Involvement of spinal NR2B-containing NMDA receptors in oxaliplatin-induced mechanical allodynia in rats.
BACKGROUND
Oxaliplatin is a platinum-based chemotherapy drug characterized by the development of acute and chronic peripheral neuropathies. The chronic neuropathy is a dose-limiting toxicity. We previously reported that repeated administration of oxaliplatin induced cold hyperalgesia in the early phase and mechanical allodynia in the late phase in rats. In the present study, we investigated the involvement of NR2B-containing N-methyl-D-aspartate (NMDA) receptors in oxaliplatin-induced mechanical allodynia in rats.


RESULTS
Repeated administration of oxaliplatin (4 mg/kg, i.p., twice a week) caused mechanical allodynia in the fourth week, which was reversed by intrathecal injection of MK-801 (10 nmol) and memantine (1 μmol), NMDA receptor antagonists. Similarly, selective NR2B antagonists Ro25-6981 (300 nmol, i.t.) and ifenprodil (50 mg/kg, p.o.) significantly attenuated the oxaliplatin-induced pain behavior. In addition, the expression of NR2B protein and mRNA in the rat spinal cord was increased by oxaliplatin on Day 25 (late phase) but not on Day 5 (early phase). Moreover, we examined the involvement of nitric oxide synthase (NOS) as a downstream target of NMDA receptor. L-NAME, a non-selective NOS inhibitor, and 7-nitroindazole, a neuronal NOS (nNOS) inhibitor, significantly suppressed the oxaliplatin-induced pain behavior. The intensity of NADPH diaphorase staining, a histochemical marker for NOS, in the superficial layer of spinal dorsal horn was obviously increased by oxaliplatin, and this increased intensity was reversed by intrathecal injection of Ro25-6981.


CONCLUSIONS
These results indicated that spinal NR2B-containing NMDA receptors are involved in the oxaliplatin-induced mechanical allodynia.
Department of Pharmacy, Kyushu University Hospital, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Yuki
Y
Mihara
Nobuaki
N
Egashira
Hikaru
H
Sada
Takehiro
T
Kawashiri
Soichiro
S
Ushio
Takahisa
T
Yano
Hiroaki
H
Ikesue
Ryozo
R
Oishi
D000818:Animals; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006930:Hyperalgesia / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D007191:Indazoles / Q000494:pharmacology; D008297:Male; D008559:Memantine / Q000494:pharmacology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D010636:Phenols / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013116:Spinal Cord / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology
D004791:Enzyme Inhibitors; D007191:Indazoles; C121001:NR2B NMDA receptor; D009944:Organoplatinum Compounds; D010636:Phenols; D010880:Piperidines; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; C109643:Ro 25-6981; D000077150:Oxaliplatin; D016291:Dizocilpine Maleate; D019001:Nitric Oxide Synthase; C010739:ifenprodil; C080122:7-nitroindazole; D019331:NG-Nitroarginine Methyl Ester; D008559:Memantine
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