Abstract
Chemotherapy-induced peripheral neuropathy (CIPN) is a common dose-limiting side-effect of all major chemotherapeutic agents. Here, we explored efficacy of voluntary exercise as a nonpharmacological strategy for suppressing two distinct adverse side effects of chemotherapy treatment. We evaluated whether voluntary running would suppress both neuropathic pain and deficits in hippocampal cell proliferation in a mouse model of CIPN induced by the taxane chemotherapeutic agent paclitaxel. Mice were given free access to running wheels or were housed without running wheels during one of three different intervention phases: 1) during the onset (i.e. development phase) of paclitaxel-induced neuropathy, 2) prior to dosing with paclitaxel or its vehicle, or 3) following the establishment (i.e. maintenance phase) of paclitaxel-induced neuropathy. Paclitaxel treatment did not alter running wheel behavior relative to vehicle-treated animals in any study. Animals that engaged in voluntary running during the development phase of paclitaxel-induced neuropathy failed to display mechanical or cold hypersensitivities relative to sedentary control animals that did not have access to running wheels. A prior history of voluntary running delayed the onset of, but did not fully prevent, development of paclitaxel-induced neuropathic pain behavior. Voluntary running reduced already established mechanical and cold allodynia induced by paclitaxel. Importantly, voluntary running did not alter mechanical or cold responsivity in vehicle-treated animals, suggesting that the observed antinociceptive effect of exercise was dependent upon the presence of the pathological pain state. In the same animals evaluated for nociceptive responding, paclitaxel also reduced cellular proliferation but not cellular survival in the dentate gyrus of the hippocampus, as measured by immunohistochemistry for Ki67 and BrdU expression, respectively. Voluntary running abrogated paclitaxel-induced reductions in cellular proliferation to levels observed in vehicle-treated mice and also increased BrdU expression levels irrespective of chemotherapy treatment. Our studies support the hypothesis that voluntary exercise may be beneficial in suppressing both neuropathic pain and markers of hippocampal cellular function that are impacted by toxic challenge with chemotherapeutic agents.
Highlights
Exercise has emerged as a potentially safe and cost-effective treatment for different types of chronic pain disorders (Chimenti et al, 2018; Lima et al, 2017)
Running wheel activity initiated during the development phase of neuropathy (Fig. 1A) did not differ between paclitaxel- and vehicletreated groups, and wheel running increased over time irrespective of chemotherapy status (Fig. 1B)
Voluntary running during the development phase of neuropathy increased mechanical paw withdrawal thresholds in paclitaxel-treated mice, mechanical thresholds changed over time and the interaction between chemotherapy status and time was significant (Fig. 1C)
Summary
Exercise has emerged as a potentially safe and cost-effective treatment for different types of chronic pain disorders (Chimenti et al, 2018; Lima et al, 2017). Recent preclinical reports suggest that exposure to treadmill or swimming exercises decreases pain responsivity in inflammatory (Terman et al, 1986; Carmody and Cooper, 1987; Kuphal et al, 2007; King-Himmelreich et al, 2017; Zheng et al, 2017), chronic muscle (Bement and Sluka, 2005) and neuropathic pain models (Stagg et al, 2011; Bobinski et al, 2015; Kim et al, 2015; Korb et al., 2010; Martins et al, 2017; Kami et al, 2016) These types of exercises allow for control over the ‘amount’ of exercise but can introduce stress, which may alter endogenous analgesic tone, and potentially impact interpretation of results (Contarteze et al, 2008; Butler and Finn, 2009). We compared three different exercise interventions, where paclitaxel or vehicle-treated mice were given access to running wheels (or no wheels) during one of three distinct temporal intervention phases either: 1) concurrent with the initiation of paclitaxel treatment; 2) under conditions in which voluntary running was initiated and terminated prior to the initiation of paclitaxel dosing; or 3) after the establishment of paclitaxel-induced neuropathic nociception
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