Topical Oxaliplatin Produces Gain- and Loss-of-Function in Multiple Classes of Sensory Afferents

Abstract

The platinum chemotherapeutic oxaliplatin produces dose-limiting pain, dysesthesia, and cold hypersensitivity in most patients immediately after infusion. An improved understanding of the mechanisms underlying these symptoms is urgently required to facilitate the development of symptomatic or preventative therapies. In this study, we have used skin-saphenous nerve recordings in vitro and behavioral experiments in mice to characterize the direct effects of oxaliplatin on different types of sensory afferent fibers. Our results confirmed that mice injected with oxaliplatin rapidly develop mechanical and cold hypersensitivities. We further noted profound changes to A fiber activity after the application of oxaliplatin to the receptive fields in the skin. Most oxaliplatin-treated Aδ- and rapidly adapting Aβ-units lost mechanical sensitivity, but units that retained responsiveness additionally displayed a novel, aberrant cold sensitivity. Slowly adapting Aβ-units did not display mechanical tachyphylaxis, and a subset of these fibers was sensitized to mechanical and cold stimulation after oxaliplatin treatment. C fiber afferents were less affected by acute applications of oxaliplatin, but a subset gained cold sensitivity. Taken together, our findings suggest that direct effects on peripheral A fibers play a dominant role in the development of acute oxaliplatin-induced cold hypersensitivity, numbness, and dysesthesia. PERSPECTIVE: The chemotherapeutic drug oxaliplatin rapidly gives rise to dose-limiting cold pain and dysesthesia. Here, we have used behavioral and electrophysiological studies of mice to characterize the responsible neurons. We show that oxaliplatin directly confers aberrant cold responsiveness to subsets of A-fibers while silencing other fibers of the same type.

Keywords: Pain; chemotherapy-induced neuropathy; ion channels; paresthesia; skin-saphenous nerve.