Pharmacological Characterization of Standard Analgesics on Oxaliplatin-Induced Acute Cold Hypersensitivity in Mice

Abstract

Some chemotherapeutic agents including platinum compounds, taxanes, vinca alkaloids, and bortezomib, cause peripheral neuropathy. However, unlike other chemotherapeutic agents, oxaliplatin, a platinum-based chemotherapeutic agent, induces a peculiar acute peripheral neuropathy, such as paresthesia and dysesthesia, which are often triggered or enhanced by exposure to cold, whereas cumulative and chronic neuropathy induced by oxaliplatin includes pain sensation (1). The acute peripheral neuropathy is induced in almost all patients during or within hours after the infusion. However, an effective pharmacological strategy for its management remains controversial (1, 2).Many studies in animal models focus on the oxaliplatininduced chronic and/or subacute painful peripheral neuro pathy that appear several days to several weeks after oxaliplatin administration (3 -5), while oxaliplatininduced acute peripheral neuropathy is poorly characterized. Recently, we have reported a mouse model of rapid-onset cold hypersensitivity induced by oxaliplatin (6). When mice are given a single administration of oxaliplatin, cold but not mechanical hypersensitivity is induced within 2 h after the administration, while it is not induced by other chemotherapeutic agents such as cisplatin and paclitaxel. These findings suggest that rapid-onset cold hypersensitivity is representative of the acute peripheral neuropathy characteristic to oxaliplatin in mice. In the present study, we assessed the effects of standard analgesics, such as non-steroidal anti-inflammatory agent (NSAID), opioid analgesics, tricyclic antidepressant, serotonin and noradrenaline reuptake inhibitor (SNRI), calcium channel a 2 -d ligand, local anesthetic, and calcium gluconate (1, 2), on the oxaliplatin-induced acute cold hypersensitivity in mice. 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan Received November 26, 2013; Accepted February 17, 2014 Abstract. Oxaliplatin, a platinum-based chemotherapeutic agent, causes an acute peripheral neuropathy triggered by cold in almost all patients during or within hours after its infusion. We recently reported that a single administration of oxaliplatin induced cold hypersensitivity 2 h after the administration in mice. In this study, we examined whether standard analgesics relieve the oxaliplatin-induced acute cold hypersensitivity. Gabapentin, tramadol, mexiletine, and calcium gluconate significantly inhibited and morphine and milnacipran decreased the acute cold hypersensitivity, while diclofenac and amitriptyline had no effects. These results suggest that gabapentin, tramadol, mexiletine, and calcium gluconate are effective against oxaliplatin-induced acute peripheral neuropathy. Pharmacological Characterization of Standard Analgesics on OxaliplatinInduced Acute Cold Hypersensitivity in Mice

Pharmacological comparison of a nonhuman primate and a rat model of oxaliplatin‐induced neuropathic cold hypersensitivity

“…2014; Zhao et al. 2014). Age, oxaliplatin dose, and behavioral test could be key considerations (further elaboration of these factors is explained in Table S1).…”

“…2014; Zhao et al. 2014). These previous findings, combined with the current findings in the macaque, support our contention that there is a potential difference in the efficacy of therapeutics based on species.…”

Effects of Adjuvant Analgesics on Cerebral Ischemia-Induced Mechanical Allodynia

“…Animals All experimental procedures were approved by the ethics committee for animals at Kobe Gakuin University (approval number: [14][15][16][17][18][19][20][21]. The experiments were performed on male ddY mice (5 weeks old, 25-30 g) obtained from SLC (Shizuoka, Japan).…”

“…The doses of all drugs were selected based on the results of previous reports. 14,15) Assessment of Mechanical Allodynia Mechanical allodynia was evaluated using von Frey filaments (Neuroscience Inc., Tokyo, Japan) as previously described. 8) Mice were placed on a 5×5 mm wire mesh grid floor, covered with an opaque cup to avoid visual stimulation, and allowed to adapt for 2-3 h prior to testing.…”

“…The SNRI milnacipran inhibited neuropathic pain by blocking noradrenaline and serotonin reuptake. 14,33) Sciatic nerve ligation in mice induces pain behavior and is used as a model of neuropathic pain. The pain behavior in these mice was not affected by a single injection of milnacipran s.c. but was significantly suppressed by repeated milnacipran injections.…”