Nociceptor hyper-responsiveness during vincristine-induced painful peripheral neuropathy in the rat.
Neuropathic pain accompanies peripheral nerve injury after a wide variety of insults including metabolic disorders, traumatic nerve injury, and neurotoxic drugs. Chemotherapy-induced neuropathic pain, caused by drugs such as vincristine and taxol, occurs in cancer patients who receive these drugs as antineoplastic agents. Although a variety of remediations have been attempted, the absence of knowledge concerning mechanisms of chemotherapy-induced neuropathic pain has hindered the development of treatment strategies. Vincristine, a widely used chemotherapeutic agent, produces painful peripheral neuropathy in humans and mechanical hyperalgesia in rats. To test the hypothesis that alterations in C-fiber nociceptor function occur during vincristine-induced painful peripheral neuropathy, we performed in vivo extracellular recordings of single neurons from the saphenous nerve of vincristine-treated rats. Forty-one percent of C-fiber nociceptors were significantly hyper-responsive to suprathreshold mechanical stimulation. As a population, these mechanically hyper-responsive nociceptors also had significantly greater responses to suprathreshold heat stimulation; however, heat hyper-responsiveness was found only in a subset of these nociceptors and was never detected in the absence of mechanical hyper-responsiveness. In addition, mean conduction velocities of A-fibers and C-fibers in vincristine-treated rats were significantly slowed. Mean heat and mechanical activation thresholds of C-fiber nociceptors, their distribution among subclasses, and the percentage of spontaneously active neurons in vincristine-treated rats were not statistically different from controls. Vincristine does not, therefore, cause generalized impairment of C-fiber nociceptor function but rather specifically interferes with mechanisms underlying responsiveness to suprathreshold stimuli. Furthermore, vincristine-induced nociceptor hyper-responsiveness may involve alterations specifically in mechanotransduction in some nociceptors and alterations in general cellular adaptation mechanisms in others.
Tanner
K D
KD
Departments of Medicine, Anatomy, and Oral and Maxillofacial Surgery, Division of Rheumatology, and Program in Neuroscience, University of California, San Francisco, California 94143-0452, USA.
Reichling
D B
DB
Levine
J D
JD
D000818:Animals; D006358:Hot Temperature; D008297:Male; D009412:Nerve Fibers / Q000187:drug effects / Q000502:physiology; D009431:Neural Conduction / Q000187:drug effects; D009475:Neurons, Afferent / Q000187:drug effects / Q000502:physiology; D009619:Nociceptors / Q000187:drug effects / Q000502:physiology*; D010146:Pain / Q000139:chemically induced* / Q000503:physiopathology; D017288:Pain Threshold / Q000502:physiology; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000503:physiopathology; D010812:Physical Stimulation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014750:Vincristine / Q000494:pharmacology
D014750:Vincristine