Milnacipran Inhibits Oxaliplatin-Induced Mechanical Allodynia through Spinal Action in Mice

Abstract

We investigated whether milnacipran, a serotonin-noradrenaline reuptake inhibitor, would have therapeutic effect on oxaliplatin-induced mechanical allodynia in mice. A single intraperitoneal injection of oxaliplatin (3 mg/kg) induced mechanical allodynia, which peaked on day 10 after injection and almost completely subsided by day 20. Ten days post-oxaliplatin injection, the intraperitoneal administration of milnacipran (3-30 mg/kg) significantly and dose-dependently inhibited the established mechanical allodynia. Intrathecal injections of milnacipran (2.1-21 µg/site) also significantly and dose-dependently inhibited mechanical allodynia, but intracisternal and intracereboventricular injections at the same doses did not. The present results suggest that milnacipran is effective against oxaliplatin-induced mechanical allodynia and that the antiallodynic effect is mainly mediated by actions on the spinal cord.Key words milnacipran; oxaliplatin; allodynia; intrathecal injection; spinal cord Oxaliplatin, a third-generation platinum-based chemotherapeutic agent, is a key drug for the treatment of colorectal cancer. However, oxaliplatin frequently causes dose-limiting adverse effects such as acute neurotoxicity and chronic peripheral neuropathy.1) The distressing symptoms of peripheral neuropathy include pain and dysesthesia.2) Although the underlying mechanisms of oxaliplatin-induced peripheral neuropathy are not completely understood, it has been reported that oxalate, a metabolite of oxaliplatin, is involved in acute peripheral neurotoxicity, especially cold dysesthesia.3,4) Several drugs, including calcium gluconate/magnesium sulfate, glutathione, carbamazepine, gabapentin, amifostine, acetyl-Lcarnitine, and α-lipoic acid, have been used to manage oxaliplatin-induced peripheral neuropathy. 4,5) Although these drugs are effective against mild neuropathy, oxaliplatin-induced peripheral neuropathy is still difficult to treat. 4,5)We have recently found that goshajinkigan, a traditional herbal medicine, suppresses oxaliplatin-induced mechanical allodynia and that this effect is, in part, mediated by both descending noradrenergic and serotonergic systems. 6)These findings imply that enhancement of descending monoaminergic systems can inhibit established mechanical allodynia. Although amitriptyline, which inhibits the reuptake of noradrenaline and serotonin, 7) has long been used for the treatment of neuropathic symptoms, especially in postherpetic neuralgia and diabetic neuropathy, it does not prevent chemotherapy-induced peripheral neuropathy in humans. 8) In contrast, prophylactic administration of venlafaxine, a serotonin-noradrenaline reuptake inhibitor (SNRI) with high potency in inhibiting serotonin reuptake, 7) has been reported to reduce oxaliplatin-induced acute neurotoxicity including spontaneous dysesthesia and daily pain in humans.9) Prophylactic administration of duloxetine, a balanced SNRI, 7) has also been reported to reduce the severity of pain after 12 weeks of treatment. 10) In this study, we examined...

Chemotherapy-induced painful neuropathy

“…Milnacipran is another clinically-available anti-depressant, also used for treatment of fibromyalgia, which could be a promising candidate for the treatment of CIPN. In mice, milnacipran prevented acute oxaliplatin-induced cold allodynia [44], inhibited established oxaliplatin-induced mechanical allodynia [42] and inhibited paclitaxel-induced mechanical allodynia with repeated dosing [110].…”

Preventive Efficacy and Safety of Yiqi-Wenjing-Fang Granules on Oxaliplatin-Induced Peripheral Neuropathy: A Protocol for a Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial

“…Through exploring the mechanism of OIPN, researchers have been trying to find potential prophylactic or therapeutic drugs all the time. Numerous clinical and preclinical studies have reported a series of effective agents for OIPN, such as calcium and magnesium injections [ 5 ], carbamazepine [ 6 ], oxcarbazepine [ 7 ], venlafaxine [ 8 ], gabapentin [ 9 ], pregabalin [ 10 ], glutathione [ 11 ], glutamine [ 12 ], alpha-lipoic acid [ 13 ], amifostine [ 14 ], Vitamin E [ 15 ], monosialoganglioside (GM1) [ 16 ], and novel agents such as niclosamide [ 17 ], fingolimod [ 18 ], N-acetylcysteine [ 19 ], milnacipran [ 20 ], riluzole [ 21 ], and a selective sigma-1 receptor antagonist MR309 [ 22 ]. Nonetheless, most studies either get negative results on further validation or remain at early stages, so that seldom drug has received recognition yet [ 1 , 23 ].…”

Searching for analgesic drug candidates alleviating oxaliplatin‐induced cold hypersensitivity in mice

“…In addition to its clinical utility, oxaliplatin is also used in pharmacological laboratories to induce a rodent model of CIPN‐related neuropathic pain that could be utilized in the search for novel therapies for CIPN prevention (Ohsawa et al., ) and treatment (Andoh, Kitamura, & Kuraishi, ; Deuis et al., ; Jiang et al., ; Kim et al., ; King et al., ; Pańczyk et al., ; K. Sałat et al., , ; Sałat & Sałat, ; Yoon, Lee, Roh, & Oh, ). To assess the effect of oxaliplatin on tactile allodynia, researchers worldwide take advantage of using von Frey filaments as an easy‐to‐use method.…”

“…In addition to its clinical utility, oxaliplatin is also used in pharmacological laboratories to induce a rodent model of CIPN-related neuropathic pain that could be utilized in the search for novel therapies for CIPN prevention (Ohsawa et al, 2014) and treatment (Andoh, Kitamura, & Kuraishi, 2015;Deuis et al, 2014;Jiang et al, 2016;Kim et al, 2016;King et al, 2017;Pańczyk et al, 2018;K. Sałat et al, 2014K.…”