title: Differential pharmacological alleviation of oxaliplatin-induced hyperalgesia/allodynia at cephalic versus extra-cephalic level in rodents.
abstract: Previous data showed that neuropathic pain induced by mechanical lesion of peripheral nerves responds differently to alleviating drugs at cephalic versus extracephalic level. Because neuropathic pain evoked by anti-cancer drugs differs from that triggered by mechanical nerve lesion, we investigated whether differences between cephalic and extracephalic levels could also be characterized in rodents rendered neuropathic by treatment with the anti-cancer platinum derivative oxaliplatin. C57BL/6J mice received two injections and Sprague-Dawley rats three injections of oxaliplatin (10 mg/kg, i.p.) or its vehicle, with three days intervals. Supersensitivity to mechanical (von Frey filaments), cold (acetone drop) and chemical/inflammatory (formalin) stimulations was assessed in vibrissae and hindpaw territories. Transcripts of neuroinflammatory markers were quantified by real-time RT-qPCR in rat ganglia and central tissues. Oxaliplatin induced mechanical allodynia, cold hyperalgesia and chemical/inflammatory supersensitivity at both hindpaw and vibrissal levels in mice and rats. Acute treatment with gabapentin (30 mg/kg i.p.), morphine (3 mg/kg s.c.) or the 5-HT1A receptor agonist 8-OH-DPAT (0.16 mg/kg s.c.) significantly reduced oxaliplatin-induced supersensitivity in hindpaw but not vibrissal territory. In contrast, the antimigraine drugs naratriptan (0.1 mg/kg s.c.) and olcegepant (0.6 mg/kg i.v.) decreased oxaliplatin-induced supersensitivity in vibrissal territory only. Among the various markers investigated, only TRPA1 transcript was upregulated in ganglia of oxaliplatin-treated rats. These data showed that oxaliplatin induced supersensitivity to various stimuli in both cephalic and extra-cephalic territories in rodents. Regional differences in the efficacy of drugs to alleviate oxaliplatin-induced allodynia/hyperalgesia further support the idea that mechanisms underlying neuropathic pain have peculiarities at cephalic versus extra-cephalic level.
authors.affiliation: INSERM U894 - CPN, Université Pierre et Marie Curie - Paris 6, Faculté de Médecine Pierre et Marie Curie, Site Pitié-Salpêtrière, UMR S677, 91, Boulevard de l'Hôpital, Paris F-75013, France. Electronic address: bemichot@yahoo.fr.
authors.forename: Benoit
authors.initials: B
authors.lastname: Michot
authors.affiliation: INSERM U894 - CPN, Université Pierre et Marie Curie - Paris 6, Faculté de Médecine Pierre et Marie Curie, Site Pitié-Salpêtrière, UMR S677, 91, Boulevard de l'Hôpital, Paris F-75013, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Kayser
authors.affiliation: Département de Pharmacologie, Université Pierre et Marie Curie - Paris 6, Faculté de Médecine Pierre et Marie Curie, Site Pitié-Salpêtrière, 91, Boulevard de l'Hôpital, Paris F-75013, France.
authors.forename: Gérard
authors.initials: G
authors.lastname: Bastian
authors.affiliation: INSERM U894 - CPN, Université Pierre et Marie Curie - Paris 6, Faculté de Médecine Pierre et Marie Curie, Site Pitié-Salpêtrière, UMR S677, 91, Boulevard de l'Hôpital, Paris F-75013, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Bourgoin
authors.affiliation: INSERM U894 - CPN, Université Pierre et Marie Curie - Paris 6, Faculté de Médecine Pierre et Marie Curie, Site Pitié-Salpêtrière, UMR S677, 91, Boulevard de l'Hôpital, Paris F-75013, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Hamon
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000008:administration & dosage; D000588:Amines / Q000008:administration & dosage; D000700:Analgesics / Q000008:administration & dosage*; D000818:Animals; D003080:Cold Temperature; D003509:Cyclohexanecarboxylic Acids / Q000008:administration & dosage; D004151:Dipeptides / Q000494:pharmacology; D005557:Formaldehyde; D000077206:Gabapentin; D005727:Ganglia, Spinal / Q000187:drug effects / Q000503:physiopathology; D006930:Hyperalgesia / Q000188:drug therapy* / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009020:Morphine / Q000008:administration & dosage; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D010879:Piperazines; D010880:Piperidines / Q000008:administration & dosage; D011799:Quinazolines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000187:drug effects / Q000503:physiopathology; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels / Q000378:metabolism; D014110:Touch; D014363:Tryptamines / Q000008:administration & dosage; D005680:gamma-Aminobutyric Acid / Q000008:administration & dosage
chemical_list: D000588:Amines; D000700:Analgesics; D003509:Cyclohexanecarboxylic Acids; D004151:Dipeptides; D009944:Organoplatinum Compounds; D010879:Piperazines; D010880:Piperidines; D011799:Quinazolines; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels; C480976:Trpa1 protein, rat; D014363:Tryptamines; D000077150:Oxaliplatin; D005557:Formaldehyde; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D009020:Morphine; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; C106783:naratriptan; C406305:olcegepant
keywords: Cold hyperalgesia; Inflammatory pain; Mechanical allodynia; Neuropathic pain; Oxaliplatin; Rodents