Effects of paclitaxel on the development of neuropathy and affective behaviors in the mouse

Abstract

Paclitaxel, one of the most commonly used cancer chemotherapeutic drugs, effectively extends the progression-free survival of breast, lung, and ovarian cancer patients. However, paclitaxel and other chemotherapy drugs elicit peripheral nerve fiber dysfunction or degeneration that leads to peripheral neuropathy in a large proportion of cancer patients. Patients receiving chemotherapy also often experience changes in mood, including anxiety and depression. These somatic and affective disorders represent major dose-limiting side effects of chemotherapy. Consequently, the present study was designed to develop a preclinical model of paclitaxel-induced negative affective symptoms in order to identify treatment strategies and their underlying mechanisms of action. Intraperitoneal injections of paclitaxel (8 mg/kg) resulted in the development and maintenance of mechanical and cold allodynia. Carboplatin, another cancer chemotherapeutic drug that is often used in combination with paclitaxel, sensitized mice to the nociceptive effects of paclitaxel. Paclitaxel also induced anxiety-like behavior, as assessed in the novelty suppressed feeding and light/dark box tests. In addition, paclitaxel-treated mice displayed depression-like behavior during the forced swim test and an anhedonia-like state in the sucrose preference test. In summary, paclitaxel produced altered behaviors in assays modeling affective states in C57BL/6J male mice, while increases in nociceptive responses were longer in duration. The characterization of this preclinical model of chemotherapy-induced allodynia and affective symptoms, possibly related to neuropathic pain, provides the basis for determining the mechanism(s) underlying severe side effects elicited by paclitaxel, as well as for predicting the efficacy of potential therapeutic interventions.