A rat model of stavudine-induced hyperalgesia
Date
2009-05-29T06:25:21Z
Authors
Weber, Juliane
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Abstract
Stavudine, a nucleoside reverse transcriptase inhibitor (NRTI) used to treat
infection by the human immunodeficiency virus (HIV), causes peripheral
neuropathy and pain in HIV-positive patients. The mechanisms of this toxic
neuropathy are poorly understood, partly because of a lack of animal models of the
disease process. I investigated whether long-term daily oral administration of
stavudine affects nociception in Sprague-Dawley rats, and whether changes in
nociception are accompanied by a general deterioration in the rats’ conditions, as
reflected in activity and appetite. Daily stavudine administration induced
mechanical hyperalgesia in rats within three weeks without affecting appetite,
growth or physical activity, and this hyperalgesia persisted throughout the six
weeks of stavudine administration. I then investigated whether central changes
underlie the hyperalgesia caused by stavudine in rats by examining inflammatory
cytokine secretion and neuronal death in the spinal cord. Daily stavudine
administration caused an increase in cytokine-induced neutrophil chemo-attractant
(CINC)-1 concentration in the spinal cord after six weeks, but early development of
stavudine-induced hyperalgesia did not depend on increases in spinal concentrations
of CINC-1 and interleukin (IL)-6, nor on apoptosis or necrosis of spinal neurones.
The neurotoxicity of stavudine is thought to derive from mitochondrial toxicity,
which has been linked to increased plasma lactate concentration and decreased
plasma adiponectin levels caused by lipodystrophy. Thus, I investigated whether a
systemic inflammatory response or metabolic dysregulation accompanied stavudine-induced hypernociception by examining plasma adiponectin, lactate,
CINC-1 and IL-6 concentrations in rats administered daily stavudine. Plasma
adiponectin, lactate, CINC-1 and IL-6 concentrations were unchanged following
three or six weeks of daily stavudine administration. Therefore, I have shown that
stavudine-induced hyperalgesia is not dependent on spinal cord plasticity, nor on a
systemic inflammatory response or extensive metabolic malfunction. Instead, the
hyperalgesia I observed may be caused by the adverse effects of stavudine on
peripheral neurone functioning. As stavudine administration to healthy rats had no
adverse effects besides inducing hyperalgesia and causing a rise in CINC-1
concentration in the spinal cord after six weeks, my results indicate that many other
side effects commonly associated with stavudine treatment in HIV-positive patients
may arise through interaction with the underlying HIV infection.