Blocking of cytokines signalling attenuates evoked and spontaneous neuropathic pain behaviours in the paclitaxel rat model of chemotherapy‐induced neuropathy

摘要

Abstract Background Chemotherapy‐induced peripheral neuropathic pain ( CIPNP ) is a serious dose‐limiting neurotoxic effect of cancer drug treatment. The underlying mechanism(s) of this debilitating condition, which lacks effective drug treatment, is incompletely understood. However, neural–immune interactions, involving increased expression and release of cytokines, are believed to be involved. Here, we examined, in the paclitaxel rat model of CIPNP , whether plasma levels of 24 cytokines/chemokines change after paclitaxel treatment, and whether blocking of signalling of some of those cytokines would reverse/attenuate behavioural signs of CIPNP . Methods To achieve these objectives luminex, pharmacological and behavioural experiments were performed on male Wistar rats (250–300?g) 31?days after the last injection of paclitaxel (1?mg/kg, i.p. on four alternate days) as well as on control (vehicle‐treated) rats. Results Compared with control rats, plasma levels of IL ‐1α, IL ‐1β, IL ‐6, TNF ‐α, INF ‐γ and MCP ‐1 were significantly upregulated in paclitaxel‐treated rats. Blocking of TNF ‐α signalling with etanercept (2?mg/kg, i.p.) or IL ‐1β with IL ‐1 receptor antagonist ( IL ‐1ra; 3?mg/kg, i.p.), significantly attenuated established mechanical and cold hypersensitivity as well as spontaneous pain behaviour (spontaneous foot lifting) 24 and 48?h postdrug treatment. Pharmacological blockade of MCP ‐1/ CCL 2 signalling with a highly selective CCR 2 receptor antagonist (S504393, 5?mg/kg, i.p.) also significantly reduced evoked, but not spontaneous, pain behaviours of CIPNP in paclitaxel‐treated rats at the same time points. Conclusions The findings support the notion that cytokines/chemokines, particularly TNF ‐α, IL ‐1 and MCP ‐1, are involved in the pathophysiology of CIPNP and suggest that strategies that target their inhibition may be effective in treating CIPNP . Significance This study demonstrates that paclitaxel‐treated rats exhibit, in addition to indices of mechanical and cold hypersensitivity, a behavioural sign of spontaneous pain, the principal compliant of patients with neuropathic pain. This was accompanied by upregulation in plasma levels of key cytokines/chemokines ( IL ‐1α, IL ‐1β, IL ‐6, TNF ‐α, INF ‐γ and MCP ‐1) 31?days post‐treatment. However, it is noteworthy that cytokine release, rather than nerve injury per se, may be causative of NP in this model of CIPNP . Nevertheless, our findings that pharmacological blockade of TNF ‐α, IL ‐1β and MCP ‐1 attenuated both evoked and spontaneous pain suggest that strategies that target inhibition of these cytokines may be effective in treating CIPNP .