Pharmacology/Drug Development

Oxaliplatin is a commonly used drug to treat cancer, extending the rate of disease-free survival by 20% in colorectal cancer. However, oxaliplatin induces a disabling form of neuropathy resulting in more than 60% of patients having to reduce or discontinue oxaliplatin, negatively impacting their chance of survival. Oxaliplatin-induced neuropathies are accompanied by degeneration of sensory fibers in the epidermis and hyperexcitability of sensory neurons. These morphological and functional changes have been associated with sensory symptoms such as dysesthesia, paresthesia and mechanical and cold allodynia. Various strategies have been proposed to prevent or treat oxaliplatin-induced neuropathies without success. The anti-diabetic drug metformin has been recently shown to exert neuroprotection in other chemotherapy-induced neuropathies, so here we aimed to test if metformin can prevent the development of oxaliplatin-induced neuropathy in a rat model of this condition. Animals treated with oxaliplatin developed significant intraepidermal fiber degeneration, a mild gliosis in the spinal cord, and mechanical and cold hyperalgesia. The concomitant use of metformin prevented degeneration of intraepidermal fibers, gliosis, and the altered sensitivity. Our evidence further supports metformin as a new approach to prevent oxaliplatin-induced neuropathy with a potential important clinical impact.

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.

The classification of chronic visceral pain is complex, resulting from persistent inflammation, vascular (ischemic) mechanisms, cancer, obstruction or distension, traction or compression, and combined mechanisms, as well as unexplained functional mechanisms. Despite the prevalence, treatment options for chronic visceral pain are limited. Given this unmet clinical need, the development of novel analgesic agents, with defined targets derived from preclinical studies, is urgently needed. While various animal models have played an important role in our understanding of visceral pain, our knowledge is far from complete. Due to the complexity of visceral pain, this document will focus on chronic abdominal pain, which is the major complaint in patients with disorders of the gut-brain interaction, also referred to as functional gastrointestinal disorders, such as irritable bowel syndrome (IBS). Models for IBS are faced with challenges including a complex clinical phenotype, which is comorbid with other conditions including anxiety, depression, painful bladder syndrome, and chronic pelvic pain. Based upon the multifactorial nature of IBS with complicated interactions between biological, psychological, and sociological variables, no single experimental model recapitulates all the symptoms of IBS. This position paper will contextualize chronic visceral pain using the example of IBS and focus on its pathophysiology while providing a critical review of current animal models that are most relevant, robust, and reliable in which to screen promising therapeutics to alleviate visceral pain and delineate the gaps and challenges with these models. We will also highlight, prioritize, and come to a consensus on the models with the highest face/construct validity.