Paclitaxel-induced neuropathic hypersensitivity in mice: Responses in 10 inbred mouse strains

Abstract

Mechanical allodynia, or hypersensitivity to tactile stimuli, is a frequent clinical symptom of neuropathy. Large interindividual differences have been observed in neuropathic pain, both in susceptibility to its development and in its severity. Identification of genetic factors relevant to this variability would be of obvious utility. Although many animal models of neuropathic pain following peripheral nerve injury have been developed, most involve intricate surgeries and are thus poorly suited for large-scale linkage mapping investigations in the mouse. Recently, a schedule of intraperitoneal injections of the chemotherapeutic agent, paclitaxel (Taxol®), has been shown to produce a long-lasting, bilateral neuropathy in the rat, featuring hypersensitivity to mechanical, thermal and cold stimuli. We present here a survey of the responses of 10 inbred mouse strains to paclitaxel injections. Virtually all strains developed statistically significant mechanical allodynia, with one strain, DBA/2J, exhibiting especially robust changes. Strain sensitivities to paclitaxel-induced mechanical allodynia were similar to those obtained previously using a surgical model of neuropathic pain, supporting our contention that genetic sensitivity to mechanical allodynia is independent of the precise mode of induction. Using sensitive DBA/2 mice and a resistant strain, C57BL/6J, for comparison, we further characterized the paclitaxel model in mice by examining cold allodynia and thermal hyperalgesia. Both strains displayed equivalent cold allodynia but neither strain developed thermal hyperalgesia. The present data confirm a genetic component in mechanical allodynia using this model, while dissociating mechanical hypersensitivity from other pain modalities.

Introduction

Chronic neuropathic pain, arising from nerve trauma, injury, or infection, is a troublesome clinical problem. Hypersensitivity to mechanical and thermal (hot and cold) stimuli are frequent symptoms of neuropathy, but the mechanisms underlying these plastic changes remain poorly understood. Entirely lacking, for example, is an explanation of why only a small subset of individuals receiving the insult go on to develop neuropathic pain. It is certainly likely that particularities of the injury or infection influence the varying outcomes, but it is also likely that susceptibility to neuropathic pain development and/or severity may be at least partially inherited. Several animal models have been developed to study the changes in the nervous system that accompany these conditions. Most of these, including spinal nerve ligation (SNL) (Kim and Chung, 1992), chronic constriction injury (Bennett and Xie, 1988), partial sciatic nerve injury (Seltzer et al., 1990), and spared nerve injury (Decosterd and Woolf, 2000) involve intricate surgical techniques meant to simulate clinically relevant nerve damage. These models produce different levels of hypersensitivity in different subjects, and a genetic component to such variability has been demonstrated directly (e.g., Mogil et al., 1999a, Mogil et al., 1999b, Shir et al., 2001).

Certain patients subjected to chemotherapeutic cancer treatment develop drug-related neuropathies, and a small but clinically significant percentage of those neuropathies feature pain. Drugs such as paclitaxel, vincristine, and cisplatin have proven effective as anti-tumor agents, but their toxicity extends to other tissues as well, including nerves. Paclitaxel (Taxol®, Bristol-Myers Squibb; Princeton, NJ, U.S.A.), a derivative of the Pacific yew tree (Taxus brevifolia), is commonly used to treat gynecological, lung, and head and neck cancers (see Rowinsky et al., 1993). Its dose-limiting side effect is a peripheral sensory neuropathy usually involving numbness and tingling in the extremeties, often accompanied by burning pain Lipton et al., 1989, Wasserheit et al., 1996. Although the mechanisms are not completely understood, it is believed that paclitaxel produces nerve damage by disrupting the action of the microtubules necessary for axonal transport Der Brabander et al., 1981, Rowinsky et al., 1988. In most clinical cases, the neuropathy is mild, disappearing after the cessation of chemotherapy; however, in a minority of patients, neuropathic pain can be long lasting and severe Rowinsky et al., 1993, Chaudry et al., 1994, van den Bent et al., 1997.

Chemotherapeutic drugs have recently been used to develop animal models of neuropathic pain Nozaki-Taguchi et al., 2001, Polomano et al., 2001. These models may be favorable alternatives to surgical models because they are easier to perform, especially in the mouse whose small size hinders surgical procedures. In the rat, four intraperitoneal (i.p.) doses of paclitaxel produce a long-lasting bilateral neuropathy; symptoms of this neuropathy include mechanical allodynia and hyperalgesia, heat hyperalgesia and cold allodynia (Polomano et al., 2001).

The present study describes a strain survey of paclitaxel-induced mechanical allodynia using 10 inbred mouse strains. Such strains are useful in determining the genetic contribution to variability in a particular trait because they are virtually isogenic (i.e., genetically identical), having been sib-mated for at least 20 generations. One aim was to assess the feasibility of linkage mapping of paclitaxel neuropathic hypersensitivity in this species, which would be facilitated by the demonstration of robust strain differences. Second, previous work in our laboratory has suggested that similar genetic factors are responsible for the various symptoms of chronic pain states (e.g., mechanical allodynia, thermal hyperalgesia) regardless of the precise nature of the injury (Mogil et al., 1999a, Mogil et al., 1999b, Lariviere et al., 2002). A comparison between strain sensitivities obtained herein and those obtained previously (Mogil et al., 1999a, Mogil et al., 1999b) using the SNL model would help establish the generalizability of this conclusion. Although the main dependent measure in these studies was mechanical allodynia, we chose two extreme-responding strains to undergo additional behavioral testing to better characterize the paclitaxel model in mice.