Supraspinal role of protein kinase C in oxaliplatin-induced neuropathy in rat.
Oxaliplatin is a platinum-based chemotherapy drug characterized by the development of a painful peripheral neuropathy which is reproduced in rodent animal models with features observed in humans. Our focus was to explore the alterations of intracellular second messengers at supraspinal level in oxaliplatin-induced mechanical hyperalgesia. In our experiments, chronic administration of oxaliplatin to rats induced mechanical hyperalgesia which lasted for many days. When the hyperalgesic rats were submitted to paw pressure test in the presence of selective PKC inhibitor Calphostin C supraspinally administered, hyperalgesic effect could be reversed showing that PKC activity in supraspinal brain regions is needed. Concurrently, oxaliplatin chronic treatment induced a specific upregulation of gamma isoforms of PKC and increased phosphorylation of gamma/epsilon PKC isoforms within thalamus and PAG. Phosphorylation was reversed when PKC activity was inhibited by Calphostin C. Distinct PKC-activated MAPK pathways, including p38MAPK, ERK1/2 and JNK, were investigated in chronic oxaliplatin rat. A dramatic phosphorylation increase, Calphostin C sensitive, could be observed in thalamus and PAG for p38MAPK. These data show that, in oxaliplatin-induced neuropathy, enhanced mechanical nociception is strictly correlated with increased phosphorylation of specific intracellular mediators in PAG and thalamus brain regions pointing to a role of these supraspinal centers in oxaliplatin-induced neuropathic pain mechanism.
Norcini
M
M
Department of Clinical and Preclinical Pharmacology, University of Florence, Italy.
Vivoli
E
E
Galeotti
N
N
Bianchi
E
E
Bartolini
A
A
Ghelardini
C
C
D000818:Animals; D000970:Antineoplastic Agents; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006930:Hyperalgesia / Q000139:chemically induced / Q000503:physiopathology; D007276:Injections, Intraventricular; D008297:Male; D009281:Naphthalenes / Q000494:pharmacology; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D010147:Pain Measurement; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced / Q000503:physiopathology*; D010766:Phosphorylation; D010812:Physical Stimulation; D004856:Postural Balance / Q000187:drug effects; D011312:Pressure; D011493:Protein Kinase C / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015290:Second Messenger Systems; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D009281:Naphthalenes; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D011493:Protein Kinase C; C058819:calphostin C