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Мелатонин и его возможности в терапии хронической боли
Мелатонин и его возможности в терапии хронической боли
Курганова Ю.М., Данилов А.Б. Мелатонин и его возможности в терапии хронической боли. Consilium Medicum. 2017; 19 (9): 49–54. DOI: 10.26442/2075-1753_19.9.49-54
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Аннотация
Цель исследования – изучение обезболивающего действия мелатонина при хронической неспецифической боли в спине.
Материал и методы. В исследовании приняли участие 178 пациентов в возрасте от 40 до 65 лет с хронической неспецифической болью в нижней части спины при длительности боли более 3 мес и интенсивности более 3 баллов по визуальной аналоговой шкале. Пациенты были разделены на 6 групп, которые составили 3 пары сравнения – основная группа и группа сравнения. В 1-й паре больные основной группы (n=31) и группы сравнения (n=29) получали комбинированный препарат глюкозамина гидрохлорида 500 мг и хондроитина сульфата 500 мг по 1 таблетке 2 раза в день на протяжении 1 мес, затем по 1 таблетке в течение 2 мес, дополнительно пациенты основной группы получали мелатонин (Мелаксен) 3 мг за 30–40 мин до сна. Во 2-й паре больные группы сравнения (n=30) принимали комбинированный препарат глюкозамина гидрохлорида 500 мг и хондроитина сульфата 500 мг по 1 таблетке 2 раза в день и диклофенак в дозе 25 мг 2–3 раза в день, пациенты из основной группы (n=30) дополнительно принимали мелатонин (Мелаксен) по аналогичной применяемой в 1-й паре сравнения схеме. В 3-й паре больные основной группы (n=29) получали диклофенак в дозе 25 мг 3 раза в день и мелатонин (Мелаксен) по описанной выше схеме, пациенты из группы сравнения (n=29) получали только диклофенак. Длительность наблюдения в 1-й паре составила 3 мес, во 2 и 3-й парах – 1 мес.
Результаты и заключение. Были получены данные, демонстрирующие статистически достоверно более значительное снижение интенсивности боли при движении и в покое во всех основных группах, чем в группах сравнения. Сделан вывод, что добавление мелатонина к стандартной схеме лечения боли в спине повышает ее эффективность.
Ключевые слова: боль, хроническая боль, хроническая боль в спине, болевые синдромы, мелатонин.
Materials and methods. The study involved 178 patients aged 40 to 65 years with chronic nonspecific pain in the lower back with a duration of pain more than 3 months and an intensity of more than 3 points on a visual analog scale. Patients were divided into 6 groups, which comprised 3 pairs of comparison - the main group and the comparison group. In the 1 st pair, the patients of the main group (n=31) and the comparison group (n = 29) received a combined preparation of glucosamine hydrochloride 500 mg and chondroitin sulfate 500 mg 1 tablet 2 times a day for 1 month, then 1 tablet per day for 2 months, in addition, patients of the main group received melatonin (Melaxen) 3 mg for 30–40 minutes before bedtime. In the 2nd pair, the comparison groups (n=30) took a combined preparation of glucosamine hydrochloride 500 mg and chondroitin sulfate 500 mg 1 tablet 2 times a day and diclofenac 25 mg 2–3 times a day, patients from the main group (n=30) additionally received melatonin (Melaxen) according to the same scheme used in the first pair of comparison. In the third pair, patients of the main group (n=29) received diclofenac 25 mg 3 times a day and melatonin (Melaxen) as described above, patients from the comparison group (n=29) received only diclofenac. The duration of follow-up in the first pair was 3 months, in the 2 nd and 3 rd couples – 1 month.
Results and conclusion. Data obtained showed statistically significantly greater reduction in pain intensity during movement and at rest in all major groups than in comparison groups. It is concluded that the addition of melatonin to the standard treatment of back pain increases its effectiveness.
Key words: pain, chronic pain, chronic back pain, pain syndromes, melatonin.
Материал и методы. В исследовании приняли участие 178 пациентов в возрасте от 40 до 65 лет с хронической неспецифической болью в нижней части спины при длительности боли более 3 мес и интенсивности более 3 баллов по визуальной аналоговой шкале. Пациенты были разделены на 6 групп, которые составили 3 пары сравнения – основная группа и группа сравнения. В 1-й паре больные основной группы (n=31) и группы сравнения (n=29) получали комбинированный препарат глюкозамина гидрохлорида 500 мг и хондроитина сульфата 500 мг по 1 таблетке 2 раза в день на протяжении 1 мес, затем по 1 таблетке в течение 2 мес, дополнительно пациенты основной группы получали мелатонин (Мелаксен) 3 мг за 30–40 мин до сна. Во 2-й паре больные группы сравнения (n=30) принимали комбинированный препарат глюкозамина гидрохлорида 500 мг и хондроитина сульфата 500 мг по 1 таблетке 2 раза в день и диклофенак в дозе 25 мг 2–3 раза в день, пациенты из основной группы (n=30) дополнительно принимали мелатонин (Мелаксен) по аналогичной применяемой в 1-й паре сравнения схеме. В 3-й паре больные основной группы (n=29) получали диклофенак в дозе 25 мг 3 раза в день и мелатонин (Мелаксен) по описанной выше схеме, пациенты из группы сравнения (n=29) получали только диклофенак. Длительность наблюдения в 1-й паре составила 3 мес, во 2 и 3-й парах – 1 мес.
Результаты и заключение. Были получены данные, демонстрирующие статистически достоверно более значительное снижение интенсивности боли при движении и в покое во всех основных группах, чем в группах сравнения. Сделан вывод, что добавление мелатонина к стандартной схеме лечения боли в спине повышает ее эффективность.
Ключевые слова: боль, хроническая боль, хроническая боль в спине, болевые синдромы, мелатонин.
________________________________________________
Materials and methods. The study involved 178 patients aged 40 to 65 years with chronic nonspecific pain in the lower back with a duration of pain more than 3 months and an intensity of more than 3 points on a visual analog scale. Patients were divided into 6 groups, which comprised 3 pairs of comparison - the main group and the comparison group. In the 1 st pair, the patients of the main group (n=31) and the comparison group (n = 29) received a combined preparation of glucosamine hydrochloride 500 mg and chondroitin sulfate 500 mg 1 tablet 2 times a day for 1 month, then 1 tablet per day for 2 months, in addition, patients of the main group received melatonin (Melaxen) 3 mg for 30–40 minutes before bedtime. In the 2nd pair, the comparison groups (n=30) took a combined preparation of glucosamine hydrochloride 500 mg and chondroitin sulfate 500 mg 1 tablet 2 times a day and diclofenac 25 mg 2–3 times a day, patients from the main group (n=30) additionally received melatonin (Melaxen) according to the same scheme used in the first pair of comparison. In the third pair, patients of the main group (n=29) received diclofenac 25 mg 3 times a day and melatonin (Melaxen) as described above, patients from the comparison group (n=29) received only diclofenac. The duration of follow-up in the first pair was 3 months, in the 2 nd and 3 rd couples – 1 month.
Results and conclusion. Data obtained showed statistically significantly greater reduction in pain intensity during movement and at rest in all major groups than in comparison groups. It is concluded that the addition of melatonin to the standard treatment of back pain increases its effectiveness.
Key words: pain, chronic pain, chronic back pain, pain syndromes, melatonin.
Полный текст
Список литературы
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11. Bilici D, Akpinar E, Kiziltunc A. Protective effect of melatonin in carrageenan-induced acute local inflammation. Pharm Res 2002; 46 (2): 133–9.
12. Mantovani M1, Pértile R, Calixto JB et al. Melatonin exerts an antidepressant-like effect in the tail suspension test in mice: evi- dence for involvement of N-methyl-D-aspartate receptors and the L-argi- nine-nitric oxide pathway. Neurosci Lett 2003; 343 (1): 1–4.
13. Tu Y, Sun RQ, Willis WD. Effects of intrathecal injections of melatonin analogs on capsaicin-induced secondary mechanical allodynia and hyperalgesia in rats. Pain 2004; 109 (3): 340–50.
14. Ulugol A, Dokmeci D, Guray G et al. Antihyperalgesic, but not antiallodynic, effect of melatonin in nerve-injured neuropathic mice: possible involvements of the L-arginine-NO pathway and opioid system. Life Sci 2006; 78 (14): 1592–7.
15. Ambriz-Tututi, Granados-Soto V. Oral and spinalmelatonin reduces tactile allodynia in rats via activation of MT2 and opioid receptors. Pain 2007; 132 (3): 273–80.
16. Masruha MR, de Sousa Vieira DS, Minett TS et al. Low urinary 6-sulphatoxymelatonin concentrations in acute migraine. J Headache Pain 2008; 9: 221–4.
17. Peres MF, Zukerman E, da Cunha Tanuri F et al. Melatonin, 3 mg, is effective for migraine prevention. Neurology 2004; 63: 757.
18. Peres MFP, Masruha MR, Zukerman E et al. Potential therapeutic use of melatonin in migraine and other headache disorders. Expert Opin Investig Drugs 2006; 15 (4): 367–75.
19. Leone M, D’Amico D, Moschiano F et al. Melatonin versus placebo in the prophylaxis of cluster headache: a double-blind pilot study with parallel groups. Cephalalgia 1996; 16: 494–6.
20. Peres MFP, Rozen TD. Melatonin in the preventive treatment of chronic cluster headache. Cephalalgia 2001; 21: 993–5.
21. Miano S, Parisi P, Pellicci A et al. Melatonin to prevent migraine or tension-type headache in children. Neuro Sci 2008; 29 (4): 285–7.
22. Wikner J, Hirsch U, Wetterberg L, Rojdmark S. Fibromyalgia – a syndrome associated with decreased nocturnal melatonin secretion. Clin Endocrinol (Oxf) 1998; 49: 179–83.
23. Hussain SA, Al-Khalifa II, Jasim NA, Gorial FI. Adjuvant use of melatonin for treatment of fibromyalgia. J Pineal Res 2011; 50: 267–71.
24. Zanette S, Vercelino R, Laste G et al. Melatonin analgesia is associated with improvement of the descending endogenous pain-modulating system in fibromyalgia: a phase II, randomized, double-dum-my, controlled trial. BMC Pharmacol Toxicol 2014.
25. Аfkhamizadeh M, Sahebari M, Seyyed-Hoseini SR. Morning melatonin serum values do not correlate with disease activity in rheumatoid arthritis: a cross-sectional study. Rheumatol Int 2014.
26. Cutolo M, Maestroni GJM, Otsa K et al. Circadian melatonin and cortisol levels in rheumatoid arthritis patients in winter time: a north and south Europe comparison. Ann Rheum Dis 2005; 64: 2: 212–6.
27. Rudra DS, Pal U, Maiti NC et al. Melatonin inhibits matrix metalloproteinase-9 activity by binding to its active site. J Pineal Res 2013; 54 (4): 398–405.
28. Данилов А.Б. Типы и патофизиологические механизмы боли – значение для клинической практики. Manage pain. 2014; 1: 4–8. / Danilov A.B. Tipy i patofiziologicheskie mekhanizmy boli – znachenie dlia klinicheskoi praktiki. Manage pain. 2014; 1: 4–8. [in Russian]
29. Wang LM, Suthana NA, Chaudhury D et al. Melatonin inhibits hippocampal long-term potentiation. Eur J Neur 2005; 22 (9): 2231–7.
30. Ayar A, Duncan JM, Ozcan M, Kelestimur H. Melatonin inhibits high voltage activated calcium currents in cultured rat dorsal root ganglion neurons. Neur Letters 2001; 313 (1–2): 73–7.
31. Coloma FM, Niles LP. Melatonin enhancement of [3H]-c-aminobutyric acid and [3H]muscimol binding in rat brain. Biochem Pharmacol 1988; 37: 1271–4.
32. Xu F, Li JC, Ma KC et al. Effects of melatonin on hypothalamic gamma-aminobutyric acid, aspartic acid, glutamic acid, beta-endorphin and serotonin levels in male mice. Biol Signals 1995; 4: 225–23.
2. Manev H, Uz T, Qu T. Early upregulation of hippocampal 5-lipoxygenase following systemic administration of kainate to rats. Rest Neurol Neurosci 1998; 12: 81–5.
3. Storr M, Koppitz P, Sibaev A et al. Melatonin reduces non-adrenergic, non-cholinergic relaxant neurotransmission by inhibition of nitric oxide synthase activity in the gastrointestinal tract of rodents in vitro. J Pineal Res 2002; 33: 101–8.
4. Maestroni GJ, Conti A, Pierpaoli W. Role of the pineal gland in immunity. Circadian synthesis and release of melatonin modulates the antibody response and antagonizes the immunosuppressive effect of corticosterone. J Neuroimmunol 1986; 13: 19–30.
5. Loo H, Dalery J, Macher JP, Payen A. Pilot study comparing in blind the therapeutic effect of two doses of agomelatine, melatoninergic agonist and selective 5HT2C receptors antagonist, in the treatment of major depressive disorders. Encephale 2002; 28: 356–62.
6. Olie P, Emsley R. Confirmed clinical efficacy of agomelatine (25–50 mg) in major depression; two randomized, double-blind controlled studies. Eur Neuropsychopharmacol 2005; 15 (Suppl. 3): S416.
7. Morris RW, Lutsch EF. Daily susceptibility rhythm to morphine analgesia. J Pharm Sci 1969; 58 (3): 374–6.
8. Wilhelmsen M, Amirian I, Reiter RJ et al. Analgesic effects of melatonin: review of current evidence from experimental and clinical studies. J Pineal Res 2011; 51 (3): 270–7.
9. Mayo JC, Sainz RM, Tan DX et al. Anti-Inflammatory Actions of Melatonin and Its Metabolites, N1-Acetyl-N2-formyl-5-methoxykynuramine (AFMK) and N1-Acetyl-5-methoxykynuramine (AMK), in Macrophages. J Neuroimmunol 2005; 165: 139–49.
10. El-Shenawy SM, Abdel-Salam OM, Baiuomy AR et al. Studies on the anti-inflammatory and anti-nociceptive effects of melatonin in the rat. Pharmacol Res 2002; 46 (3): 235–43.
11. Bilici D, Akpinar E, Kiziltunc A. Protective effect of melatonin in carrageenan-induced acute local inflammation. Pharm Res 2002; 46 (2): 133–9.
12. Mantovani M1, Pértile R, Calixto JB et al. Melatonin exerts an antidepressant-like effect in the tail suspension test in mice: evi- dence for involvement of N-methyl-D-aspartate receptors and the L-argi- nine-nitric oxide pathway. Neurosci Lett 2003; 343 (1): 1–4.
13. Tu Y, Sun RQ, Willis WD. Effects of intrathecal injections of melatonin analogs on capsaicin-induced secondary mechanical allodynia and hyperalgesia in rats. Pain 2004; 109 (3): 340–50.
14. Ulugol A, Dokmeci D, Guray G et al. Antihyperalgesic, but not antiallodynic, effect of melatonin in nerve-injured neuropathic mice: possible involvements of the L-arginine-NO pathway and opioid system. Life Sci 2006; 78 (14): 1592–7.
15. Ambriz-Tututi, Granados-Soto V. Oral and spinalmelatonin reduces tactile allodynia in rats via activation of MT2 and opioid receptors. Pain 2007; 132 (3): 273–80.
16. Masruha MR, de Sousa Vieira DS, Minett TS et al. Low urinary 6-sulphatoxymelatonin concentrations in acute migraine. J Headache Pain 2008; 9: 221–4.
17. Peres MF, Zukerman E, da Cunha Tanuri F et al. Melatonin, 3 mg, is effective for migraine prevention. Neurology 2004; 63: 757.
18. Peres MFP, Masruha MR, Zukerman E et al. Potential therapeutic use of melatonin in migraine and other headache disorders. Expert Opin Investig Drugs 2006; 15 (4): 367–75.
19. Leone M, D’Amico D, Moschiano F et al. Melatonin versus placebo in the prophylaxis of cluster headache: a double-blind pilot study with parallel groups. Cephalalgia 1996; 16: 494–6.
20. Peres MFP, Rozen TD. Melatonin in the preventive treatment of chronic cluster headache. Cephalalgia 2001; 21: 993–5.
21. Miano S, Parisi P, Pellicci A et al. Melatonin to prevent migraine or tension-type headache in children. Neuro Sci 2008; 29 (4): 285–7.
22. Wikner J, Hirsch U, Wetterberg L, Rojdmark S. Fibromyalgia – a syndrome associated with decreased nocturnal melatonin secretion. Clin Endocrinol (Oxf) 1998; 49: 179–83.
23. Hussain SA, Al-Khalifa II, Jasim NA, Gorial FI. Adjuvant use of melatonin for treatment of fibromyalgia. J Pineal Res 2011; 50: 267–71.
24. Zanette S, Vercelino R, Laste G et al. Melatonin analgesia is associated with improvement of the descending endogenous pain-modulating system in fibromyalgia: a phase II, randomized, double-dum-my, controlled trial. BMC Pharmacol Toxicol 2014.
25. Аfkhamizadeh M, Sahebari M, Seyyed-Hoseini SR. Morning melatonin serum values do not correlate with disease activity in rheumatoid arthritis: a cross-sectional study. Rheumatol Int 2014.
26. Cutolo M, Maestroni GJM, Otsa K et al. Circadian melatonin and cortisol levels in rheumatoid arthritis patients in winter time: a north and south Europe comparison. Ann Rheum Dis 2005; 64: 2: 212–6.
27. Rudra DS, Pal U, Maiti NC et al. Melatonin inhibits matrix metalloproteinase-9 activity by binding to its active site. J Pineal Res 2013; 54 (4): 398–405.
28. Danilov A.B. Tipy i patofiziologicheskie mekhanizmy boli – znachenie dlia klinicheskoi praktiki. Manage pain. 2014; 1: 4–8. [in Russian]
29. Wang LM, Suthana NA, Chaudhury D et al. Melatonin inhibits hippocampal long-term potentiation. Eur J Neur 2005; 22 (9): 2231–7.
30. Ayar A, Duncan JM, Ozcan M, Kelestimur H. Melatonin inhibits high voltage activated calcium currents in cultured rat dorsal root ganglion neurons. Neur Letters 2001; 313 (1–2): 73–7.
31. Coloma FM, Niles LP. Melatonin enhancement of [3H]-c-aminobutyric acid and [3H]muscimol binding in rat brain. Biochem Pharmacol 1988; 37: 1271–4.
32. Xu F, Li JC, Ma KC et al. Effects of melatonin on hypothalamic gamma-aminobutyric acid, aspartic acid, glutamic acid, beta-endorphin and serotonin levels in male mice. Biol Signals 1995; 4: 225–23.
2. Manev H, Uz T, Qu T. Early upregulation of hippocampal 5-lipoxygenase following systemic administration of kainate to rats. Rest Neurol Neurosci 1998; 12: 81–5.
3. Storr M, Koppitz P, Sibaev A et al. Melatonin reduces non-adrenergic, non-cholinergic relaxant neurotransmission by inhibition of nitric oxide synthase activity in the gastrointestinal tract of rodents in vitro. J Pineal Res 2002; 33: 101–8.
4. Maestroni GJ, Conti A, Pierpaoli W. Role of the pineal gland in immunity. Circadian synthesis and release of melatonin modulates the antibody response and antagonizes the immunosuppressive effect of corticosterone. J Neuroimmunol 1986; 13: 19–30.
5. Loo H, Dalery J, Macher JP, Payen A. Pilot study comparing in blind the therapeutic effect of two doses of agomelatine, melatoninergic agonist and selective 5HT2C receptors antagonist, in the treatment of major depressive disorders. Encephale 2002; 28: 356–62.
6. Olie P, Emsley R. Confirmed clinical efficacy of agomelatine (25–50 mg) in major depression; two randomized, double-blind controlled studies. Eur Neuropsychopharmacol 2005; 15 (Suppl. 3): S416.
7. Morris RW, Lutsch EF. Daily susceptibility rhythm to morphine analgesia. J Pharm Sci 1969; 58 (3): 374–6.
8. Wilhelmsen M, Amirian I, Reiter RJ et al. Analgesic effects of melatonin: review of current evidence from experimental and clinical studies. J Pineal Res 2011; 51 (3): 270–7.
9. Mayo JC, Sainz RM, Tan DX et al. Anti-Inflammatory Actions of Melatonin and Its Metabolites, N1-Acetyl-N2-formyl-5-methoxykynuramine (AFMK) and N1-Acetyl-5-methoxykynuramine (AMK), in Macrophages. J Neuroimmunol 2005; 165: 139–49.
10. El-Shenawy SM, Abdel-Salam OM, Baiuomy AR et al. Studies on the anti-inflammatory and anti-nociceptive effects of melatonin in the rat. Pharmacol Res 2002; 46 (3): 235–43.
11. Bilici D, Akpinar E, Kiziltunc A. Protective effect of melatonin in carrageenan-induced acute local inflammation. Pharm Res 2002; 46 (2): 133–9.
12. Mantovani M1, Pértile R, Calixto JB et al. Melatonin exerts an antidepressant-like effect in the tail suspension test in mice: evi- dence for involvement of N-methyl-D-aspartate receptors and the L-argi- nine-nitric oxide pathway. Neurosci Lett 2003; 343 (1): 1–4.
13. Tu Y, Sun RQ, Willis WD. Effects of intrathecal injections of melatonin analogs on capsaicin-induced secondary mechanical allodynia and hyperalgesia in rats. Pain 2004; 109 (3): 340–50.
14. Ulugol A, Dokmeci D, Guray G et al. Antihyperalgesic, but not antiallodynic, effect of melatonin in nerve-injured neuropathic mice: possible involvements of the L-arginine-NO pathway and opioid system. Life Sci 2006; 78 (14): 1592–7.
15. Ambriz-Tututi, Granados-Soto V. Oral and spinalmelatonin reduces tactile allodynia in rats via activation of MT2 and opioid receptors. Pain 2007; 132 (3): 273–80.
16. Masruha MR, de Sousa Vieira DS, Minett TS et al. Low urinary 6-sulphatoxymelatonin concentrations in acute migraine. J Headache Pain 2008; 9: 221–4.
17. Peres MF, Zukerman E, da Cunha Tanuri F et al. Melatonin, 3 mg, is effective for migraine prevention. Neurology 2004; 63: 757.
18. Peres MFP, Masruha MR, Zukerman E et al. Potential therapeutic use of melatonin in migraine and other headache disorders. Expert Opin Investig Drugs 2006; 15 (4): 367–75.
19. Leone M, D’Amico D, Moschiano F et al. Melatonin versus placebo in the prophylaxis of cluster headache: a double-blind pilot study with parallel groups. Cephalalgia 1996; 16: 494–6.
20. Peres MFP, Rozen TD. Melatonin in the preventive treatment of chronic cluster headache. Cephalalgia 2001; 21: 993–5.
21. Miano S, Parisi P, Pellicci A et al. Melatonin to prevent migraine or tension-type headache in children. Neuro Sci 2008; 29 (4): 285–7.
22. Wikner J, Hirsch U, Wetterberg L, Rojdmark S. Fibromyalgia – a syndrome associated with decreased nocturnal melatonin secretion. Clin Endocrinol (Oxf) 1998; 49: 179–83.
23. Hussain SA, Al-Khalifa II, Jasim NA, Gorial FI. Adjuvant use of melatonin for treatment of fibromyalgia. J Pineal Res 2011; 50: 267–71.
24. Zanette S, Vercelino R, Laste G et al. Melatonin analgesia is associated with improvement of the descending endogenous pain-modulating system in fibromyalgia: a phase II, randomized, double-dum-my, controlled trial. BMC Pharmacol Toxicol 2014.
25. Аfkhamizadeh M, Sahebari M, Seyyed-Hoseini SR. Morning melatonin serum values do not correlate with disease activity in rheumatoid arthritis: a cross-sectional study. Rheumatol Int 2014.
26. Cutolo M, Maestroni GJM, Otsa K et al. Circadian melatonin and cortisol levels in rheumatoid arthritis patients in winter time: a north and south Europe comparison. Ann Rheum Dis 2005; 64: 2: 212–6.
27. Rudra DS, Pal U, Maiti NC et al. Melatonin inhibits matrix metalloproteinase-9 activity by binding to its active site. J Pineal Res 2013; 54 (4): 398–405.
28. Данилов А.Б. Типы и патофизиологические механизмы боли – значение для клинической практики. Manage pain. 2014; 1: 4–8. / Danilov A.B. Tipy i patofiziologicheskie mekhanizmy boli – znachenie dlia klinicheskoi praktiki. Manage pain. 2014; 1: 4–8. [in Russian]
29. Wang LM, Suthana NA, Chaudhury D et al. Melatonin inhibits hippocampal long-term potentiation. Eur J Neur 2005; 22 (9): 2231–7.
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Авторы
Ю.М.Курганова*, А.Б.Данилов
ФГАОУ ВО «Первый Московский государственный медицинский университет им. И.М.Сеченова» Минздрава России. 119991, Россия, Москва, ул. Трубецкая, д. 8, стр. 2
*j.kurganova@yandex.ru
I.M.Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation. 119991, Russian Federation, Moscow, ul. Trubetskaia, d. 8, str. 2
*j.kurganova@yandex.ru
ФГАОУ ВО «Первый Московский государственный медицинский университет им. И.М.Сеченова» Минздрава России. 119991, Россия, Москва, ул. Трубецкая, д. 8, стр. 2
*j.kurganova@yandex.ru
________________________________________________
I.M.Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation. 119991, Russian Federation, Moscow, ul. Trubetskaia, d. 8, str. 2
*j.kurganova@yandex.ru
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