pigs. Neurosci Lett 122:270–272;1991.
Tempel A, Zukin RS. Neuroanatomical patterns of the μ, δ and κ opioid receptors of rat brain as determined by quantitative in vitro autoradiography. Proc Natl Acad Sci USA 84:4308–4312;1987.
Tokuyama S, Feng YZ, Wakabayashi H, Ho IK. Ca2+ channel blocker, diltiazem, prevents physical dependence and the enhancement of protein kinase C activity by opioid infusion in rats. Eur J Pharmacol 279:93–98;1995.
Tokuyama S, Feng YZ, Wakabayashi H, Ho IK. Possible involvement of protein kinases in physical dependence on opioids: Studies using protein kinase inhibitors, H-7 and H-8. Eur J Pharmacol 284:101–107;1995.
Tokuyama S, Wakabayashi H, Ho IK. Direct evidence for a role of glutamate in the expression of the opioid withdrawal syndrome. Eur J Pharmacol 295:123–129;1996.
Wang Z, Bilsky EJ, Porreca F, Sadee W. Constitutive μ opioid receptor activation as a regulatory mechanism underlying narcotic tolerance and dependence. Life Sci 54:339–350;1994.
Watkins JC, Krogsgaard-Larsen P, Honore T. Structure-activity relationships in the development of excitatory amino acid receptor agonists and competitive antagonists. In: Lodge D, Collingridge G, eds. The Pharmacology of Excitatory Amino Acids. Tips Special Report. Cambridge, Elsevier, 4: 1990.
Zhang T, Feng YZ, Rockhold RW, Ho IK. Naloxone-precipitated morphine withdrawal increases pontine glutamate levels in the rat. Life Sci 55:25–31;1994.
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Tokuyama, S., Zhu, H., Wakabayashi, H. et al. The role of glutamate in the locus coeruleus during opioid withdrawal and effects of H-7, a protein kinase inhibitor, on the action of glutamate in rats. J Biomed Sci 5, 45–53 (1998). https://doi.org/10.1007/BF02253355
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DOI: https://doi.org/10.1007/BF02253355