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Effects of Isoniazid on Expression and Acquisition of Tolerance to High-Dose Morphine-Induced Hyperlocomotion in Male Mice
Document Type : Original Article
Authors
Department of Biology, Faculty of Basic Science, University of Maragheh, Maragheh, Iran
Abstract
Isoniazid, a hydrazine derivative, can influence the GABAergic system, which plays an important role in modulating morphine tolerance. This study aimed to assess how isoniazid effects on both the expression and acquisition of tolerance to morphine-induced hyperlocomotion in mice. Nineteen groups of male mice (n=8 per group) were used. The locomotor activity of the animals was measured for a duration of 20 minutes using an actimeter after administration of morphine (1-30 mg/kg, s.c.) or isoniazid (25-75 mg/kg, i.p.). Tolerance was induced by administering morphine (30 mg/kg) twice daily for three consecutive days. The same dose on the fourth day served as a challenge to assess tolerance development. To investigate how isoniazid affects tolerance expression and acquisition, mice were divided into eight groups. Four groups received saline or isoniazid one hour before the final morphine dose (expression test). The remaining four groups were administered isoniazid prior to each morphine injection during the tolerance induction phase (acquisition test). Morphine produced two distinct effects on locomotor activity: at a low dose (1 mg/kg, s.c.) it reduced locomotion in mice (P<0.05), while at a high dose (30 mg/kg, s.c.) it increased locomotor activity (P<0.01). Isoniazid administration one hour before the test significantly increased locomotor activity. Isoniazid administration before morphine suppressed both the expression (P<0.01) and the acquisition (P<0.01) of morphine-induced hyperlocomotion. However, isoniazid’s effect on tolerance expression may be due to its ability to increase locomotor activity. Isoniazid could be a promising candidate for attenuating morphine tolerance development.
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[1] Wiffen, P.J., Wee, B., Moore, R.A., Oral morphine for cancer pain. Cochrane Database of Systematic Reviews, 2016, (4).
[2] Nadeau, S.E., Lawhern, R.A., Opioids: Analgesia, euphoria, dysphoria, and oblivion: Observations and a hypothesis. Medical Research Archives, 2024, 12(6).
[3] Judd, D., King, C.R., Galke, C., King, C., Galke, C., The opioid epidemic: A review of the contributing factors, negative consequences, and best practices. Cureus, 2023, 15(7).
[4] Baldo, B.A., Toxicities of opioid analgesics: Respiratory depression, histamine release, hemodynamic changes, hypersensitivity, serotonin toxicity. Archives of Toxicology, 2021, 95(8), 2627-2642.
[5] Badshah, I., Anwar, M., Murtaza, B., Khan, M.I., Molecular mechanisms of morphine tolerance and dependence; novel insights and future perspectives. Molecular and Cellular Biochemistry, 2024, 479(6), 1457-1485.
[6] Listos, J., Łupina, M., Talarek, S., Mazur, A., Orzelska-Górka, J., Kotlińska, J., The mechanisms involved in morphine addiction: An overview. International Journal of Molecular Sciences, 2019, 20(17), 4302.
[7] Webster, L., Schmidt, W.K., Dilemma of addiction and respiratory depression in the treatment of pain: A prototypical endomorphin as a new approach. Pain Medicine, 2020, 21(5), 992-1004.
[8] Sahraei, M., Nasiri, A., Hossein-Mardi, L., Faraji, N., Sahraei, H., Ascorbic acid inhibits the acquisition and expression of morphine-induced conditioned place preference and sensitization in male swiss-webster mice. Physiology and Pharmacology, 2022, 26(4), 440-450.
[9] Sahraei, H., Shams, J., Faghih-Monzavi, Z., Zardooz, H., Pashaei-Rad, S., Pourmotabbed, A., Ghoshooni, H., Kamalinejad, M., Effects of papaver rhoeas Extract on the development and expression of tolerance to morphine-induced locomotor activity in mice. Pharmaceutical Biology, 2007, 45(6), 475-480.
[10] Kayukova, L., Berikova, E., Modern anti-tuberculosis drugs and their classification. Part i: First-line drugs. Pharmaceutical Chemistry Journal, 2020, 54(6), 555-563.
[11] Nau, R., Sörgel, F., Eiffert, H., Penetration of drugs through the blood-cerebrospinal fluid/blood-brain barrier for treatment of central nervous system infections. Clinical Microbiology Reviews, 2010, 23(4), 858-883.
[12] Appaji, R., Thomas, L., Baral, T., Saravu, K., Undela, K., Rao, M., Characteristics of isoniazid-induced psychosis: A systematic review of case reports and case series. European Journal of Clinical Pharmacology, 2024, 1-16.
[13] Raharjo, D.N., Mutiara, Y.M., Wahjudi, M., Andrajati, R., Sartika, R.A.D., The interaction of isoniazid on 3d structure variation of nat2 gene and its effect on drug blood levels. Journal of Medicinal and Chemical Sciences, 2024, 7(12), 1969-1981.
[14] Branch, N.T., Characterization of mutations in the rpob and katg gene of mycobacterium tuberculosis isolates from pasteur institute of tehran. International Journal of Advanced Biological and Biomedical Research, 2014, 2(8), 2461-2465.
[15] O’Brien, M.E., Gandhi, R.G., Kotton, C.N., Adamsick, M.L., Risk of serotonin syndrome with isoniazid. Antimicrobial Agents and Chemotherapy, 2020, 65(1), 10.1128/aac. 01455-01420.
[16] Celestine, U.O., Jude, A.I., Asogwa, F.K., Maduabuchi, O.R., Nnamdi, N.S., Anticonvulsant activity of methanol extract of harungana madagascariensis leaf on mice model of isoniazid-induced siezure. Journal of Advanced in Medical and Pharmaceutical Sciences, 2022, 24(8), 34-41.
[17] Landheer, K., Prinsen, H., Petroff, O.A., Rothman, D.L., Juchem, C., Elevated homocarnosine and gaba in subject on isoniazid as assessed through 1h mrs at 7t. Analytical Biochemistry, 2020, 599, 113738.
[18] Pedrón, V.T., Canero, E.M., Varani, A.P., Aon, A.J., Maldonado, R., Balerio, G.N., Baclofen prevents morphine rewarding effects and associated biochemical alterations in male and female mice. European Journal of Pharmacology, 2024, 979, 176768.
[19] Genaro, K., Yoshimura, R., Doan, B., Johnstone, T., Hogenkamp, D., Gee, K., Allosteric modulators of the δ gabaa receptor subtype demonstrate a therapeutic effect in morphine-antinociceptive tolerance and withdrawal in mice. Neuropharmacology, 2022, 219, 109221.
[20] Patti, C.L., Frussa-Filho, R., Silva, R.H., Carvalho, R.C., Kameda, S.R., Takatsu-Coleman, A.L., Cunha, J.L., Abílio, V.C., Behavioral characterization of morphine effects on motor activity in mice. Pharmacology Biochemistry and Behavior, 2005, 81(4), 923-927.
[21] Paul, A.K., Gueven, N., Dietis, N., Profiling the effects of repetitive morphine administration on motor behavior in rats. Molecules, 2021, 26(14), 4355.
[22] Funada, M., Suzuki, T., Misawa, M., The role of dopamine d1-receptors in morphine-induced hyperlocomotion in mice. Neuroscience Letters, 1994, 169(1-2), 1-4.
[23] Wasserman, D.I., Tan, J.M., Kim, J.C., Yeomans, J.S., Muscarinic control of rostromedial tegmental nucleus gaba neurons and morphine‐induced locomotion. European Journal of Neuroscience, 2016, 44(1), 1761-1770.
[24] Colombo, G., Melis, S., Brunetti, G., Serra, S., Vacca, G., Carai, M.A., Gessa, G.L., Gabab receptor inhibition causes locomotor stimulation in mice. European Journal of Pharmacology, 2001, 433(1), 101-104.
[25] Barzegari, A., Shahabi, K., The effects of isoniazid on the acquisition and expression of morphine-induced conditioned place preference in mice. Journal of Kerman University of Medical Science, 2020, 27(1), 69-81.
[26] Nair, A.B., Jacob, S., A simple practice guide for dose conversion between animals and human. Journal of Basic and Clinical Pharmacy, 2016, 7(2), 27.
[27] Mehrabadi, S., Karimiyan, S.M., Morphine tolerance effects on neurotransmitters and related receptors: Definition, overview and update. Journal of Pharmaceutical Research International, 2018, 23(6), 1-11.
[28] Wang, Y., Krishnan, H.R., Ghezzi, A., Yin, J.C.P., Atkinson, N.S., Drug-induced epigenetic changes produce drug tolerance. PLoS biology, 2007, 5(10), e265.
[29] Uniyal, A., Gadepalli, A., Akhilesh, Tiwari, V., Underpinning the neurobiological intricacies associated with opioid tolerance. ACS Chemical Neuroscience, 2020, 11(6), 830-839.
[30] Alavian, F., Ghiasvand, S., The effect of gabab receptors in ca1 region of hippocampus on morphine tolerance in female wistar race rats by conditioned place preference. 2020.
[31] Pysiewicz, A., Mazur, A., Kotlińska, J., Baranowska-Bosiacka, I., Fronc, K., Łupina, M., Kruk-Słomka, M., Listos, J., The influence of topiramate on morphine dependence in mice. Biomolecules, 2025, 15(5), 730.
[32] Ranjbaran, M., Javadzadeh, S., Khosravi, M., Ghoshooni, H., Fatemi, S.M., Shams, J., Sahraei, H., Dual effect of topiramate on the expression of tolerance to analgesic effects of morphine in mice. Physiology and Pharmacology, 2014, 17(4), 413-422.
[33] Fernandes, G.F.d.S., Salgado, H.R.N., Santos, J.L.d., Isoniazid: A review of characteristics, properties and analytical methods. Critical Reviews in Analytical Chemistry, 2017, 47(4), 298-308.
[34] Barzegari, A.A., Shahabi, K., Effects of isoniazid on tolerance and sensitization to the rewarding properties of morphine: A conditioned place preference procedure investigation in mice. Basic and Clinical Neuroscience, 2020, 11(4), 481.
[35] Bhargava, H., Kim, H., Structure activity relationship studies with hypothalamic peptide hormones—iii. Effect of melanotropin-release inhibiting factor and analogs on tolerance to morphine in the rat. Neuropharmacology, 1982, 21(9), 917-922.
[36] Mehrabadi, S., Manaheji, H., Effect of sub-effective dose of gaba agonists on attenuation of morphine tolerance in rats: Behavioral and electrophysiological studies. International Journal of Advanced Biological and Biomedical Research, 2019.
[37] Murphy, N.P., Lam, H.A., Maidment, N.T., A comparison of morphine‐induced locomotor activity and mesolimbic dopamine release in c57bl6, 129sv and dba2 mice. Journal of Neurochemistry, 2001, 79(3), 626-635.
[38] Drouin, C., Blanc, G., Trovero, F., Glowinski, J., Tassin, J.P., Cortical α1-adrenergic regulation of acute and sensitized morphine locomotor effects. Neuroreport, 2001, 12(16), 3483-3486.
[39] Woo, S.H., Kim, H.S., Yun, J.S., Lee, M.K., Oh, K.-W., Seong, Y.H., Oh, S.K., Jang, C.G., Inhibition of baclofen on morphine-induced hyperactivity, reverse tolerance and postsynaptic dopamine receptor supersensitivity. Pharmacological Research, 2001, 43(4), 335-340.
[40] Steidl, S., Yeomans, J.S., M5 muscarinic receptor knockout mice show reduced morphine-induced locomotion but increased locomotion after cholinergic antagonism in the ventral tegmental area. The Journal of Pharmacology and Experimental Therapeutics, 2009, 328(1), 263-275.
[41] Chen, J., Guo, N., Ruan, Y., Mai, Y., Liao, W., Feng, Y., Isoniazid improves cognitive performance, clears aβ plaques, and protects dendritic synapses in app/ps1 transgenic mice. Frontiers in Aging Neuroscience, 2023, 15, 1105095.
[42] Kest, B., Palmese, C., Hopkins, E., A comparison of morphine analgesic tolerance in male and female mice. Brain Research, 2000, 879(1-2), 17-22.
Volume 14, Issue 2
March and April 2026Pages 215-226
- Receive Date 27 August 2025
- Revise Date 29 October 2025
- Accept Date 14 November 2025
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