Elsevier

NeuroToxicology

Volume 24, Issue 6, December 2003, Pages 797-805
NeuroToxicology

A New Animal Model of Vincristine-Induced Nociceptive Peripheral Neuropathy

https://doi.org/10.1016/S0161-813X(03)00043-3Get rights and content

Abstract

Using doses close to those used clinically, we have developed an animal model of vincristine-induced nociceptive sensory neuropathy after repeated intravenous injection in male Sprague–Dawley rats. In order to validate the model, three different doses (50, 100 and 150 μg/kg) of vincristine were injected every 2nd day until five injections had been given. The sensory behavioural assessment revealed mechanical hyperalgesia and allodynia associated with cold thermal hyperalgesia and allodynia. With regard to electrophysiological evaluation, we observed a decrease in the nerve conduction velocity in the highest dose group. Morphological studies revealed few degenerated fibers in the sciatic nerve and many degenerated myelinated axons in the fine nerve fibers of the subcutaneous paw tissue. Finally, to develop an animal model, we chose the 150 μg/kg dose because of the good general clinical status of the rats without motor function changes associated with severe sensation disorders like hyperalgesia and allodynia. This model of vincristine-induced painful neuropathy will be used to explore physiopathological mechanisms implied in the genesis of neuropathic pain and also to test new analgesic and neuroprotective drugs.

Section snippets

INTRODUCTION

A complete knowledge of the pathophysiology of neuropathic pain requires the development of additional new models with different aetiologies than those presently used such as the trauma and metabolic models (Bennett and Xie, 1988, Courteix et al., 1993). The absence of knowledge concerning mechanisms of chemotherapy-induced neuropathic pain has hindered the development of new treatment strategies. Vincristine, an antineoplastic agent widely used in cancer therapy for both solid tumors and

Animals

Two hundred and fifty-two male Sprague–Dawley rats (Charles River, St-Aubin-Lès-Elbeuf, France) weighing 160–180 g at the beginning of the experiment were used (nine rats/test per dose). The rats were housed in plastic cages on a 12 h light/12 h dark cycle with access to water and food ad libitum. Room temperature was maintained at 22 °C and relative humidity was usually between 50 and 60%. Animals were allowed a 1 week acclimatisation period before being used in experiments.

Drugs

Vincristine-treated

Assessment of General Toxicity

No rat died in the vincristine groups irrespective of the dose used. All animals received the five injections as scheduled in the protocol.

In the vincristine 50 μg/kg group, body weight was only significantly decreased compared to saline 3 days after the last injection (P<0.05; −5%). Rats receiving 100 μg/kg showed a significantly lower body weight gain compared to saline from the 4th day to the end of the study (P<0.001; −13%). The highest dose, 150 μg/kg, also induced a significant decrease in

DISCUSSION

This study describes a new model of peripheral nociceptive neuropathy produced after toxic injury of the peripheral nervous system by the antineoplastic agent, vincristine. This model displays all the characteristics of a peripheral sensory neuropathy, i.e. behavioural signs as mechanical and thermal allodynia, mechanical and thermal hyperalgesia, and are associated with significant electrophysiological and histological disorders. The lack of motor disorders is very important for a predictive

Acknowledgements

This work was supported by the local committee of the Ligue Contre le Cancer. We wish thank Dr. P. Duprat and Dr. Sylvain Molon-Noblot for advice and support, Dr. A.S. Gross for comments on the manuscript and C. Graulière for technical assistance.

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