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. 1998 Aug 15;18(16):6480-91.
doi: 10.1523/JNEUROSCI.18-16-06480.1998.

Nociceptor hyper-responsiveness during vincristine-induced painful peripheral neuropathy in the rat

K D Tanner  1 , D B Reichling, J D Levine
Affiliations

Nociceptor hyper-responsiveness during vincristine-induced painful peripheral neuropathy in the rat

K D Tanner et al. J Neurosci. .

Abstract

Neuropathic pain accompanies peripheral nerve injury after a wide variety of insults including metabolic disorders, traumatic nerve injury, and neurotoxic drugs. Chemotherapy-induced neuropathic pain, caused by drugs such as vincristine and taxol, occurs in cancer patients who receive these drugs as antineoplastic agents. Although a variety of remediations have been attempted, the absence of knowledge concerning mechanisms of chemotherapy-induced neuropathic pain has hindered the development of treatment strategies. Vincristine, a widely used chemotherapeutic agent, produces painful peripheral neuropathy in humans and mechanical hyperalgesia in rats. To test the hypothesis that alterations in C-fiber nociceptor function occur during vincristine-induced painful peripheral neuropathy, we performed in vivo extracellular recordings of single neurons from the saphenous nerve of vincristine-treated rats. Forty-one percent of C-fiber nociceptors were significantly hyper-responsive to suprathreshold mechanical stimulation. As a population, these mechanically hyper-responsive nociceptors also had significantly greater responses to suprathreshold heat stimulation; however, heat hyper-responsiveness was found only in a subset of these nociceptors and was never detected in the absence of mechanical hyper-responsiveness. In addition, mean conduction velocities of A-fibers and C-fibers in vincristine-treated rats were significantly slowed. Mean heat and mechanical activation thresholds of C-fiber nociceptors, their distribution among subclasses, and the percentage of spontaneously active neurons in vincristine-treated rats were not statistically different from controls. Vincristine does not, therefore, cause generalized impairment of C-fiber nociceptor function but rather specifically interferes with mechanisms underlying responsiveness to suprathreshold stimuli. Furthermore, vincristine-induced nociceptor hyper-responsiveness may involve alterations specifically in mechanotransduction in some nociceptors and alterations in general cellular adaptation mechanisms in others.

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Figures

Fig. 1.
Fig. 1.
Experimental paradigm. A, Schematic of the experimental timeline. Rats were injected intravenously with vincristine sulfate (V) at 100 μg/kg on days 1–5 and 8–12. The arrow shows the period during which electrophysiological recordings were made from sensory fibers in the saphenous nerves of vincristine-treated rats. Data from the 5 recording days were pooled. B, The requirement that each C-fiber studied show a slowed conduction velocity in response to electrical stimulation after mechanical stimulation of the receptive field. This “collision test” established that the mechanical receptive field under study was innervated by the C-fiber whose latency to electrical stimulation was shifted. Top, The activation of a C-fiber with a latency of 46 msec in response to electrical stimulation of the whole nerve. Bottom, Electrical activation of the same C-fiber, at this time with a latency of 56 msec, after mechanical stimulation of its receptive field. This C-fiber had a conduction velocity of 0.70 m/sec and a mechanical threshold of 1.7 gm. Note that another fiber conducted at 16 msec both before and after the collision test.
Fig. 2.
Fig. 2.
Vincristine causes a slowing of the conduction velocity of both A-fibers and C-fibers. Conduction velocities were determined by dividing the distance between the recording and stimulating electrodes by the latency of an individual AP from an afferent after an electrical stimulus to the whole nerve. Thefilled bars represent data from vincristine-treated rats, and the open bars represent data from control rats. A, Left, The distribution of C-fiber conduction velocities for 693 vincristine-treated and 401 control C-fibers. Bin width is 0.1 m/sec. Right, The average C-fiber conduction velocity in control and vincristine-treated rats. These averages were calculated from the values in the histogram on the left. Error bars in this and subsequent figures represent SEM. B, Left, The distribution of A-fiber conduction velocities for 561 vincristine-treated and 264 control A-fibers. Bin width is 2 m/sec. Right, The average A-fiber conduction velocity in control and vincristine-treated rats. These averages were calculated from the values in the histogram on the left.
Fig. 3.
Fig. 3.
Vincristine does not decrease the heat or mechanical activation thresholds of C-fiber nociceptors.A, Left, The distribution of C-fiber heat activation thresholds for 37 vincristine-treated and 45 control C-fibers. Right, The average heat activation threshold for control C-fibers (open bars) and for vincristine-treated C-fibers (filled bars). Bin width is 2°C. B, Left, The distribution of C-fiber mechanical thresholds for 57 vincristine-treated and 60 control C-fibers. Right, The average mechanical activation threshold for control C-fibers (open bars) and for vincristine-treated C-fibers (filled bars). Each bin on thex-axis is the intensity in grams of a VFH used to test C-fiber mechanical threshold, with the exception of the “>60” bin that combines all VFHs of intensities >60 gm.
Fig. 4.
Fig. 4.
Vincristine causes increased responsiveness to sustained mechanical stimulation in a subset of C-fibers.A, The response of a C-fiber from a control rat. This fiber had a conduction velocity of 0.78 m/sec, had a mechanical threshold of 1.7 gm, and fired no APs during the 2 min immediately preceding stimulation (only the last 10 sec is shown). The fiber fired 63, 51, 52, and 67 APs during the four stimulation trials for an average of 58.3 ± 4.0 APs per stimulation. The peak firing frequency during the burst for the four trials was 10, 11, 13, and 9 Hz, respectively. B, The response of a hyper-responsive C-fiber from a vincristine-treated rat. This fiber had a conduction velocity of 0.62 m/sec, had a mechanical threshold of 1.7 gm, and fired no APs during the 2 min immediately preceding stimulation. The fiber fired 146, 137, 120, and 149 APs during the four stimulation trials for an average of 138 ± 6.5 APs per stimulation. The peak firing frequency during the burst for the four trials was 14, 9, 16, and 14 Hz, respectively. Bin width is 1 sec.
Fig. 5.
Fig. 5.
The responses of C-fibers to sustained mechanical stimulation in vincristine-treated rats are bimodal. The total number of APs fired in response to 1 min of 10 gm stimulation of the receptive field is plotted for 37 control C-fibers (open bars) and 39 vincristine-treated C-fibers (filled bars). The percentage of C-fibers that fired >100 APs in response to the 1 min 10 gm stimulus, referred to as high-firing C-fibers, is 2.7% of control C-fibers (1 of 37) and 41% of vincristine-treated C-fibers (16 of 39).
Fig. 6.
Fig. 6.
Time course of responses to sustained mechanical stimulation in control and vincristine-treated C-fibers.A, The average time course of the response of C-fibers to sustained mechanical stimulation to the receptive field plotted for all control C-fibers (■; n = 37) and all vincristine-treated C-fibers (▪; n = 39).B, The average time course of the response to sustained mechanical stimulation to the receptive field plotted for high-firing vincristine-treated C-fibers firing more than 100 APs during stimulation (▴; n = 16), for low-firing vincristine-treated C-fibers firing less than 100 APs during stimulation (•; n = 23), and for all control C-fibers (■; n = 37). Bin width is 10 sec. Some error bars are contained within the symbols.
Fig. 7.
Fig. 7.
Vincristine causes heat hyper-responsiveness in high-firing vincristine-treated nociceptors. Example responses to mechanical stimulation (1 min; 10 gm) and heat stimulation (ramp from 30 to 53°C at 1°C/sec) for a C-fiber from a control rat with a mechanical threshold of 1.7 gm and a heat threshold of 40.4°C (A), a low-firing C-fiber from a vincristine-treated rat with a mechanical threshold of 0.6 gm and a heat threshold of 44.6°C (B), and a high-firing C-fiber from a vincristine-treated rat with a mechanical threshold of 1.0 gm and a heat threshold of 42.8°C (C). The number of APs fired during each stimulation trial is shown in theupper right of each trial.
Fig. 8.
Fig. 8.
Heat hyper-responsiveness occurs in high-firing but not in low-firing vincristine-treated nociceptors.A, The average response to mechanical stimulation (10 gm; 1 min) for control C-fibers studied with both heat and mechanical stimulation (n = 12) is shown in the open bar. For vincristine-treated C-fibers studied with both heat and mechanical stimulation, the average response to mechanical stimulation is shown in the filled bars for all vincristine-treated C-fibers (n = 19), for low-firing vincristine-treated C-fibers (n = 12), and for high-firing vincristine-treated C-fibers (n= 7). B, The average response to heat stimulation (ramp from 30 to 53°C at 1°C/sec) for control C-fibers studied (n = 12) is shown in the open bar. The average response to heat stimulation for all vincristine-treated C-fibers studied (n = 19), for low-firing vincristine-treated C-fibers (n = 12), and for high-firing vincristine-treated C-fibers (n = 7) is shown in the filled bars. * p < 0.05 or less.
Fig. 9.
Fig. 9.
Heat hyper-responsiveness occurs in some, but not all, high-firing vincristine-treated nociceptors. A, The response to mechanical stimulation for control C-fibers plotted against the response to heat stimulation of that nociceptor for control C-fibers (n = 12; ■), for low-firing vincristine-treated C-fibers (n = 12; •), and for high-firing vincristine-treated C-fibers (n = 7; ▴). B, The response to heat stimulation plotted against the heat threshold of that nociceptor for control C-fibers (n = 16; ■), for low-firing vincristine-treated C-fibers (n = 12; •), and for high-firing vincristine-treated C-fibers (n = 7; ▴). The regression line for control data is shown for reference.
Fig. 10.
Fig. 10.
Mechanical hyper-responsiveness in nociceptors is not correlated with receptive field location, conduction velocity, or mechanical or heat threshold. A, The receptive field locations for all C-fibers studied are shown for control C-fibers (left) and for vincristine-treated C-fibers (right). Low-firing nociceptors are represented by •, and high-firing, mechanically hyper-responsive nociceptors are represented by *. In this drawing of the left hindpaw,top is medial, and bottom is lateral.B, The average conduction velocity for control C-fibers studied (n = 33) is shown in the open bar. The average conduction velocity for all vincristine-treated C-fibers studied (n = 39), for low-firing vincristine-treated C-fibers (n = 23), and for high-firing vincristine-treated C-fibers (n= 16) is shown in the filled bars. C, The average mechanical threshold for all control C-fibers studied (n = 33) is shown in the open bar. The average mechanical threshold for all vincristine-treated C-fibers studied (n = 39), for low-firing vincristine-treated C-fibers (n = 23), and for high-firing vincristine-treated C-fibers (n = 16) is shown in the filled bars. D, The average heat threshold for all control C-fibers studied (n = 12) is shown in the open bar. The average heat threshold for all vincristine-treated C-fibers studied (n = 19), for low-firing vincristine-treated C-fibers (n = 12), and for high-firing vincristine-treated C-fibers (n = 7) is shown in the filled bars. There are no significant differences between the groups.
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References

    1. Ahlgren SC, Levine JD. Protein kinase C inhibitors decrease hyperalgesia and C-fiber hyperexcitability in the streptozotocin-diabetic rat. J Neurophysiol. 1994;72:684–692. - PubMed
    1. Ahlgren SC, White DM, Levine JD. Increased responsiveness of sensory neurons in the saphenous nerve of the streptozotocin-diabetic rat. J Neurophysiol. 1992;68:2077–2085. - PubMed
    1. Ahmad FJ, Baas PW. Microtubules released from the neuronal centrosome are transported into the axon. J Cell Sci. 1993;108:2761–2792. - PubMed
    1. Aley KO, Reichling DB, Levine JD. Vincristine hyperalgesia in the rat: a model of painful vincristine neuropathy in humans. Neuroscience. 1996;73:259–265. - PubMed
    1. Allan V, Vale R, Navone F. Microtubule-based organelle transport in neurons. In: Burgoyne R, editor. The neuronal cytoskeleton. Wiley-Liss; New York: 1991. pp. 257–282.

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