Abstract
The antitumor drug, oxaliplatin, induces neuropathic pain, which is resistant to available analgesics, and novel mechanism-based therapies are being evaluated for this debilitating condition. Since activated microglia, impaired serotonergic and noradrenergic neurotransmission and overexpressed sodium channels are implicated in oxaliplatin-induced pain, this in vivo study assessed the effect of minocycline, a microglial activation inhibitor used alone or in combination with ambroxol, a sodium channel blocker, or duloxetine, a serotonin and noradrenaline reuptake inhibitor, on oxaliplatin-induced tactile allodynia and cold hyperalgesia. To induce neuropathic pain, a single dose (10 mg/kg) of intraperitoneal oxaliplatin was used. The mechanical and cold pain thresholds were assessed using mouse von Frey and cold plate tests, respectively. On the day of oxaliplatin administration, only duloxetine (30 mg/kg) and minocycline (100 mg/kg) used alone attenuated both tactile allodynia and cold hyperalgesia 1 h and 6 h after administration. Minocycline (50 mg/kg), duloxetine (10 mg/kg) and combined minocycline + duloxetine influenced only tactile allodynia. Seven days after oxaliplatin, tactile allodynia (but not cold hyperalgesia) was attenuated by minocycline (100 mg/kg), duloxetine (30 mg/kg) and combined minocycline and duloxetine. These results indicate a potential usefulness of minocycline used alone or combination with duloxetine in the treatment of oxaliplatin-induced pain.
Highlights
Chemotherapy-induced peripheral neuropathy (CIPN) is a major dose-limiting adverse effect of several chemotherapeutic agents, such as vincristine, taxanes, platinum derivatives, or bortezomib
1–12 h after administration (Figure 7C,D); the 30 mg/kg dose, similar to the effect observed in the von Frey test, increased the cold pain threshold during the early phase of the observation, 1 h after intraperitoneal injection (Figure 7C). Considering this finding, we propose combination drug therapy based on the sequential use of duloxetine, a drug with a rapid onset of action, and minocycline, a drug with 12 h antiallodynic and antihyperalgesic activities, as an approach to relieve tactile allodynia and cold hyperalgesia that occur in the course of oxaliplatin-induced neuropathic pain
Since many causal mechanisms of CIPN occur simultaneously and can reinforce each other [1], we conclude that both minocycline in monotherapy as well as combination drug therapy based on minocycline and duloxetine may attenuate the symptoms of CIPN
Summary
Chemotherapy-induced peripheral neuropathy (CIPN) is a major dose-limiting adverse effect of several chemotherapeutic agents, such as vincristine, taxanes, platinum derivatives (cisplatin, oxaliplatin), or bortezomib. Effective preventative and treatment options for CIPN and its main symptom, i.e., neuropathic pain, are limited. This clinical entity is often resistant to available analgesics, and is regarded as a challenging and complex chronic disease with a major and prolonged impact on patients’ quality of life [1]. CIPN induced by this drug is one of the most frequent and dose-limiting adverse effects. It is characterized by acute, transient neuropathy that occurs in almost 90%
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