The behavioral and neurotropic effects of naloxone in mice

S. Yu. Shtrygol’, I. M. Podolsky, D. P. Kavraiskyi

Abstract


The methodological recommendations describe various methods for research of the physical dependence development. Most of them recommend provocation using a naloxone injection as the way to induce the withdrawal symptoms and the following evaluation of the animals’ behavior. However, the current methodological recommendations do not give any comments about the effects of naloxone in provoking the withdrawal syndrome that can be mistakenly interpreted as signs of abstinence.
Aim. To study the effects of naloxone in the open field test, the rotarod-test and its ability to cause specific signs of the withdrawal syndrome in mice.
Materials and methods. The study was carried out on random bred mice in two stages. At the first stage, the initial indicators of the animals’ behavior in the open field test, as well as coordination of movements and the muscle tone in the rotarod-test, were examined. At the second stage, the similar studies were performed after injection of naloxone in the doses of 5 mg/kg and 10 mg/kg. Additionally, the state of mice was studied for the purpose of revealing the specific signs of withdrawal.
Results. It has been found that the administration of naloxone caused certain changes in the state of mice (development of blepharoptosis and head shakes) and a decrease in all open field test subtests at the second stage of the experiment.
Conclusions. The study has shown the ability of naloxone to cause certain changes of the state in mice that can be mistakenly interpreted as “recessive” signs of abstinence. The dose-dependent sedative effect of naloxone in the open field test has been proven; therefore, it should also be taken into account in psychopharmacological studies.


Keywords


naloxone; abstinence; blepharoptosis; the open field test; the rotarod-test; dose-dependency

References


Stefanov, O. V. (2001). Doklinichni doslidzhennia likarskykh zasobiv. Kyiv: Avitsena, 528.

Mironov, A. N. et al. (2012). Rukovotstvo po provedeniiu doklinicheskikh issledovanii lekarstvennykh sredstv. Moscow: Grif i

K, 944.

Morgan, M. M., Christie M. J. (2011). Analysis of opioid efficacy, tolerance, addiction and dependence from cell culture to human.

British Journal of Pharmacology, 164 (4), 1322–1334. doi: 10.1111/j.1476–5381.2011.01335.x

Spasov, A. A., Grechko, O. Yu., Eliseeva, N. V. (2009). Biulleten Volgogradskogo nauchnogo centra RAMN, 3 (23), 22–25.

Kavraiskyi, D. P., Shtrygol, S. Yu., Tsyvunin, V. V. et al. (2016). Ukrainskyi zhurnal klіnіchnoi ta laboratornoi medytsyny, 11 (3),

–62.

Vogel, H. (2008). Drug Discovery and Evaluation: Pharmacological Assays. Springer, Berlin, Heidelberg: New York, 2068.

Curzon, P., Zhang, M., Radek, R. J., et al. (2009). The Behavioral Assessment of Sensorimotor Processes in the Mouse: Acoustic

Startle, Sensory Gating, Locomotor Activity, Rotarod, and Beam Walking. In: Buccafusco JJ, editor. Methods of Behavior

Analysis in Neuroscience. 2nd edition. Boca Raton (FL): CRC Press / Taylor & Francis; 2009. Chapter 8. Available at: https://

www.ncbi.nlm.nih.gov/books/NBK5236/

Nadorova, A. V., Kozlovskaja, M. M., Seredenin, S. B. (2009). Naloxone Effects on Behavior of Inbred Mice with Different Response to Emotional

Stress in Open Field Test. Bulletin of Experimental Biology and Medicine, 148 (4), 609–611. doi: 10.1007/s10517–010–0776–8

Seredenin, S. B., Nadorova, A. V., Kolik, L. G., Yarkova, M. A. (2013). Effects of Phenazepam on the Behavior of C57Bl/6 and

BALB/c Mice in the Open Field Test after Naloxone Pretreatment. Bulletin of Experimental Biology and Medicine, 155 (3),

–349. doi: 10.1007/s10517–013–2150–0

Hodgson, S. R., Hofford, R. S., Norris, C. J., Eitan, S. (2008). Increased elevated plus maze open–arm time in mice during naloxone–

precipitated morphine withdrawal. Behavioural Pharmacology, 19 (8), 805–811. doi: 10.1097/fbp.0b013e32831c3b57

Belzung, C., Agmo, A. (1997). Naloxone blocks anxiolytic–like effects of benzodiazepines in Swiss but not in Balb/c mice.

Psychopharmacology, 132 (2), 195–201. doi: 10.1007/s002130050336

Belzung, C., Ågmo, A. (1997). Naloxone potentiates the effects of subeffective doses of anxiolytic agents in mice. European

Journal of Pharmacology, 323 (2–3), 133–136. doi: 10.1016/s0014–2999(97)00142–8

Deacon, R. M. J. (2006). Housing, husbandry and handling of rodents for behavioral experiments. Nature Protocols, 1 (2),

–946. doi: 10.1038/nprot.2006.120

Rebrova, O. Yu. (2006). Statisticheskii analiz meditcinskikh dannykh. Primenenie paketa prikladnykh programm STATISTICA,

izd. Moscow: Media Sfera, 312.

Suzuki, T., Hayashi, Y., Misawa, M. (1992). The role of mu1 receptor in physical dependence on morphine using the mu receptor

deficient CXBK mouse. Life Sciences, 50 (12), 849–856. doi: 10.1016/0024–3205(92)90203–2

Sadeghi, M., Movafegh, A., Nouralishahi, B. (2008). The effect of an intravenous bolus of ultra–low–dose naloxone on intraoperative

sedation, post–operative pain intensity and morphine consumption in cesarean section patients under spinal

anesthesia. Research Journal of Biological Sciences, 3 (10), 1223–1226.


GOST Style Citations


1. Доклінічні дослідження лікарських засобів : метод. рек. / за ред. О. В. Стефанова. – К. : Авіценна, 2001. – 528 с.

2. Руководство по проведению доклинических исследований лекарственных средств / А. Н. Миронов и др. – М. : Гриф
и К, 2012. – 944 с.

3. Morgan, M. M. Analysis of opioid efficacy, tolerance, addiction and dependence from cell culture to human / M. M. Morgan,
M. J. Christie // British J. of Pharmacol. – 2011. – Vol. 164, Issue 4. – P. 1322–1334. doi: 10.1111/j.1476–5381.2011.01335.x

4. Спасов, А. А. Сравнительное изучение наркогенного потенциала опиоидных агонистов / А. А. Спасов, О. Ю. Гречко,
Н. В. Елисеева // Бюл. Волгоградского научного центра РАМН. – 2009. – № 3 (23). – С. 22–25.

5. Перспективний антиконвульсант 1–(4–метоксифеніл)–5–{2–[4–(4–метоксифеніл)піперазин–1–іл]–2–оксоетил}–1,5–
дигідро–4H–піразоло[3,4–d]піридин–4–он має протизапальну та знеболювальну активність та позбавлений адик-
тивного потенціалу / Д. П. Каврайський, С. Ю. Штриголь, В. В. Цивунін та ін. // Укр. журн. клінічної та лабораторної
медицини. – 2016. – Т. 11, № 3. – С. 52–62.

6. Drug Discovery and Evaluation : Pharmacological Assays / H. G. Vogel (ed.). – 3-rd ed. – Springer, Berlin, Heidelberg,
NewYork, 2008. – 2068 p.

7. The Behavioral Assessment of Sensorimotor Processes in the Mouse : Acoustic Startle, Sensory Gating, Locomotor Activity,
Rotarod, and Beam Walking / P. Curzon, M. Zhang, R. J. Radek et al. // In : Buccafusco JJ, editor. Methods of Behavior
Analysis in Neuroscience. – 2-nd ed. Boca Raton (FL) : CRC Press / Taylor & Francis; 2009. Chapter 8. Available at : https://
www.ncbi.nlm.nih.gov/books/NBK5236/

8. Nadorova, A. V. Naloxone Effects on Behavior of Inbred Mice with Different Response to Emotional Stress in Open Field Test
/ A. V. Nadorova, M. M. Kozlovskaja, S. B. Seredenin // Bul. of Experimental Biol. and Medicine. – 2009. – Vol. 148, Issue 4. –
P. 609–611. doi: 10.1007/s10517–010–0776–8

9. Effects of phenazepam on the behavior of C57BL/6 and BALB/c mice in the open field test after naloxone pretreatment /
S. B. Seredenin, A. V. Nadorova, L. G. Kolik, M. A. Yarkova // Bul. of Experimental Biol. and Medicine. – 2013. – Vol. 155, Issue 3. –
P. 346–349. doi: 10.1007/s10517–013–2150–0

10. Increased elevated plus maze open–arm time in mice during naloxone–precipitated morphine withdrawal / S. R. Hodgson,
R. S. Hofford, C. J. Norris, S. Eitan // Behavioural Pharmacol. – 2008. –Vol. 19, Issue 8. – P. 805–811. doi: 10.1097/fbp.0b013e32831c3b57

11. Belzung, C. Naloxone blocks anxiolytic–like effects of benzodiazepines in Swiss but not in Balb/c mice / C. Belzung, A. Agmo
// Psychopharmacol. – 1997. – Vol. 132, Issue 2. – P. 195–201. doi: 10.1007/s002130050336

12. Belzung, C. Naloxone potentiates the effects of subeffective doses of anxiolytic agents in mice / C. Belzung, A. Agmo //
European J. of Pharmacol. – 1997. – Vol. 323, Issue 2–3. – P. 133–136. doi: 10.1016/s0014–2999(97)00142–8

13. Deacon, R. M. Housing, husbandry and handling of rodents for behavioral experiments / R. M. Deacon // Nature Protocols.
– 2006. – Vol. 1, Issue 2. – P. 936–946. doi: 10.1038/nprot.2006.120

14. Реброва, О. Ю. Статистический анализ медицинских данных. Применение пакета прикладных программ Statistica.
– М. : Медиасфера, 2006. – 312 с.

15. Suzuki, T. The role of mu1 receptor in physical dependence on morphine using the mu receptor deficient CXBK mouse /
T. Suzuki, Y. Hayashi, M. Misawa // Life Sci. – 1992. – Vol. 50, Issue 12. – P. 849–856. doi: 10.1016/0024–3205(92)90203–2

16. Sadeghi, M. The effect of an intravenous bolus of ultra–low–dose naloxone on intraoperative sedation, post–operative
pain intensity and morphine consumption in cesarean section patients under spinal anesthesia / M. Sadeghi, A. Movafegh,
B. Nouralishahi // Res. J. of Biol. Sci. – 2008. – Vol. 3, Issue 10. –P. 1223–1226.





DOI: https://doi.org/10.24959/cphj.17.1435

Abbreviated key title: Klìn. farm.

ISSN 2518-1572 (Online), ISSN 1562-725X (Print)