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Received: 2011-01-23

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Journal of Zhejiang University SCIENCE B 2011 Vol.12 No.12 P.1016-1023


Different effects of L-arginine on morphine tolerance in sham and ovariectomized female mice

Author(s):  Reza Karami, Mahmoud Hosseini, Fatimeh Khodabandehloo, Leila Khatami, Zahra Taiarani

Affiliation(s):  Neuroscience Research Center and Department of Physiology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran, Pharmacological Research Center of Medicinal Plants, Department of Physiology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

Corresponding email(s):   Hosseinim@mums.ac.ir

Key Words:  L-arginine, Ovariectomized mice, Morphine, Tolerance

Reza Karami, Mahmoud Hosseini, Fatimeh Khodabandehloo, Leila Khatami, Zahra Taiarani. Different effects of L-arginine on morphine tolerance in sham and ovariectomized female mice[J]. Journal of Zhejiang University Science B, 2011, 12(12): 1016-1023.

@article{title="Different effects of L-arginine on morphine tolerance in sham and ovariectomized female mice",
author="Reza Karami, Mahmoud Hosseini, Fatimeh Khodabandehloo, Leila Khatami, Zahra Taiarani",
journal="Journal of Zhejiang University Science B",
publisher="Zhejiang University Press & Springer",

%0 Journal Article
%T Different effects of L-arginine on morphine tolerance in sham and ovariectomized female mice
%A Reza Karami
%A Mahmoud Hosseini
%A Fatimeh Khodabandehloo
%A Leila Khatami
%A Zahra Taiarani
%J Journal of Zhejiang University SCIENCE B
%V 12
%N 12
%P 1016-1023
%@ 1673-1581
%D 2011
%I Zhejiang University Press & Springer
%DOI 10.1631/jzus.B1100029

T1 - Different effects of L-arginine on morphine tolerance in sham and ovariectomized female mice
A1 - Reza Karami
A1 - Mahmoud Hosseini
A1 - Fatimeh Khodabandehloo
A1 - Leila Khatami
A1 - Zahra Taiarani
J0 - Journal of Zhejiang University Science B
VL - 12
IS - 12
SP - 1016
EP - 1023
%@ 1673-1581
Y1 - 2011
PB - Zhejiang University Press & Springer
ER -
DOI - 10.1631/jzus.B1100029

Objective: The roles of gonadal hormones and nitric oxide (NO) on the analgesic effects of morphine, tolerance to morphine, and their interactions have been widely investigated. In the present study, the effect of l-arginine (an NO precursor) on morphine tolerance in sham and ovariectomized (OVX) female mice was investigated. Methods: Forty mice were divided into sham and OVX groups. On the first day, a hot plate test ((55±0.2) °C; cut-off 30 s) was carried out as a base record 15 min before injection of morphine (10 mg/kg, subcutaneously (s.c.)) and was repeated every 15 min after injection. The sham group was then divided into two subgroups: sham-tolerance-l-arginine (Sham-Tol-LA) and sham-tolerance-saline (Sham-Tol-Sal) which received either l-arginine 50 mg/kg (intraperitoneally (i.p.)) or saline 10 ml/kg (i.p.), respectively, three times in a day for three consecutive days. morphine tolerance was induced in animals by injecting 30 mg/kg morphine (s.c.) three times/day for three days. This treatment was also used for OVX subgroups. On the fifth day, the hot plate test was repeated. The analgesic effect of morphine was calculated as the maximal percent effect (MPE). The results were compared using repeated measure analysis of variance (ANOVA). Results: There was no significant difference in MPE between the OVX and sham groups. The MPEs in both the Sham-Tol-Sal and OVX-Tol-Sal groups were lower than those in both the sham and OVX groups (P<0.01). The MPE in the OVX-Tol-Sal group was greater than that in the Sham-Tol-Sal group (P<0.01). The MPE in the Sham-Tol-LA group was higher than that in the Sham-Tol-Sal group (P<0.01). However, there was no significant difference between the Sham-Tol-LA and sham groups or between the OVX-Tol-LA and OVX-Tol-Sal groups. Conclusions: The results of the present study showed that repeated administration of morphine causes tolerance to the analgesic effect of morphine. l-arginine could prevent tolerance to morphine but its effect was different in the presence of ovarian hormones.

Darkslateblue:Affiliate; Royal Blue:Author; Turquoise:Article


[1]Azizi-Malekabadi, H., Hosseini, M., Saffarzadeh, F., Karami, R., Khodabandehloo, F., 2011. Chronic treatment with the nitric oxide synthase inhibitor, L-NAME, attenuates estradiol-mediated improvement of learning and memory in ovariectomized rats. Clinics, 66(4):673-679.

[2]Bourne, N., 2008. Managing acute pain in opioid tolerant patients. J. Perioper. Pract., 18(11):498-503.

[3]Budzinski, M., Misterek, K., Gumulka, W., Dorociak, A., 1999. Inhibition of inducible nitric oxide synthase in persistent pain. Life Sci., 66(4):301-305.

[4]Cataldo, G., Bernal, S., Markowitz, A., Ogawa, S., Ragnauth, A., Pfaff, D.W., Bodnar, R.J., 2005. Organizational manipulation of gonadal hormones and systemic morphine analgesia in female rats: effects of adult ovariectomy and estradiol replacement. Brain Res., 1059(1):13-19.

[5]Ceylan-Isik, A.F., Erdogan-Tulmac, O.B., Ari, N., Ozansoy, G., Ren, J., 2009. Effect of 17β-oestradiol replacement on vascular responsiveness in ovariectomized diabetic rats. Clin. Exp. Pharmacol. Physiol., 36(11):e65-e71.

[6]Craft, R.M., 2007. Modulation of pain by estrogens. Pain, 132(S1):S3-S12.

[7]Craft, R.M., Mogil, J.S., Aloisi, A.M., 2004. Sex differences in pain and analgesia: the role of gonadal hormones. Eur. J. Pain, 8(5):397-411.

[8]Dina, O.A., Aley, K.O., Isenberg, W., Messing, R.O., Levine, J.D., 2001. Sex hormones regulate the contribution of PKCepsilon and PKA signalling in inflammatory pain in the rat. Eur. J. Neurosci., 13(12):2227-2233.

[9]Farsetti, A., Grasselli, A., Bacchetti, S., Gaetano, C., Capogrossi, M.C., 2009. The telomerase tale in vascular aging: regulation by estrogens and nitric oxide signaling. J. Appl. Physiol., 106(1):333-337.

[10]Fatehi-Hassanabad, Z., Jafarzadeh, M., Fatehi, M., Razavi-Tossi, M., 2005. Sex affects the feeling of pain in the mice, possible involvement of nitric oxide. Daru, 13(3):116-119.

[11]Garry, M.G., Richardson, J.D., Hargreaves, K.M., 1994. Sodium nitroprusside evokes the release of immunoreactive calcitonin gene-related peptide and substance P from dorsal horn slices via nitric oxide-dependent and nitric oxide-independent mechanisms. J. Neurosci., 14(7):4329-4337.

[12]Gatchel, R.J., Peng, Y.B., Peters, M.L., Fuchs, P.N., Turk, D.C., 2007. The biopsychosocial approach to chronic pain: scientific advances and future directions. Psychol. Bull., 133(4):581.

[13]Grohé, C., Kann, S., Fink, L., Djoufack, P.C., Paehr, M., van Eickels, M., Vetter, H., Meyer, R., Fink, K.B., 2004. 17β-estradiol regulates nNOS and eNOS activity in the hippocampus. Neuroreport, 15(1):89-93.

[14]Heinzen, E.L., Pollack, G.M., 2004. Pharmacodynamics of morphine-induced neuronal nitric oxide production and antinociceptive tolerance development. Brain Res., 1023(2):175-184.

[15]Heinzen, E.L., Booth, R.G., Pollack, G.M., 2005. Neuronal nitric oxide modulates morphine antinociceptive tolerance by enhancing constitutive activity of the mu-opioid receptor. Biochem. Pharmacol., 69(4):679-688.

[16]Hernández, L., Romero, A., Almela, P., Garcia-Nogales, P., Laorden, M.L., Puig, M.M., 2009. Tolerance to the antinociceptive effects of peripherally administered opioids: expression of β-arrestins. Brain Res., 1248:31-39.

[17]Hishikawa, K., Nakaki, T., Marumo, T., Suzuki, H., Kato, R., Saruta, T., 1995. Up-regulation of nitric oxide synthase by estradiol in human aortic endothelial cells. FEBS Lett., 360(3):291-293.

[18]Hosseini, M., Sadeghnia, H.R., Salehabadi, S., Alavi, H., Gorji, A., 2009. The effect of L-arginine and L-NAME on pentylenetetrazole induced seizures in ovariectomized rats, an in vivo study. Seizure, 18(10):695-698.

[19]Hosseini, M., Headari, R., Oryan, S., Hadjzadeh, M.A., Saffarzadeh, F., Khazaei, M., 2010. The effect of chronic administration of L-arginine on the learning and memory of estradiol-treated ovariectomized rats tested in the morris water maze. Clinics, 65(8):803-807.

[20]Hosseini, M., Taiarani, Z., Hadjzadeh, M.A., Salehabadi, S., Tehranipour, M., Alaei, H.A., 2011. Different responses of nitric oxide synthase inhibition on morphine-induced antinociception in male and female rats. Pathophysiology, 18(2):143-149.

[21]Janicki, P., Jeske-Janicka, M., 1998. Relevance of nitric oxide in pain mechanisms and pain management. Curr. Pain Headache Rep., 2(4):211-216.

[22]Kelly, M.J., Loose, M.D., Ronnekleiv, O.K., 1992. Estrogen suppresses mu-opioid- and GABAB-mediated hyperpolarization of hypothalamic arcuate neurons. J. Neurosci., 12(7):2745-2750.

[23]Kolesnikov, Y.A., Pick, C.G., Pasternak, G.W., 1992. NG-nitro-L-arginine prevents morphine tolerance. Eur. J. Pharmacol., 221(2-3):399-400.

[24]Kugaya, A., Epperson, C.N., Zoghbi, S., van Dyck, C.H., Hou, Y., Fujita, M., Staley, J.K., Garg, P.K., Seibyl, J.P., Innis, R.B., 2003. Increase in prefrontal cortex serotonin 2A receptors following estrogen treatment in postmenopausal women. Am. J. Psychiatry, 160(8):1522-1524.

[25]Langerman, L., Zakowski, M., Piskoun, B., Grant, G., 1995. Hot plate versus tail flick: evaluation of acute tolerance to continuous morphine infusion in the rat model. J. Pharmacol. Toxicol. Methods, 34(1):23-27.

[26]Li, H.C., Chen, Q.Z., Ma, Y., Zhou, J.F., 2006. Imbalanced free radicals and antioxidant defense systems in schizophrenia: a comparative study. J. Zhejiang Univ.-Sci. B, 7(12):981-986.

[27]Liu, S.Z., Yan, H., Hou, W.K., Xu, P., Tian, J., Tian, L.F., Zhu, B.F., Ma, J., Lu, S.M., 2009. Relationships between endothelial nitric oxide synthase gene polymorphisms and osteoporosis in postmenopausal women. J. Zhejiang Univ.-Sci. B, 10(8):609-618.

[28]Loyd, D.R., Murphy, A.Z., 2008. Androgen and estrogen (α) receptor localization on periaqueductal gray neurons projecting to the rostral ventromedial medulla in the male and female rat. J. Chem. Neuroanat., 36(3-4):216-226.

[29]Loyd, D.R., Morgan, M.M., Murphy, A.Z., 2007. Morphine preferentially activates the periaqueductal gray-rostral ventromedial medullary pathway in the male rat: a potential mechanism for sex differences in antinociception. Neuroscience, 147(2):456-468.

[30]Luo, Z.D., Cizkova, D., 2000. The role of nitric oxide in nociception. Curr. Pain Headache Rep., 4(6):459-466.

[31]Meng, G., Wu, N., Zhang, C., Su, R.B., Lu, X.Q., Liu, Y., Yun, L.H., Zheng, J.Q., Li, J., 2008. Analgesic activity of ZC88, a novel N-type voltage-dependent calcium channel blocker, and its modulation of morphine analgesia, tolerance and dependence. Eur. J. Pharmacol., 586(1-3):130-138.

[32]Mitsushima, D., Takase, K., Takahashi, T., Kimura, F., 2009. Activational and organisational effects of gonadal steroids on sex-specific acetylcholine release in the dorsal hippocampus. J. Neuroendocrinol., 21(4):400-405.

[33]Moghaddam, H.F., Kesmati, M., Kargar, H.M.P., Rezaei, S., 2004. The effect of electrical lesion of paragigantocellularis lateralis nucleus on acute pain perception in presence of clonidine (α2 adrenergic agonist) in rat. Iran. J. Basic Med. Sci., 7(2):3 (in Persian).

[34]Moncada, S., Higgs, E., Hodson, H., Knowles, R., López-Jaramillo, P., McCall, T., Palmer, R., Radomski, M., Rees, D., Schulz, R., 1991. The L-arginine: nitric oxide pathway. J. Cardiovasc. Pharmacol., 17(s3):S1-S9.

[35]Nematbakhsh, M., Khazaei, M., 2004. The effect of estrogen on serum nitric oxide concentrations in normotensive and DOCA Salt hypertensive ovariectomized rats. Clin. Chim. Acta, 344(1-2):53-57.

[36]Ojewole, J.A., 2008. Analgesic, anti-inflammatory and hypoglycaemic effects of Securidaca longepedunculata (Fresen.) [Polygalaceae] root-bark aqueous extract. Inflammopharmacology, 16(4):174-181.

[37]Pan, J.W., Zhan, R.Y., Tong, Y., Zhou, Y.Q., Zhang, M., 2005. Expression of endothelial nitric oxide synthase and vascular endothelial growth factor in association with neovascularization in human primary astrocytoma. J. Zhejiang Univ.-Sci. B, 6(7):693-698.

[38]Pataki, I., Telegdy, G., 1998. Further evidence that nitric oxide modifies acute and chronic morphine actions in mice. Eur. J. Pharmacol., 357(2-3):157-162.

[39]Patchev, V.K., Hayashi, S., Orikasa, C., Almeida, O.F.X., 1999. Ontogeny of gender-specific responsiveness to stress and glucocorticoids in the rat and its determination by the neonatal gonadal steroid environment. Stress, 3(1):41-54.

[40]Romano, G.J., Harlan, R.E., Shivers, B.D., Howells, R.D., Pfaff, D.W., 1988. Estrogen increases proenkephalin messenger ribonucleic acid levels in the ventromedial hypothalamus of the rat. Mol. Endocrinol., 2(12):1320-1328.

[41]Russell, K., Haynes, M., Caulin-Glaser, T., Rosneck, J., Sessa, W., Bender, J., 2000. Estrogen stimulates heat shock protein 90 binding to endothelial nitric oxide synthase in human vascular endothelial cells. J. Biol. Chem., 275(7):5026.

[42]Sadeghipour, H., Ghasemi, M., Sadeghipour, H., Riazi, K., Soufiabadi, M., Fallahi, N., Dehpour, A., 2007. Nitric oxide involvement in estrous cycle-dependent changes of the behavioral responses of female rats in the elevated plus-maze test. Behav. Brain Res., 178(1):10-17.

[43]Saffarzadeh, F., Eslamizade, M.J., Nemati Karimooy, H.A., Hadjzadeh, M.A., Khazaei, M., Hosseini, M., 2010. The effect of L-arginine on Morris water maze tasks of ovariectomized rats. Acta Physiol. Hung., 97(2):216-223.

[44]Saleh, T.M., Connell, B.J., 2003. Estrogen-induced autonomic effects are mediated by NMDA and GABAA receptors in the parabrachial nucleus. Brain Res., 973(2):161-170.

[45]Sepehri, G., Shafeiee, M.N., 2006. Effect of cuneiformis nucleus inactivation by lidocaine microinjection on the analgesic response of morphine in rats. Iran. Biomed. J., 10(1):21-26.

[46]Shekunova, E.V., Bespalov, A.Y., 2006. Effects of memantine on estrogen-dependent acute tolerance to the morphine analgesia in female rats. Eur. J. Pharmacol., 535(1-3):78-85.

[47]Shih, C.D., 2009. Activation of estrogen receptor-dependent nitric oxide signaling mediates the hypotensive effects of estrogen in the rostral ventrolateral medulla of anesthetized rats. J. Biomed. Sci., 16(1):60.

[48]Shughrue, P.J., Lane, M.V., Merchenthaler, I., 1997. Comparative distribution of estrogen receptor-α and -β mRNA in the rat central nervous system. J. Comp. Neurol., 388(4):507-525.

[49]Stefano, G.B., Prevot, V., Beauvillain, J.C., Cadet, P., Fimiani, C., Welters, I., Fricchione, G.L., Breton, C., Lassalle, P., Salzet, M., et al., 2000. Cell-surface estrogen receptors mediate calcium-dependent nitric oxide release in human endothelia. Circulation, 101(13):1594-1597.

[50]Terner, J., Lomas, L., Picker, M., 2005. Influence of estrous cycle and gonadal hormone depletion on nociception and opioid antinociception in female rats of four strains. J. Pain, 6(6):372-383.

[51]Toda, N., Kishioka, S., Hatano, Y., Toda, H., 2009. Modulation of opioid actions by nitric oxide signaling. Anesthesiology, 110(1):166-181.

[52]Wiesenfeld-Hallin, Z., 2005. Sex differences in pain perception. Gend. Med., 2(3):137-145.

[53]Zhang, W., Wei, Q.W., Wang, Z.C., Ding, W., Wang, W., Shi, F.X., 2011. Cell-specific expression and immunolocalization of nitric oxide synthase isoforms and the related nitric oxide/cyclic GMP signaling pathway in the ovaries of neonatal and immature rats. J. Zhejiang Univ.-Sci. B (Biomed. & Biotechnol.), 12(1):55-64.

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