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.

Comparison of Chemotherapy Effects on Mechanical Sensitivity and Food-Maintained Operant Responding in Male and Female Rats

“…induced mechanical hypersensitivity in the present study generally agrees with previous studies in rats and mice using paclitaxel (Polomano et al, 2001;Pascual et al, 2010;Boyette-Davis et al, 2011;Hwang et al, 2012;Ko et al, 2014;Toma et al, 2017;, vincristine (Ji et al, 2013;Linglu et al, 2014;Amoateng et al, 2015), oxaliplatin Liu et al, 2013;Fujita et al, 2015), and bortezomib (Chiorazzi et al, 2013;Janes et al, 2013;Yamamoto et al, 2015). However, direct comparison of chemotherapy effects has been complicated by use of different doses and dosing regimens across studies.…”

“…These findings with chemotherapy-induced neuropathy also agree with the failure of a surgical neuropathy manipulation (spinal nerve ligation) to decrease operant responding maintained either by food or by electrical brain stimulation (Ewan and Martin, 2011;Ewan and Martin, 2014;Okun et al, 2016). Moreover, in agreement with the present failure of any chemotherapy to decrease sucrose preference, paclitaxel treatment sufficient to produce mechanical hypersensitivity also failed to produce a sustained reduction of sucrose preference in mice, and paclitaxel also failed to depress nesting behavior in mice (Toma et al, 2017).…”

Gut microbiota‐immune‐brain interactions in chemotherapy‐associated behavioral comorbidities

“…Mice that receive treatment with chemotherapeutic agents (eg, taxanes, antimetabolites, alkylating agents) mirror behaviors hypothesized to be homologous to the anxiety, depression, 15,16 and cognitive impairments observed in patients with cancer. 17,18 Most rodent studies report increases in these negative behaviors, although the duration and magnitude of behavioral changes vary.…”

Long-lasting Analgesia via Targetedin vivoEpigenetic Repression of Nav1.7

“…tactile allodynia) and cold. Paclitaxel is a commonly used chemotherapeutic that increases the expression of Na V 1.7 in the nociceptive afferents 63,64 and induces a robust allodynia in the animal models [65][66][67] . Finally, ATP (adenosine triphosphate) by an action on a variety of purine receptors expressed on afferent terminals and second order neurons and non neuronal cells has been broadly implicated in inflammatory, visceral and neuropathic pain states [57][58][59][60] .…”