Brain activity changes in a macaque model of oxaliplatin-induced neuropathic cold hypersensitivity

Kazuaki Nagasaka,Shinya Ogawa,Noriyuki Higo,Kazunori Yamanaka,Hiroyuki Takamatsu

doi:10.1038/s41598-017-04677-7

Abstract

The antineoplastic agent oxaliplatin induces a painful peripheral neuropathy characterized by an acute cold hypersensitivity. There is a lack of effective treatments to manage oxaliplatin-induced cold hypersensitivity which is due, in part, to a lack of understanding of the pathophysiology of oxaliplatin-induced cold hypersensitivity. Thus, brain activity in oxaliplatin-treated macaques was examined using functional magnetic resonance imaging (fMRI). Oxaliplatin treatment reduced tail withdrawal latency to a cold (10 °C) stimulus, indicating cold hypersensitivity and increased activation in the secondary somatosensory cortex (SII) and the anterior insular cortex (Ins) was observed. By contrast, no activation was observed in these areas following cold stimulation in untreated macaques. Systemic treatment with an antinociceptive dose of the serotonergic-noradrenergic reuptake inhibitor duloxetine decreased SII and Ins activity. Pharmacological inactivation of SII and Ins activity by microinjection of the GABAA receptor agonist muscimol increased tail withdrawal latency. The current findings indicate that SII/Ins activity is a potential mediator of oxaliplatin-induced cold hypersensitivity.

Highlights

Chemotherapy-induced peripheral neuropathy (CIPN) is a common adverse side effect in patients receiving anticancer drugs, and greatly diminishes quality of life[1, 2]
Cold hypersensitivity was observed after each infusion of oxaliplatin in the macaques used in the present study (Fig. 1a), as was observed in a previous study[7]
To identify regional brain activity in macaques with oxaliplatin-induced peripheral neuropathy characterized by cold hypersensitivity, functional magnetic resonance imaging (fMRI) scans were performed (Fig. 1b)

Summary

Introduction

Chemotherapy-induced peripheral neuropathy (CIPN) is a common adverse side effect in patients receiving anticancer drugs, and greatly diminishes quality of life[1, 2]. A number of drugs, including pregabalin, extensively used in the management of various neuropathic pains, have demonstrated significant antinociceptive efficacy in rodent models of oxaliplatin-induced peripheral neuropathy[7]. In an attempt to improve translation of preclinical findings to clinically useful treatments, a preclinical model of oxaliplatin-induced peripheral neuropathy was recently developed in macaques, which exhibited a robust, dose-dependent, early-onset and short-lasting cold hypersensitivity[7], paralleling clinical findings[1, 8]. The primary objective of the current study is to identify regional brain activity in macaques with oxaliplatin-induced peripheral neuropathy using functional magnetic resonance imaging (fMRI). The macaque has an advantage over other experimental animal species in that brain areas involved in pain processing are similar to that of humans[13,14,15,16,17]. The present study investigated modulation of brain activity in oxaliplatin-treated macaques by systemic administration of an antinociceptive dose of duloxetine and by microinjection of the GABAA receptor agonist muscimol in order to confirm a potential association between brain activity and behavior

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Conclusion