In Vivo Models and Assessment of Pharmacotherapeutics for Chemotherapy-Induced Neuropathic Pain

Many chemotherapeutic agents produce significant neuropathies that can lead to cessation of treatment, even in the absence of alternate therapy. Symptoms are typically peripheral and sensory, consisting of mechanical, heat, and cold sensitivities with ongoing burning pain, tingling, and numbness in a glove and stocking distribution. In the worst cases damage can be permanent. There are no Food and Drug Administration (FDA)-approved drugs for the treatment of such neuropathies (chemotherapy-induced peripheral neuropathies [CIPNs]), and mechanisms by which chemotherapeutics induce CIPN remain under investigation. For example, they can affect cellular microtubules and alter axonal transport, disrupt mitochondrial function, or impair DNA synthesis, all of which lead to damage to peripheral nerves. This distal peripheral nerve injury leads to sensitization and spontaneous activity of these fibers. Such nerve injury also leads to hyperexcitability in the dorsal column of the spinal cord and induces infiltration of activated microglia and proinflammatory cytokines, leading to ascending pain pathway sensitization and related changes in substance P and glutamate release. There are also functional changes to the descending inhibitory pain pathway, such as a loss of GABA-releasing neurons and alterations in serotonin and norepinephine signaling, further amplifying the effects of central sensitization. On the basis of these mechanisms, potential therapeutic targets for treatment of CIPN include sodium and calcium channels, GABA receptors, serotonin and norepinephine receptors, N-methyl-aspartic acid (NMDA) receptors, cannabinoid receptors, and agents that suppress cytokine release and activation of microglia, among others. In vivo models of chemotherapy-induced neuropathy are currently being used to continue the study into the mechanisms of neurotoxicity and to evaluate the efficacy of putative pharmacotherapies to reverse or prevent CIPN.