Involvement of spinal NR2B-containing NMDA receptors in oxaliplatin-induced mechanical allodynia in rats

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.These results indicated that spinal NR2B-containing NMDA receptors are involved in the oxaliplatin-induced mechanical allodynia.Glutamate is a major excitatory transmitter in the spinal cord and N-methyl-D-aspartate (NMDA) receptors are known to be involved in the painful neuropathy [1,2]. The NMDA receptor antagonist inhibits the pain hypersensitivity in chronic constriction injury (CCI) model. Moreover, the expression of spinal NR2B-containing NMDA receptors is increased with the pain hypersensitivity induced by CCI or chronic compression of the dorsal root ganglia (CCD) [3-6]. Selective NR2B antagonists inhibit mechanical allodynia without causing motor dysfunction in CCI, CCD and spinal nerve-ligated (SNL) neuropathic models [5-8]. In addition, the NR2B subunits are localized to the superficial dorsal horn of the spinal cord [7,9], suggesting a possible involvement in pain transmission. Thus, the NR2B-containing NMDA re