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. 2011 May 11;106(1):274–279. doi: 10.1152/jn.00141.2011

Abnormal muscle afferent function in a model of Taxol chemotherapy-induced painful neuropathy

Xiaojie Chen 1, Paul G Green 1, Jon D Levine 1,2,✉
PMCID: PMC3129739  PMID: 21562188

Abstract

Despite muscle pain being a well-described symptom in patients with diverse forms of peripheral neuropathy, the role of neuropathic mechanisms in muscle pain have received remarkably little attention. We have recently demonstrated in a well-established model of chemotherapy-induced painful neuropathy (CIPN) that the anti-tumor drug paclitaxel (Taxol) produces mechanical hyperalgesia in skeletal muscle, of similar time course to and with shared mechanism with cutaneous symptoms. In the present study, we evaluated muscle afferent neuron function in this rat model of CIPN. The mechanical threshold of muscle afferents in rats exposed to paclitaxel was not significantly different from the mechanical threshold of muscle afferents in control animals (P = 0.07). However, paclitaxel did produce a marked increase in the number of action potentials elicited by prolonged suprathreshold fixed intensity mechanical stimulation and a marked increase in the conduction velocity. In addition, the interspike interval (ISI) analysis (to evaluate the temporal characteristics of the response of afferents to sustained mechanical stimulation) showed a significant difference in rats treated with paclitaxel; there was a significantly greater ISI percentage of paclitaxel-treated muscle afferents with 0.01- and 0.02-s ISI. In contrast, an analysis of variability of neuronal firing over time (CV2 analysis) showed no effect of paclitaxel administration. These effects of paclitaxel on muscle afferent function contrast with the previously reported effects of paclitaxel on the function of cutaneous nociceptors.

Keywords: paclitaxel, skeletal muscle, hyperalgesia, peripheral neuropathy, sensory afferents, conduction velocity

whereas the concept of neuropathic muscle pain has received remarkably little attention, a number of reports describe muscle pain as a prominent symptom in patients with diverse forms of peripheral neuropathy (Bradley et al. 1970; Gardner 1972; Kunitoh et al. 1998; Marchettini et al. 2006; Peltier and Russell 2006; van de Glind et al. 2007; Vittadini et al. 2001). However, the muscle pain experienced by these patients can be incapacitating and resistant to treatment (Jacobson et al. 2003). Basic and clinical research on chemotherapy-induced peripheral neuropathy (CIPN), which has focused on nociceptors that innervate the cutaneous domain (Baron 2009; Costigan et al. 2009), has revealed much about underlying mechanisms. In contrast, very little is known about the muscle pain produced by the same insult to the peripheral nervous system.

Paclitaxel (Taxol), an antineoplastic agent used to treat various types of cancer (Cavaletti et al. 1995; Chaudhry et al. 1994; Rowinsky et al. 1993; Socinski et al. 2002; Vaishampayan et al. 1999), induces cytotoxicity by promoting stabilization of tubulin polymers, resulting in microtubule dysfunction (Arnal and Wade 1995; Authier et al. 2000; Cavaletti et al. 1995, 1997; Schiff and Horwitz 1980). It also induces painful peripheral neuropathy (Tanner et al. 1998a,b) as a major dose-limiting side effect; the incidence of this form of peripheral neuropathy is often >50% and approaches 90% with some dosage regimens (Cavaletti et al. 1995; Rowinsky 1993). Paclitaxel containing chemotherapeutic regimens often also produce a pain syndrome characterized by intense myalgias (Jacobson et al. 2003; Kunitoh et al. 1998), which can persist for months (Kunitoh et al. 1998). We recently demonstrated, in an established model of paclitaxel CIPN, persistent muscle pain, manifest as mechanical hyperalgesia, comparable in time course with, and sharing underlying mechanisms with, paclitaxel-induced cutaneous mechanical hyperalgesia (Alvarez et al. 2011). The rapid onset and time-to-peak symptoms in this model of paclitaxel CIPN is consistent with the myalgias reported by patients, which usually begins a few days after its administration and rapidly reaches an intensity requiring opioid treatment (Jacobson et al. 2003; Loprinzi et al. 2007). To better understand the neuropathic changes in muscle sensory afferents underlying this pain syndrome, in the present study, we evaluated muscle sensory afferent function in a rat model of paclitaxel CIPN (Alessandri-Haber et al. 2004; Dina et al. 2001, 2004; Tanner et al. 1998a,b).

METHODS

Animals.

Experiments were performed on 250- to 400-g adult male Sprague-Dawley rats (Charles River, Hollister, CA). Animals were housed in the Laboratory Animal Resource Center of the University of California, San Francisco, under a 12:12-h light-dark cycle and environmentally controlled conditions (lights on 7 AM to 7 PM; ambient room temperature, 21–23°C) with food and water available ad libitum. Animal care and use conformed to National Institutes of Health (NIH) guidelines, and measures were taken to minimize pain and discomfort. A total of 40 and 31 fibers were evaluated from 33 control and 19 paclitaxel-treated rats, respectively; n values refer to numbers of individual fibers. Experimental protocols were approved by the Institutional Animal Care and Use Committee of the University of California, San Francisco.

Drugs.

All chemicals were obtained from Sigma-Aldrich (St. Louis, MO).

Paclitaxel-induced neuropathy.

Paclitaxel was administered as previously described (Dina et al. 2001; Polomano et al. 2001); because of its poor aqueous solubility, it was formulated in a vehicle composed of absolute ethanol and Cremophor EL (1:1; BASF, Mount Olive, NJ) at a concentration of 1 mg/ml. A final concentration of 1 mg/ml was made by adding sterile NaCl (0.9%) just before injection. Rats were injected intraperitoneally with paclitaxel (1 mg/kg) on days 0, 2, 4, and 6. Using this protocol, rats demonstrate robust mechanical hyperalgesia in the gastrocnemius muscle for at least 14 days (Alvarez et al. 2011), the period during which muscle sensory afferent function was evaluated in the present study.

Single-fiber electrophysiology.

The in vivo single-fiber electrophysiology technique employed was similar to that used previously in recordings from cutaneous afferents (Chen et al. 1999). Rats were anesthetized with sodium pentobarbital (initially 50 mg/kg ip with additional doses given throughout the experiment to maintain areflexia), their trachea cannulated, and heart rate monitored. Body temperature was maintained at 37 ± 0.5°C using a heating blanket regulated by a rectal temperature sensor. Anesthetized animals were positioned on their right side, and an incision was made on the dorsal skin of the left leg, between the midthigh and calf, and the biceps femoris muscle were partially removed to expose the sciatic nerve and gastrocnemius muscle. The edges of the incised skin were fixed to a metal loop to provide a pool that was filled with warm mineral oil to bathe the sciatic nerve and gastrocnemius muscle.

The sciatic nerve was cut proximally to prevent flexor reflexes during electrical stimulation of sensory neurons. Fine fascicles of axons were then dissected from the distal stump and placed on a recording electrode. Single units were first detected by mechanical stimulation of the gastrocnemius muscle with a small blunt-tipped glass bar. Bipolar stimulating electrodes were then placed and held on the center of the receptive field of the muscle afferent by a micromanipulator (MM-3; Narishige). Conduction velocity of each fiber was calculated by dividing the distance between the stimulating and recording electrodes by the latency of the electrically evoked action potential. All recorded muscle afferents had conduction velocities in the range of type III (12%) or type IV (88%) fibers (Diehl et al. 1993); muscle afferents are grouped by conduction velocity: approximately 2.5–30 m/s for group III and <2.5 m/s for group IV (Berberich et al. 1988). To exclude the possibility of mechanical activation of afferent fibers when applying electrical stimulation for determination of conduction velocity, repeated electrical stimuli were delivered to confirm the electrically evoked action potential, which also helps exclude mechanical activation of afferent fibers. Mechanical threshold was determined with calibrated von Frey hairs (VFH; Ainsworth, London, United Kingdom) and defined as the lowest force that elicited at least 2 spikes within 1 s in at least 50% of trials. Sustained (60-s) suprathreshold (10-g) mechanical stimulation was accomplished by use of a mechanical stimulator that consisted of a force-measuring transducer (Entran Devices, Fairfield, NJ) with a blunt plastic tip that was applied by a micromanipulator (BC-3 and BE-8; Narishige) on the center of the receptive field for 60 s. We did not systematically analyze the spontaneous discharge. Neural activity and timing of stimulus onset and termination were monitored and stored on a Windows OS computer with Micro1401 interface (CED, Cambridge, United Kingdom) and analyzed offline with Spike2 software (CED).

Interspike interval analysis.

Interspike interval (ISI) analysis, used to evaluate the temporal characteristics of the response of nerve fibers to sustained mechanical stimulation, was adopted from our study of afferent activity in the rat model of vincristine-induced painful neuropathy (Tanner et al. 2003). The ISIs for the responses of each afferent were grouped into 100-ms bins between 0 and 499 ms; the few ISIs greater than or equal to 500 ms were not further analyzed (Tanner et al. 2003). This bin width also allows comparison of data with those from previous studies (Arendt-Nielsen et al. 2000; Franck et al. 1993; Miller and Woolf 1996). The number of intervals occurring in each bin was expressed as the percentage of the total number of ISIs in the trial. This normalization procedure allowed the distribution of ISIs from several fibers to be averaged together.

Coefficient of variation analysis.

ISIs do not give an accurate estimate of the variability of neuronal firing if the mean firing rate changes over time, a common occurrence. Therefore, we also calculated the coefficient of variability (CV2), which compares the relative difference between adjacent ISIs (Holt et al. 1996). CV2 is defined as 2 multiplied by the SD of two ISIs divided by their mean (Holt et al. 1996):

CV2=2|Δti+1−Δti|Δti+1+Δti

where ti is the latency for the ith action potential. Thus CV2 is a dimensionless number that is independent of absolute firing rate.

That differences in CV2 reflect physiologically meaningful differences between functionally important classes of neurons was recently demonstrated in a study separating slowly adapting type I from type II afferents fibers (Wellnitz et al. 2010).

Statistical analyses.

Group data are expressed as means ± SE of n distinct observations. Statistical comparisons were made by Student's t-test (for 1 or 2 independent populations) or by 1-way ANOVA for comparing multiple treatments (GraphPad Prism statistical software). Data were tested for normality using the D'Agostino and Pearson omnibus normality test; if data did not pass the normality test for Gaussian distribution, Welch correction for the Student's t-test was used (GraphPad Prism). To compare change from baseline, 1-way repeated-measures ANOVAs with a Greenhouse-Geisser-adjusted P value was used (SPSS statistical software). To compare CV2 analyses, a 1-way repeated-measures ANOVA was used. P < 0.05 was considered statistically significant.

RESULTS

Mechanical threshold.

We first evaluated the effect of paclitaxel treatment on the mechanical threshold of afferents in the gastrocnemius muscle of the rat. Whereas the mechanical threshold of muscle afferents exposed to paclitaxel (0.89 ± 0.09 mN, n = 31) was lower than the mechanical threshold of muscle afferents in naïve control animals (1.11 ± 0.11 mN, n = 40; Fig. 1), this difference did not reach statistical significance (P = 0.07).

Fig. 1.

Fig. 1.

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Mechanical threshold of muscle afferents. Mechanical threshold in afferents innervating the gastrocnemius muscle of paclitaxel-treated rats were not significantly different from the threshold in afferents from naïve control rats. Scattergram of mechanical thresholds of individual muscle afferents from naïve control and paclitaxel-treated rats is also shown.

Response to sustained stimulation.

We next evaluated the effect of paclitaxel treatment on the response of afferents to a uniform intensity, sustained suprathreshold mechanical stimulus. The response of muscle afferents to a 60-s suprathreshold (10-g) mechanical stimulus in paclitaxel-treated rats (431.80 ± 93.46 action potentials/60-s stimulus, n = 31) was significantly greater than in muscle afferents from naïve control animals (215.80 ± 49.91 action potentials/60-s stimulus, n = 40; P = 0.047, Student's t-test, Welch correction; Fig. 2).

Fig. 2.

Fig. 2.

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Response of muscle afferents to a sustained mechanical stimulus. The responses of afferents innervating the gastrocnemius muscle of paclitaxel-treated rats to mechanical stimuli (60-s suprathreshold 10-g von Frey hair, n = 31) were significantly higher than those of control rats (n = 40; *P < 0.05). Scattergram of individual responses of muscle afferents from naïve control and paclitaxel-treated rats is also shown.

Afferent firing pattern/variability.

Since we have previously observed changes in firing pattern in afferents in muscle (Chen et al. 2010) and skin (Chen and Levine 2003; Tanner et al. 2003), in models of painful peripheral neuropathy, we evaluated firing pattern in muscle afferents in rats treated with paclitaxel. To examine the pattern of neural activity, we first generated ISI histograms and performed CV2 analyses for muscle afferents recorded in paclitaxel-treated and control rats.

The peak in the ISI distribution of muscle afferents from paclitaxel-treated rats was shifted to the left, compared with afferents from control animals, reflecting the greater number of action potentials elicited by the 10-g VFH stimulus in afferents from paclitaxel-treated rats. In rats treated with paclitaxel, there was a significantly greater ISI percentage of paclitaxel-treated muscle afferents with 0.01- and 0.02-s ISI and significantly smaller percentage with those with >2.9-s ISI (2-way repeated-measures ANOVA, with Bonferroni post hoc test, P < 0.05, control vs. paclitaxel exposed; Fig. 3). Although we found no difference in CV2 values for muscle afferents in paclitaxel-treated compared with control rats (data not shown), in addition to substantial increased response to sustained suprathreshold stimulation in muscle afferents from paclitaxel-treated rats, there was also a change in firing patterns in theses afferents.

Fig. 3.

Fig. 3.

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Interspike interval (ISI) distribution of muscle afferents in response to sustained mechanical stimuli. No significant differences were observed in the ISI distribution of muscle afferents (from 0 to 0.28 s, in 0.01-s bin width, and >0.29 s), from control and paclitaxel-treated rats, in response to mechanical stimulation (60-s suprathreshold 10-g von Frey hair). *P < 0.05.

Conduction velocity.

In paclitaxel-treated rats, the conduction velocity of muscle afferents (2.09 ± 0.17 m/s, n = 31) was significantly faster than that of afferents in control animals (1.25 ± 0.11 m/s, n = 40; Student's t-test, with Welch correction, P < 0.0001; D'Agostino and Pearson omnibus normality test for control fibers, P = 0.006 does not pass normality test; paclitaxel-treated fibers, passes normality test; Fig. 4). The frequency distribution of conduction velocities in fibers of paclitaxel-treated and control fibers indicates a shift in the distribution of conduction velocity, with a higher percentage of faster-conducting fibers in paclitaxel-treated rats (Fig. 5). Thus, although not excluding a contribution of a difference in percentage of types III and IV fibers that were sampled in the paclitaxel-treated vs. control groups of rats, the shift in distribution is most compatible with the suggestion that our findings are explained by an increase in conduction velocity induced by paclitaxel in muscle afferents. Although it is possible that paclitaxel treatment has a preferential effect on a subset of neurons, e.g., more superficial neurons, leaving a greater proportion of deeper terminals that may require more force to be activated, our methodology does not distinguish the superficiality of a receptive field of a particular fiber. However, given the relatively large increase in conduction velocity (∼67%), it is likely that at least some of the observed difference is due to changes in conduction velocity in the axon. Furthermore, the average mechanical threshold is not significantly different between the paclitaxel-treated and control groups, supporting the idea that we are not sampling a different population of fibers in the experimental and control animals. Finally, we have recently shown a similar change in another model of muscle pain (Chen et al. 2011).

Fig. 4.

Fig. 4.

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Conduction velocity in muscle afferents. Mean conduction velocities from paclitaxel-treated rats (2.09 ± 0.17 m/s, n = 31) were significantly greater than from naïve rats (1.25 ± 0.11 m/s, n = 40; Student's t-test, *P < 0.05). Scattergram of conduction velocities of muscle afferents in naïve control and paclitaxel-treated rats is also shown.

Fig. 5.

Fig. 5.

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Paclitaxel treatment stress shifts muscle afferent conduction velocity frequency distribution. A plot of frequency distribution of conduction velocity indicates that there is a shift to faster conducting fibers in paclitaxel-treated rats. Graph overlay shows smoothing curve of data (6th order polynomial, 4 neighbor averaging) to illustrate shift in conduction velocity distribution.

DISCUSSION

Although as a clinical entity, neuropathic muscle pain has been largely neglected, many forms of peripheral neuropathy manifest persistent, sometimes debilitating, and often difficult to treat pain in skeletal muscle (Bradley et al. 1970; Gardner 1972; Kunitoh et al. 1998; Marchettini et al. 2006; Peltier and Russell 2006; van de Glind et al. 2007; Vittadini et al. 2001). We have recently observed mechanical hyperalgesia in skeletal muscle in three models of painful peripheral neuropathy, namely CIPN induced by two chemotherapeutic drugs that have CIPN as dose-limiting side effects, paclitaxel (Alessandri-Haber et al. 2004; Dina et al. 2001, 2004)- and oxaliplatin (Ferrari et al. 2010; Joseph et al. 2008; Joseph and Levine 2009)-induced CIPN and the painful peripheral neuropathy associated with chronic alcohol consumption (Dina et al. 2000, 2007, 2008), where the mechanical hyperalgesia in these forms of painful peripheral neuropathy have a time course that parallels cutaneous hyperalgesia in the same animal, and they share mechanisms in common (Alvarez et al. 2011).

In the present study, we evaluated the function of muscle afferents in rats with one of these forms of neuropathy, paclitaxel-induced painful peripheral neuropathy. Although paclitaxel treatment did not produce a significant change in mechanical threshold, a marked increase in number of action potentials induced by a sustained (60-s) suprathreshold (10-g) mechanical stimulus and a marked increase in conduction velocity were seen, both of which were statistically significant. Using ISI and CV2 analyses, we demonstrated the variability in evoked activity in muscle afferents.

These present findings of the effects of paclitaxel on muscle afferents contrast markedly with those in our previous study of cutaneous C-fiber function in rats with paclitaxel-induced CIPN (Dina et al. 2001). In that study, we found no significant difference in mechanical threshold, response to sustained suprathreshold mechanical stimulation, or conduction velocity in C-fibers innervating the skin on the dorsum of the rat's hind paw. Although the mean number of action potentials evoked by a sustained (60-s) threshold and suprathreshold (10-g) stimulus was higher for afferents from paclitaxel-treated animals than in those from control rats, the difference did not reach statistical significance, similar to what we have previously observed in models of diabetic (Ahlgren and Levine 1994; Chen and Levine 2001)-, vincristine (Tanner et al. 1998b)-, and alcohol (Dina et al. 2000)-induced painful peripheral neuropathy. However, as in these other models, paclitaxel treatment produced a subpopulation of cutaneous C-fibers with increased number of action potentials evoked by sustained (60-s) threshold and suprathreshold (10-g) stimulation of cutaneous C-fibers. The high-firing-frequency C-fibers had an ∼3-fold higher firing rate compared with controls during a 60-s stimulus, whereas the low-firing-frequency fibers had responses similar to those of C-fibers in control rats. Of note, this isolated population of afferents, with very high response rates, was not observed in the present study of muscle afferent function in paclitaxel-induced CIPN in the rat. The reasons for these marked differences in the effect of paclitaxel on afferent function in muscle compared with skin is currently unknown. Unfortunately, compared with the many detailed analyses of the cell biology of the cutaneous afferent, our knowledge of the cell biology of muscle afferent is still very rudimentary.

The finding that the conduction velocity in muscle afferents was increased by paclitaxel was unexpected, not only because of our prior finding that paclitaxel did not produce a change in conduction velocity in cutaneous afferent, but also because in the setting of peripheral neuropathy, if changes in conduction velocity are observed, they have usually been reported to be a decrease in conduction velocity. Although in the setting of hypersensitivity states, one might expect to observe an increase in conduction velocity, as a reflection of a change in ionic conductance in the axon (Hodgkin 1975; Waxman et al. 1999), in the setting of inflammatory pain, conduction velocity has generally been unchanged (Baba et al. 1999; Nakatsuka et al. 1999), whereas in peripheral neuropathies, even those associated with pain, changes when observed have in general been in the form of a slowing in conduction velocity (Elliott et al. 2009; Meyer et al. 2010; Nakatsuka et al. 1999). These paradoxical findings may be due, in part, to the fact that clinically, in patients with peripheral neuropathies (Nardone and Schieppati 2004; Shefner et al. 1991; Truini et al. 2009), and in animal models of neuropathic pain (Authier et al. 2000; Brussee et al. 2008; Cermenati et al. 2010; Jolivalt et al. 2009; Meyer et al. 2010), conduction velocity is generally measured in myelinated, nonnociceptive afferents. However, there are also studies in which slowing of C-fiber conduction velocity in neuropathic pain models [e.g., ddC (Chen and Levine 2007)] and in clinical studies on cutaneous unmyelinated fibers patients with neuropathic pain [e.g., erythromelalgia (Orstavik and Jorum 2010)] have been reported. Methodological differences may also play a role, since whereas Baba and colleagues (1999) observed no change in C-fiber conduction velocity when complete Freund's adjuvant was injected in the rat's hind paw, Djouhri and Lawson (2001) observed increased conduction velocity after complete Freund's adjuvant was injected into the limb as well as the paw. Thus direct exposure of the peripheral nerve to the neuropathic effect of cytokines may produce enhancement of conduction velocity. Possibly related to this, Lu and colleagues (2010) have recently shown that persistent inflammation alters the density and distribution of voltage-activated ion channels in DRG neurons. Alternatively, complete Freund's adjuvant may have different effects on cutaneous afferents and those innervating deep tissues (e.g., muscle, tendon, or bone). In support of this, we have recently demonstrated that water avoidance stress, which produces mechanical hyperalgesia in muscle, produced changes in muscle afferent function very similar to those induced by paclitaxel, including significant increase in conduction velocity (Chen et al. 2011). Although the underlying mechanism(s) responsible for the increased conduction velocity in muscle afferents are unknown, they are likely due to changes in ionic conductances in the afferent axon (Quasthoff 1998). Paclitaxel-induced changes in ion channel function will be evaluated in future studies.

In conclusion, we have shown that persistent muscle hyperalgesia in a rat model of paclitaxel CIPN (Alessandri-Haber et al. 2004; Dina et al. 2001, 2004; Tanner et al. 1998a,b) is associated with enhanced activity in muscle afferents. These changes are markedly different from those previously reported for the effect of paclitaxel on cutaneous afferent function (Alessandri-Haber et al. 2004; Dina et al. 2001, 2004). The cell biological basis of the differences between muscle and cutaneous afferents responsible for the different effects of paclitaxel on the function of these two types of afferents remain to be elucidated.

GRANTS

This work was supported by NIH Grant AR-054635.

DISCLOSURES

The authors of this manuscript have no conflicts of interest with regard to publishing these data.

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