Involvement of Spinal NR2B-Containing NMDA Receptors in Oxaliplatin-Induced Mechanical Allodynia in Rats

Abstract

BackgroundOxaliplatin 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.ResultsRepeated 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.ConclusionThese results indicated that spinal NR2B-containing NMDA receptors are involved in the oxaliplatin-induced mechanical allodynia.

Gabapentin Prevents Oxaliplatin-Induced Mechanical Hyperalgesia in Mice

“…In addition, oxaliplatin also enhance the generation of sodium channel resurgent current, which is also responsible for peripheral neural excitation (13). Phosphorylation of the NR2B subunit of the Nmethyldaspartate (NMDA) receptor is also increased after repeated treatment with oxaliplatin (14). Clinically, the calcium channel subunit a 2 d 1 blocker gabapentin, which is used as an antiepileptic drug, is widely prescribed for treatment of chronic pain.…”

Repeated Administration of Amitriptyline Reduces Oxaliplatin-Induced Mechanical Allodynia in Rats

“…once a day for 27 days (from day 1). The doses of these drugs were chosen based on previous reports (6,7,9). Behavioral tests were performed blindly with respect to drug administration.…”

“…H Sada et al 4,7,11,14, 18, and 21, test was performed before drug administration. Rats were placed in a clear plastic box (20 × 17 × 13 cm) with a wire mesh floor and allowed to habituate for 30 min prior to testing.…”

Integrins and Nitric Oxide in the Regulation of Glial Cells: Potential Roles in Pathological Pain

“…In conditions of pathological pain, altered states of synaptic transmission have been observed, including the following: an increase in neurotransmitter release from the primary afferent neurons [9,10]; activation of NMDA receptor in secondary neurons [14][15][16][17][18]; and activation of glial cell [1][2][3]5,[18][19][20][21][22][23]. All of these alterations favor intensification in synaptic transmission, thereby resulting in hyperalgesia and allodynia.…”

“…Activation of any of these steps can result in the onset of this vicious cycle. Expression of the NR2B-bearing NMDA receptor is known to be upregulated under the following settings: in chronic nerve constriction injury, in chronic compression of the dorsal root ganglia [24,25], and in oxaliplatin-induced neuropathic pain, in which NOS inhibition reduces pain levels [17].…”