Novel mechanism of enhanced nociception in a model of AIDS therapy-induced painful peripheral neuropathy in the rat.
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.
Joseph
Elizabeth K
EK
Department of Medicine, Division of Neuroscience and Biomedical Sciences Program, and UCSF-NIH-Pain Center, University of California, San Francisco, CA 94143-0440, USA. aley@itsa.ucsf.edu
Chen
Xiaojie
X
Khasar
Sachia G
SG
Levine
Jon D
JD
D000634:Aminoquinolines / Q000627:therapeutic use; D000818:Animals; D019380:Anti-HIV Agents / Q000009:adverse effects*; D000970:Antineoplastic Agents / Q000009:adverse effects; D001522:Behavior, Animal; D002121:Calcium Channel Blockers / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005071:Evoked Potentials / Q000187:drug effects; D005707:Gallic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D036421:Nerve Fibers, Unmyelinated / Q000187:drug effects; D009431:Neural Conduction / Q000187:drug effects; D010146:Pain / Q000139:chemically induced* / Q000188:drug therapy; D010147:Pain Measurement / Q000187:drug effects; D017288:Pain Threshold / Q000187:drug effects; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000188:drug therapy; D051381:Rats; D017207:Rats, Sprague-Dawley; D018894:Reverse Transcriptase Inhibitors / Q000009:adverse effects*; D013498:Suramin / Q000009:adverse effects
D000634:Aminoquinolines; D019380:Anti-HIV Agents; D000970:Antineoplastic Agents; D002121:Calcium Channel Blockers; D004791:Enzyme Inhibitors; D018894:Reverse Transcriptase Inhibitors; C006014:8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate; D013498:Suramin; D005707:Gallic Acid; C035739:Quin2