To elucidate the underlying mechanisms involved in
AIDS therapy-induced
peripheral neuropathy, we have developed a model of
nucleoside analog reverse transcriptase inhibitor-induced painful
peripheral neuropathy in the rat, using
2',3'-dideoxycytidine (ddC),
2',3'-dideoxyinosine (ddI) and
2',3'-didehydro-3'-deoxythymidine (
d4T),
AIDS chemotherapeutic drugs that are also components of
AIDS highly active anti-retroviral
therapy. Administration of ddC, ddI and
d4T produced dose-dependent mechanical
hypersensitivity and
allodynia. Peripheral administration of inhibitors of
protein kinase A,
protein kinase C,
protein kinase G, p42/p44-
mitogen-activated protein kinase (ERK1/2) and
nitric oxide synthase, which have demonstrated anti-hyperalgesic effects in other models of metabolic and toxic painful
peripheral neuropathies, had no effect on ddC-, ddI- and d4T-induced
hypersensitivity. Since
suramin, an anti-parasitic and anti-
cancer drug, which shares with the anti-retroviral
nucleoside analogs, mitochondrial toxicity, altered regulation of intracellular
calcium, and a sensory neuropathy in humans, also produced mechanical
hypersensitivity that was not sensitive to the above second messenger inhibitors we evaluated the role of intracellular
calcium. Intradermal or
spinal injection of intracellular
calcium modulators (TMB-8 and Quin-2), which had no effect on nociception in control rats, significantly attenuated and together eliminated ddC and
suramin-induced mechanical
hypersensitivity. In electrophysiology experiments in ddC-treated rats, C-fibers demonstrated alterations in pattern of firing as indicated by changes in the distribution of interspike intervals to sustained suprathreshold stimuli without change in mechanical activation thresholds or in number of action potentials in response to threshold and suprathreshold stimulation. This study provides evidence for a novel,
calcium-dependent, mechanism for
neuropathic pain in a model of
AIDS therapy-induced painful
peripheral neuropathy.