Elsevier

Neuroscience

Volume 118, Issue 3, 25 May 2003, Pages 809-817
Neuroscience

Research paper
Altered temporal pattern of evoked afferent activity in a rat model of vincristine-induced painful peripheral neuropathy

https://doi.org/10.1016/S0306-4522(03)00023-XGet rights and content

Abstract

It is known that the level of activity in nociceptive primary afferent nerve fibers increases in neuropathic conditions that produce pain, but changes in the temporal patterning of action potentials have not been analyzed in any detail. Because the patterning of action potentials in sensory nerve fibers might play a role in the development of pathological pain states, we studied patterning of mechanical stimulus-evoked action potential trains in nociceptive primary afferents in a rat model of vincristine-induced painful peripheral neuropathy. Systemic administration of vincristine (100 μg/kg) caused approximately half the C-fiber nociceptors to become markedly hyperresponsive to mechanical stimulation. Instantaneous frequency plots showed that vincristine induced an irregular pattern of action-potential firing in hyperresponsive C-fibers, characterized by interspersed occurrences of high- and low-frequency firing. This pattern was associated with an increase in the percentage of interspike intervals 100–199 ms in duration compared with that in C-fibers from control rats and vincristine-treated C-fibers that did not become hyperresponsive. Variability in the temporal pattern of action potential firing was quantified by determining the coefficient of variability (CV2) for adjacent interspike intervals. This analysis revealed that vincristine altered the pattern of action-potential timing, so that combinations of higher firing frequency and higher variability occurred that were not observed in control fibers.

The abnormal temporal structure of nociceptor responses induced by vincristine in some C-fiber nociceptors could contribute to the pathogenesis of chemotherapy-induced neuropathic pain, perhaps by inducing activity-dependent post-synaptic effects in sensory pathways.

Section snippets

Animals

Experiments were performed on 200–400-g male Sprague–Dawley rats (Bantin and Kingman, Fremont, CA, USA). Rats were housed in a temperature- and humidity-controlled environment and were maintained on a 12-h light/dark cycle. Food and water were available ad libitum. Experiments were approved by the Committee on Animal Research at UCSF, and were carried out in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals. All efforts were made to minimize

Vincristine-induced hyperresponsiveness in a subset of C-fiber nociceptors

A subset (41%) of C-fiber nociceptors become hyperresponsive in vincristine-treated rats, firing more than twice as many action potentials in response to a 1-min 10-g mechanical stimulus compared with C-fibers in untreated control rats or to non-hyperresponsive C-fiber nociceptors in vincristine-treated rats (Tanner et al., 1998b). There were no significant differences between the conduction velocities and mechanical thresholds of hyperresponsive vincristine-treated C-fibers compared with

Are the increase in variability and shift in interspike interval distribution specific effects of vincristine or mere consequences of the fibers’ firing at a higher frequency?

It could be hypothesized that the distinctive variable firing patterns we observed in hyperresponsive nociceptors may not be caused by specific vincristine-induced alterations in function, but instead may simply be a consequence of firing at twice the average frequency exhibited by control or non-hyperresponsive vincristine-treated nociceptors. It is difficult to test this experimentally because it has not been possible to drive control nociceptors to fire at as high an average frequency as is

Conclusions

This study demonstrates that the temporal structure of responses in a subpopulation of nociceptive nerve fibers is altered in the vincristine-induced neuropathic pain state. In the subset of C-fiber nociceptors with increased firing rates, the level of variability in interspike intervals at the higher firing rates exceeds that which occurs in normal fibers. We speculate that this distinctive increase in variability might exacerbate pain by promoting synaptic plasticity in central sensory

Acknowledgements

The authors thank Dr. Ken Miller (Sloane Center for Computational Neuroscience and Keck Center for Integrative Neuroscience) for advice on developing the analytical model. This research was supported by NIH (NS21647 and DE08973) and the American Cancer Society. KDT was supported by a NSF Predoctoral Fellowship and an American Heart Association Predoctoral Fellowship.

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