title: Sensory neuron subpopulation-specific dysregulation of intracellular calcium in a rat model of chemotherapy-induced peripheral neuropathy.
abstract: The purpose of the present study was to test the prediction that the unique manifestation of chemotherapeutic-induced peripheral neuropathy (CIPN) would be reflected in a specific pattern of changes in the regulation of the intracellular Ca(2+) concentration ([Ca(2+)]i) in subpopulations of cutaneous neurons. To test this prediction, we characterized the pattern of changes in mechanical nociceptive threshold associated with paclitaxel administration (2mg/kg, iv, every other day for four days), as well as the impact of target of innervation and paclitaxel treatment on the regulation of [Ca(2+)]i in subpopulations of putative nociceptive and non-nociceptive neurons. Neurons innervating the glabrous and hairy skin of the hindpaw as well as the thigh were identified with retrograde tracers, and fura-2 was used to assess changes in [Ca(2+)]i. Paclitaxel was associated with a persistent decrease in mechanical nociceptive threshold in response to stimuli applied to the glabrous skin of the hindpaw, but not the hairy skin of the hindpaw or the thigh. However, in both putative nociceptive and non-nociceptive neurons, resting [Ca(2+)]i was significantly lower in neurons innervating the thigh after treatment. The magnitude of the depolarization-evoked Ca(2+) transient was also lower in putative non-nociceptive thigh neurons. More interestingly, while paclitaxel had no detectable influence on either resting or depolarization-evoked Ca(2+) transients in putative non-nociceptive neurons, in putative nociceptive neurons there was a subpopulation-specific decrease in the duration of the evoked Ca(2+) transient that was largely restricted to neurons innervating the glabrous skin. These results suggest that peripheral nerve length alone, does not account for the selective distribution of CIPN symptoms. Rather, they suggest the symptoms of CIPN reflect an interaction between the toxic actions of the therapeutic and unique properties of the neurons deleteriously impacted.
authors.affiliation: Center for Neuroscience, University of Pittsburgh, United States; Center for Pain Research, United States.
authors.forename: E
authors.initials: E
authors.lastname: Yilmaz
authors.affiliation: Center for Neuroscience, University of Pittsburgh, United States; Center for Pain Research, United States; Department of Anesthesiology, University of Pittsburgh School of Medicine, United States. Electronic address: msg22@pitt.edu.
authors.forename: M S
authors.initials: MS
authors.lastname: Gold
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000633:toxicity*; D002118:Calcium / Q000378:metabolism*; D004195:Disease Models, Animal; D005727:Ganglia, Spinal / Q000187:drug effects / Q000503:physiopathology; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D059226:Nociceptive Pain / Q000139:chemically induced / Q000503:physiopathology; D009619:Nociceptors / Q000187:drug effects* / Q000502:physiology; D017239:Paclitaxel / Q000633:toxicity*; D010147:Pain Measurement; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000503:physiopathology; D017207:Rats, Sprague-Dawley; D012867:Skin / Q000294:innervation; D014110:Touch
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D017239:Paclitaxel; D002118:Calcium
keywords: dorsal root ganglion; neuropathic pain; nociceptor; von Frey test