Antiallodynic and Antihyperalgesic Effect of Milnacipran in Mice with Spinal Nerve Ligation

Suzuki, Takahiro; Ueta, Kazuyoshi; Tamagaki, Shinji; Mashimo, Takashi

doi:10.1213/ane.0b013e318167889a

Cited by 33 publications

(27 citation statements)

References 51 publications

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“…However, the antiallodynic and antihyperalgesic effects of milnacipran in neuropathic pain models were predominantly attenuated by the noradrenergic system rather than by the serotonergic system at the spinal level (9,28). Moreover, modulation of the noradrenergic system is likely to be more effective than that of the serotonergic system for the control of pain (9,22,28,30). We confirmed that when administered concurrently with paclitaxel or after cessation of paclitaxel treatment, repeated milnacipran significantly attenuated paclitaxel-induced mechanical allodynia.…”

Section: Discussionsupporting

confidence: 63%

“…Milnacipran and fluvoxamine are used for the treatment of acute and neuropathic pain as a supplementary analgesic (16,21). There have been several reports indicating that milnacipran and fluvoxamine have significant antinociceptive effects against nociceptive and inflammatory pain (20,22,27,28,30). Furthermore, milnacipran was more effective than SSRIs such as fluvoxamine, paroxetine, and citalopram in attenuating persistent pain (30) and neuropathic pain (9), and more effective than amitriptyline (TCAs) in attenuating cold allodynia (4°C cold plate stimuli) (1).…”

Section: Discussionmentioning

confidence: 99%

“…Obata et al reported the involvement of both NA and 5-HT in the antiallodynic effect of milnacipran in a rat neuropathic pain model (20). However, the antiallodynic and antihyperalgesic effects of milnacipran in neuropathic pain models were predominantly attenuated by the noradrenergic system rather than by the serotonergic system at the spinal level (9,28). Moreover, modulation of the noradrenergic system is likely to be more effective than that of the serotonergic system for the control of pain (9,22,28,30).…”

Section: Discussionmentioning

confidence: 99%

“…One typical SNRI, milnacipran, has been shown to be efficacious for the prevention and/or reversal of pain in several preclinical models of acute and chronic pain in rodents. Yokogawa et al demonstrated that milnacipran significantly attenuated late phase paw licking behavior in the formalin test (30) and also reversed mechanical allodynia in the chronic constriction injury model or spinal nerve ligation model of neuropathic pain (9,28). In addition, milnacipran had an antiallodynic effect on the streptozotocin-induced diabetic neuropathy model (9) and potentiated the antihyperalgesic effect of tramadol (opioid analgesic) (21).…”

Section: Time Course and Dose-response Of Paclitaxel-induced Mechanicmentioning

confidence: 99%

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Effects of repeated milnacipran and fluvoxamine treatment on mechanical allodynia in a mouse paclitaxel-induced neuropathic pain model

et al. 2013

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Paclitaxel is widely used in cancer chemotherapy for the treatment of solid tumors, but it frequently causes peripheral neuropathy. Milnacipran, a serotonin/noradrenaline reuptake inhibitor and fluvoxamine, a selective serotonin reuptake inhibitor, have shown efficacy against several chronic pain syndromes. In this study, we investigated the attenuation of paclitaxel-induced mechanical allodynia in mice by milnacipran and fluvoxamine. Paclitaxel was administered once per day (2 mg/kg, intraperitoneally (i.p.)) for 5 days to mice. Mechanical allodynia was evaluated by measuring the withdrawal response to stimulation with a von Frey filament. In paclitaxel-treated mice, mechanical allodynia was observed on days 3-15 of paclitaxel administration. A single administration of milnacipran (20 mg/kg, i.p.) or fluvoxamine (40 mg/kg, i.p.) had no effect on paclitaxel-induced mechanical allodynia. However, repeated administration of milnacipran (10, 20 mg/kg, once per day, i.p.) for 5 days significantly reduced paclitaxel-induced mechanical allodynia. In contrast, repeated fluvoxamine administration (40 mg/kg, once per day, i.p.) for 5 days resulted in a weak attenuation of paclitaxel-induced mechanical allodynia. These results suggest that chronic paclitaxel administration induces mechanical allodynia, and that repeated milnacipran administration may be an effective therapeutic approach for the treatment of neuropathic pain caused by paclitaxel treatment for cancer.Peripheral neurotoxicity induced by antineoplastic drugs (taxanes, vinca-alkaloids and platin-based compounds) is a clinically significant complication that can be dose-limiting and can substantially diminish quality of life. Paclitaxel is commonly used for the treatment of solid tumors and ovarian and breast cancers. Paclitaxel induces antimitotic actions by impeding the cell cycle in the late phases of mitosis, stabilizing microtubule formation, and ultimately inducing apoptosis (26). However, paclitaxelinduced peripheral neuropathy is a side-effect of chemotherapeutic treatment which often manifests as bilateral pain in the extremities in a stocking and glove-type distribution (6), sometimes greatly impairing the patients' quality of life and their ability to perform normal activities of daily living. To date, therapeutic drugs have been evaluated using various animal models of paclitaxel-induced allodynia. Ethosuximide (7), gabapentin (14), thalidomide and minocycline (3), neurotropin (11) and acetyl-L-carnitine (8) have been examined against the paclitaxelinduced neuropathic pain model, although studies regarding their efficacy have not been conclusive. Supplementary analgesics (antidepressants and anticonvulsants) have suppressive effects on opioid-resistant neuropathic pain (16,24), and antidepressants are widely used for the treatment of neuropathic pain. Antidepressants, especially tricyclic antidepressants (TCAs), are regarded as first-line drugs for the treatment of neuropathic pain (16). Recently, more selective monoamine reuptake inhibitors...

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Section: Discussionsupporting

confidence: 63%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Time Course and Dose-response Of Paclitaxel-induced Mechanicmentioning

confidence: 99%

See 2 more Smart Citations

Effects of repeated milnacipran and fluvoxamine treatment on mechanical allodynia in a mouse paclitaxel-induced neuropathic pain model

et al. 2013

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“…The effective dose at which intrathecal injection of milnacipran produces antiallodynic and antihyperalgesic effect is > 7 mg/site (11). Lower intrathecal doses of milnacipran (0.21 -2.1 mg/site) do not produce any effects (11).…”

Section: Short Communicationmentioning

confidence: 99%

Milnacipran Inhibits Itch-Related Responses in Mice Through the Enhancement of Noradrenergic Transmission in the Spinal Cord

2013

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Abstract. We investigated whether milnacipran, a serotonin-noradrenaline reuptake inhibitor, exhibits an antipruritic effect through the spinal action in mice. Intrathecal injections of milnacipran (0.1 -10 mg/site) significantly suppressed serotonininduced biting, which is an itchrelated response. However, such an effect was not observed with fluvoxamine (10 mg/site), which is a selective serotonin reuptake inhibitor. Furthermore, an intraperitoneal injection of milnacipran (10 mg/kg) inhibited serotonininduced biting. When phentolamine (1.0 mg/site), a nonselective aadrenoceptor antagonist, was intrathecally injected, it inhibited the above response of milnacipran. These results suggest that milnacipran suppresses itching through the inhibition of noradrenaline reuptake in the spinal cord.

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Pharmacological characterization of lysophosphatidic acid‐induced pain with clinically relevant neuropathic pain drugs

Ogawa

Takasu

Shinohara

et al. 2011

European Journal of Pain

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Lysophosphatidic acid (LPA), an initiator of neuropathic pain, causes allodynia. However, few studies have evaluated the pharmacological profile of LPA-induced pain. In this study, a LPA-induced pain model was developed and pharmacologically characterized with clinically relevant drugs used for neuropathic pain, including antiepileptics, non-steroidal anti-inflammatory agents, analgesics, local anaesthetics/antiarrhythmics and antidepressants. Gabapentin (1-30 mg/kg, p.o.) significantly reversed LPA-induced allodynia, but neither indomethacin (30 mg/kg, p.o.) nor morphine (0.3-3 mg/kg, s.c.) did, which indicates that LPA-induced pain consists mostly of neuropathic rather than inflammatory pain. Both pregabalin (0.3-10 mg/kg, p.o.) and ω-CgTX MVIIA (0.01-0.03 μg/mouse, i.t.) completely reversed LPA-induced allodynia in a dose-dependent manner. Lidocaine (1-30 mg/kg, s.c.), mexiletine (1-30 mg/kg, p.o.) and carbamazepine (10-100 mg/kg, p.o.) significantly ameliorated LPA-induced allodynia dose dependently. Milnacipran (30 mg/kg, i.p.) produced no significant analgesic effect in LPA-induced allodynia. In LPA-injected mice, expression of the α2δ1 subunit of the voltage-gated calcium channel (VGCC) was increased in the dorsal root ganglion (DRG) and spinal dorsal horn. Furthermore, the VGCC current was potentiated in both the DRG from LPA-injected mice and LPA (1 μM)-treated DRG from saline-injected mice, and the potentiated VGCC current was amended by treatment with gabapentin (100 μM). The LPA-induced pain model described here mimics aspects of the neuropathic pain state, including the sensitization of VGCC, and may be useful for the early assessment of drug candidates to treat neuropathic pain.

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Antiallodynic and Antihyperalgesic Effect of Milnacipran in Mice with Spinal Nerve Ligation

Abstract: We concluded that the antiallodynic and antihyperalgesic effects of milnacipran on neuropathic pain induced by spinal nerve ligation are principally mediated through action at supraspinal and spinal sites via activation of the spinal noradrenergic system.

Cited by 33 publications

References 51 publications

Effects of repeated milnacipran and fluvoxamine treatment on mechanical allodynia in a mouse paclitaxel-induced neuropathic pain model

Effects of repeated milnacipran and fluvoxamine treatment on mechanical allodynia in a mouse paclitaxel-induced neuropathic pain model

Milnacipran Inhibits Itch-Related Responses in Mice Through the Enhancement of Noradrenergic Transmission in the Spinal Cord

Pharmacological characterization of lysophosphatidic acid‐induced pain with clinically relevant neuropathic pain drugs

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