Behavioral and immunohistological assessment of painful neuropathy induced by a single oxaliplatin injection in the rat.
In clinical use, a single infusion of oxaliplatin, widely used to treat metastatic colorectal cancer, induces specific sensory neurotoxicity signs triggered or aggravated by exposure to cold. To study the pathophysiology of these symptoms, we developed and characterized an animal model that reproduces the effects of a single intraperitoneal oxaliplatin administration (3, 6 and 12 mg/kg). Significant allodynia and hyperalgesia to cold stimuli were rapidly observed from 24 h to day 5 with a maximum lowering of 76% at t+30 h versus control. Other behavioral assessments revealed rapid persistent mechanical allodynia, but no thermal hyperalgesia or allodynia to heat and no hyperalgesia to mechanical stimuli. An immunohistochemical study in the superficial layers of the spinal dorsal horn revealed a marked increase in substance P immunoreactivity versus controls (12% versus 4%), whereas calcitonin gene-related peptide (CGRP) immunoreactivity was unchanged. This new animal model for the first time closely mimics the effects observed in humans after a single oxaliplatin infusion, especially onset and highly intense sensory disturbances, hypersensitivity to cold with allodynia and hyperalgesia signs. This model may help to elucidate the mechanisms of this thermal hypersensitivity, especially the possible involvement of small-diameter A-fibers in cold allodynia symptoms. These selective effects may clue up the mechanistic basis for the acute oxaliplatin neuropathy leading to a better understanding of the clinical condition and to optimize its treatment.
Ling
Bing
B
INSERM U766, F63001 Clermont-Ferrand, France.
Coudoré-Civiale
Marie-Ange
MA
Balayssac
David
D
Eschalier
Alain
A
Coudoré
François
F
Authier
Nicolas
N
D018712:Analgesics, Non-Narcotic / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents; D001522:Behavior, Animal / Q000187:drug effects*; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D002220:Carbamazepine / Q000494:pharmacology; D006930:Hyperalgesia / Q000139:chemically induced / Q000523:psychology; D007150:Immunohistochemistry; D008274:Magnesium / Q000494:pharmacology; D008297:Male; D009475:Neurons, Afferent / Q000187:drug effects; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D010146:Pain / Q000209:etiology* / Q000523:psychology*; D010147:Pain Measurement / Q000187:drug effects; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000473:pathology / Q000523:psychology*; D020671:Posterior Horn Cells / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013373:Substance P / Q000378:metabolism
D018712:Analgesics, Non-Narcotic; D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D013373:Substance P; D002220:Carbamazepine; D008274:Magnesium; D015740:Calcitonin Gene-Related Peptide