Milnacipran is an inhibitor of the serotonin transporter (Ki = 31 nM) and the monoamine transporter (Ki = 8.5 nM). Milnacipran boosts synaptic monoamine levels and helps regulate pathways related to descending pain inhibition, easing chronic pain. Milnacipran is useful for research on major depressive disorder, fibromyalgia, anxiety disorders, and neuropathic pain[1-4].
In vitro, treatment with 0.1-10μM Milnacipran for 24 hours increased GluR2 Q/R site RNA editing efficiency, decreased ADAR2 mRNA expression, and elevated GluR2 mRNA and GluR2 pre-mRNA expression in modified HeLa cells stably expressing GluR2 pre-mRNA[5]. Treatment with 2.5-40μg/mL Milnacipran for 24-48 hours increased chromosomal aberrations, sister chromatid exchanges, and micronucleus frequency, decreased mitotic index, and increased comet tail length, tail intensity, and tail moment in peripheral blood lymphocytes[6]. Treatment with 10-100μM Milnacipran for 24 hours did not affect cell viability in esophageal squamous cell carcinoma cell lines (KYSE30, KYSE150, KYSE180, KYSE450)[7].
In vivo, intraperitoneal injection of 3-30mg/kg Milnacipran or intrathecal injection of 2.1-21μg/site Milnacipran inhibited pain in C57BL/6 mouse models of mechanical allodynia[8]. Intrathecal injection of 0.1-10μg/site Milnacipran or intraperitoneal injection of 1, 10mg/kg Milnacipran dose-dependently inhibited itch-related behaviors in serotonin-induced ICR mice[9]. Single intraperitoneal injection of 30mg/kg Milnacipran suppressed food intake after fasting in C57BL/6J mice and Ay mice. Twice-daily intraperitoneal injection of 30mg/kg Milnacipran for 3 days decreased food intake and body weight and increased hypothalamic POMC and CART mRNA levels in mice[10].
References:[1] Gupta H, Girma B, Jenkins JS, et al. Milnacipran for the Treatment of Fibromyalgia. Health Psychol Res. 2021 Jul 10;9(1):25532.
[2] Keks NA, Hope J, Keogh S, et al. Milnacipran: serotonin-noradrenaline reuptake inhibitor approved for fibromyalgia may be a useful antidepressant. Australas Psychiatry. 2018 Oct;26(5):537-540.
[3] Spencer CM, Wilde MI. Milnacipran. A review of its use in depression. Drugs. 1998 Sep;56(3):405-27.
[4] Kyle JA, Dugan BD, Testerman KK. Milnacipran for treatment of fibromyalgia. Ann Pharmacother. 2010 Sep;44(9):1422-9.
[5] Sawada J, Yamashita T, Aizawa H, et al. Effects of antidepressants on GluR2 Q/R site-RNA editing in modified HeLa cell line. Neuroscience Research. 2009 Jul;64(3):251-258.
[6] Avuloglu Yilmaz E, Unal F, Yuzbasioglu D, et al. Evaluation of cytogenetic and DNA damage induced by the antidepressant drug-active ingredients, trazodone and milnacipran, in vitro. Drug Chem Toxicol. 2016;Early Online:1-10.
[7] Bao S, Zhang Y, Zeng J, et al. Innovative role of the antidepressant imipramine in esophageal squamous cell carcinoma treatment: Promoting apoptosis and protective autophagy. International Immunopharmacology. 2025;147:113969.
[8] Andoh T, Kitamura R, Kuraishi Y. Milnacipran inhibits oxaliplatin-induced mechanical allodynia through spinal action in mice. Biol Pharm Bull. 2015;38(1):151-154.
[9] Andoh T, Gotoh Y, Kuraishi Y, et al. Milnacipran inhibits itch-related responses in mice through the enhancement of noradrenergic transmission in the spinal cord. J Pharmacol Sci. 2013;123:199-202.
[10] Nonogaki K, Nozue K, Kuboki T, et al. Milnacipran, a serotonin and norepinephrine reuptake inhibitor, induces appetite-suppressing effects without inducing hypothalamic stress responses in mice. Am J Physiol Regul Integr Comp Physiol. 2007 May;292(5):R1775-81.