Abstract
The opiate withdrawal induced by administration of naloxone to morphine-dependent mice correlates with an increment of calcium- dependent nitric oxide synthase (NOS) activity in the cerebellum. L-NAME, an irreversible competitive inhibitor of NOS (0.5, 5, 25, 50 mg/kg) injected sc. 45 min. prior to naloxone significantly reduced the number of escape jumps and other motor symptoms of abstinence. In addition, L-NAME also decreased NOS activity in cerebellum. L-arginine, but not D-arginine, when coadministered with L-NAME, prevented both the inhibition of NOS activity and the reduction of withdrawal symptoms induced by L-NAME in morphine-withdrawn animals. These results demonstrate a hyperactivity of the L-arginine: NO pathway in opiate withdrawal and suggests the possibility of a therapeutic use of NOS inhibitors in this state.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Abbreviations
- EAA:
-
Excitatory amino acid
- LC:
-
Locus coeruleus
- L-NAME:
-
Nω-nitro L-arginine methyl ester
- NMDA:
-
N-methyl-D-aspartate
- NO:
-
Nitric oxide
- NOS:
-
Nitric oxide synthase
References
Adams ML, Kalicki JM, Meyer ER, Cicero TJ (1993) Inhibition of the morphine withdrawal syndrome by a nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester. Life Sci 52:245–249
Aghajanian GK, Kogan JH, Moghaddam B (1994) Opiate withdrawal increases glutamate and aspartate efflux in the locus coeruleus: an in vivo microdialysis study. Brain Res 636:126–130
Baker TB, Tiffany ST (1985) Morphine tolerance as habituation. Psychol Rev 92:78–108
Bianchetti A, Giudice A, Nava F, Manara L (1986) Dissociation of morphine withdrawal diarrhea and jumping in mice by the peripherally selective opioid antagonist SR 58001 C. Life Sci 39:2297–2303
Blasig J, Herz A, Reinhold K, Zieglgansberger S (1973) Development of physical dependence of morphine in respect to time and dosage and quantification of the precipitated withdrawal syndrome in rats. Psychopharmacologia 33:19–38
Bliss TVP, Collingridge GL (1993) A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361:31–39
Bredt DS, Snyder SH (1989) Nitric oxide mediates glutamate-linked enhancement of cGMP levels in the cerebellum. Proc Natl Acad Sci USA 86:9030–9033
Calignano A, Persico P, Mancuso F, Sorrentino L (1993) Endogenous nitric oxide modulates morphine-induced changes in locomotion and food intake in mice. Eur J Pharmacol 231:415–419
Cappendijk SLT, de Vries R, Dzoljic MR (1993) Inhibitory effects of nitric oxide (NO) synthase inhibitors on naloxone-precipitated withdrawal syndrome in morphine-dependent mice. Neurosci Lett 162:97–100
Cappendijk SLT, Garrelds IM, Dzoljic MR (1994) Nitric oxide in the nervous system. Laurentians Mountains, Montreal, Canada, July 1994. Abstracts pp 1. 18
Cappendijk SLT, Duval SY, de Vries R, Dzoljic MR (1995) Comparative study of normotensive and hypertensive nitric oxide synthase inhibitors on morphine withdrawal syndrome in rats. Neurosci Lett 183:67–70
Choi DW (1988) Glutamate neurotoxicity and diseases of the nervous system. Neuron 1:623–634
Cooper JR, Bloom FE, Roth RH (1991) Norepinephrine and epinephrine. In: Cooper JR, Bloom FE. Roth RH (eds) The biochemical basis of neuropharmacology. Oxford University Press, New York, pp 220–461
De Sarro GG, Donato Di Paola E, De Sarro A, Vidal MJ (1993) L-arginine potentiates excitatory amino acid-induced seizures in the deep prepiriform cortex. Eur J Pharmacol 230:151–158
Garthwaite J (1991) Glutamate, nitric oxide and cell-cell signalling in the nervous system. Trends Neurosci 14:60–67
Garthwaite J (1993) Nitric oxide signalling in the nervous system. Semin Neurosci 5:171–180
Garthwaite J, Charles SL, Chess-Williams R (1988) Endothelium-derived relaxing factor release on activation of NMDA receptor suggests a role as intracellular messenger in the brain. Nature 336:385–388
Gibson RD, Tingstad TE (1970) Formulation of a morphine implantation pellet suitable for tolerance-physical dependence studies in mice. J Pharm Sci 59:42642–42647
Hecker M, Mitchell JA, Harris HJ, Katsura M, Thiemermann C, Vane JR (1990) Endothelial cells metabolize NG-monomethyl-L-arginine to L-citrulline and subsequently to L-arginine. Biochem Biophys Res Commun 167:1037–1043
Kimes AS, Vaupel DB, London DE (1993) Attenuation of some signs of opioid withdrawal by inhibitors of nitric oxide synthase. Psychopharmacology 112:521–524
Kolesnikov YA, Pick CG, Ciszewska G, Pasternak GW (1993) Blockade of tolerance to morphine but not to kappa opioids by a nitric oxide synthase inhibitor. Proc Nail Acad Sci USA 90:5162–5166
Laschka E, Herz A, Blasig J (1976) Sites of action of morphine involved in the development of physical dependence in rats I. Comparison of precipitated morphine withdrawal after intraperitoneal and intraventricular injection of morphine antagonists. Psychopharmacologia 46:133–139
Maldonado R, Stinus L, Gold LH, Koob GF (1992) Role of different brain structures in the expression of the physical morphine withdrawal syndrome. J Pharmacol Exp Ther 261:669–677
Meldrum B, Garthwaite J (1990) Excitatory amino acid neurotoxicity and neurodegenerative disease. Trends Pharmacol Sci 11:379–387
Mollace V, Bagetta G, Nistico G (1991) Evidence that L-arginine possesses proconvulsant effects mediated though nitric oxide. Neuroreport 2:269–272
Moncada S, Palmer RMJ, Higgs EA (1989) Biosynthesis of nitric oxide from L-arginine. A pathway for the regulation of cell function and communication. Biochem Pharmacol 38:1709–1715
Moncada S, Palmer RMJ, Higgs EA (1991) Nitric oxide: physiology, patophysiology and pharmacology. Pharmacol Rev 43:109–142
Moore PK, Oluyomi AO, Babbedge RC, Wallace P, Hart SL (1991) L-NG-nitro arginine methyl ester exhibits antinociceptive activity in the mouse. Br J Pharmacol 102:198–202
Navarro M, Lizasoain I, Leza JC, Lorenzo P (1991) An original method for assessment of the jumping test. Methods Find Exp Clin Pharmacol 13:443–447
Przewlocki R, Machelska H, Przewlocka B (1994) Modulation of morphine and cocaine effects by inhibition of nitric oxide synthase. Regul Pept 54:233–235
Rasmussen K, Fuller RW, Stockton ME, Perry KW, Swinford RM, Ornstein PL (1991a) NMDA receptor antagonists supress behaviors but not norepinephrine turnover of locus coeruleus unit activity induced by opiate withdrawal. Eur J Pharmacol 197:9–16
Rasmussen K, Krystal JH, Aghajanian GK (1991b) Excitatory amino acids and morphine withdrawal: differential effects of central and peripheral kynurenic acid administration. Psychopharmacology 105:508–512
Redmond DE, Krystal JH (1984) Multiple mechanisms of withdrawal from opioid drugs. Ann Rev Neurosci 7:443–478
Rodrigo J, Springall DR, Uttenthal O, Bentura ML, Abadia-Molina F, Riveros-Moreno V, Martinez-Murillo R, Polak JM, Moncada S (1994) Localization of nitric oxide in the adult rat brain. Phil Trans R Soc Lend B 345:175–221
Saelens JK, Granat FR, Sawyer WK (1971) The mouse jumping test. A simple screening method to estimate the physical dependence capacity of analgesics. Arch Int Pharmacodyn Ther 190:213–218
Salter M, Knowles RG, Moncada S (1991) Widespread tissue distribution, species distribution and changes in activity of Ca2+-dependent and Ca2+-independent nitric oxide synthases. FEBS Lett 291:145–149
Shibuki K, Okada D (1991) Endogenous nitric oxide release required for long-term synaptic depression in the cerebellum. Nature 349:326–328
Tanganelli S, Antonelli T, Morari M, Bianchi C, Beani L (1991) Glutamate antagonists prevent morphine withdrawal in mice and guinea pigs. Neurosci Lett 122:270–272
Thorat SN, Barjavel MJ, Matwyshyn GA, Bhargava HN (1994) Comparative effects of NG-monomethyl L-arginine and MK-801 on the abstinence syndrome in morphine dependent mice. Brain Res 642:153–159
Trujillo KA, Akil H (1991) Inhibition of morphine tolerance and dependence by the NMDA receptor antagonist MK-801. Science 251:85–87
Tung CS, Grenhoff J, Svensson TH (1990) Morphine withdrawal responses of rat locus coeruleus neurons are blocked by an excitatory amino-acid antagonist. Acta Physiol Scand 138:581–582
Xu ZQ, Pieribone VA, Zhang X, Grillner S, Hökfelt T (1994) A functional role for nitric oxide in locus coeruleus: immunohistochemical and electrophysiological studies. Exp Brain Res 98:75–83
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Leza, J.C., Lizasoain, I., Cuéllar, B. et al. Correlation between brain nitric oxide synthase activity and opiate withdrawal. Naunyn-Schmiedeberg's Arch Pharmacol 353, 349–354 (1996). https://doi.org/10.1007/BF00168639
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00168639