ABSTRACT
BACKGROUND: This study investigated the role of NR2B in a modulated pain process in the painful diabetic neuropathy (PDN) rat using various pain stimuli. METHODS: Thirty-two Sprague-Dawley male rats were randomly allocated into four groups (n=8): control, diabetes mellitus (DM) rats and diabetic rats treated with ifenprodil at a lower dose (0.5 µg/day) (I 0.5) or higher dose (1.0 µg/day) (I 1.0). DM was induced by a single injection of streptozotocin at 60 mg/kg on day 0 of experimentation. Diabetic status was assessed on day 3 of the experimentation. The responses on both tactile and thermal stimuli were assessed on day 0 (baseline), day 14 (pre-intervention), and day 22 (post-intervention). Ifenprodil was given intrathecally for 7 days from day 15 until day 21. On day 23, 5% formalin was injected into the rats' hind paw and the nociceptive responses were recorded for 1 hour. The rats were sacrificed 72 hours post-formalin injection and an analysis of the spinal NR2B expression was performed. RESULTS: DM rats showed a significant reduction in pain threshold in response to the tactile and thermal stimuli and higher nociceptive response during the formalin test accompanied by the higher expression of phosphorylated spinal NR2B in both sides of the spinal cord. Ifenprodil treatment for both doses showed anti-allodynic and anti-nociceptive effects with lower expression of phosphorylated and total spinal NR2B. CONCLUSION: We suggest that the pain process in the streptozotocin-induced diabetic rat that has been modulated is associated with the higher phosphorylation of the spinal NR2B expression in the development of PDN, which is similar to other models of neuropathic rats.
Subject(s)
Animals , Humans , Male , Rats , Diabetes Mellitus , Diabetic Neuropathies , Formaldehyde , Hyperalgesia , N-Methylaspartate , Pain Measurement , Pain Threshold , Phosphorylation , Rats, Sprague-Dawley , Receptors, N-Methyl-D-Aspartate , Spinal Cord , StreptozocinABSTRACT
Ifenprodil, NMDA receptor antagonist, was very effective in the treatment of 3 patients with severe trigeminal neuralgia. <b>Patient 1</b>：A 70-year-old female had been treated for macroglobulinemia in our hospital. She had been suffered from severe trigeminal neuralgia for more than ten years. Carbamazepine given in another hospital was ineffective. We gave ifenprodil to her and it reduced her pain within 4 weeks. However, her pain relapsed after 1.5 years, so we gave pregabalin instead of ifenprodil to her. <b>Patient 2</b>：A 89-year-old male had been treated for myelodysplastic syndrome in our hospital. He also had been treated for trigeminal neuralgia in another hospital. Carbamazepine was ineffective and nerve block relieved his pain temporarily. We gave ifenprodil to him and it reduced his pain within 2 months. <b>Patient 3</b>：A 62-year-old female was referred to our hospital for the treatment of trigeminal neuralgia. She had been suffered from severe pain for about 10 years. She had taken carbamazepine with no effect. We gave ifenprodil to her and it reduced her pain within 4 weeks. Ketamin, non-selective NMDA receptor antagonist, is known to be effective in neuropathic pain, but it has various side effects. Ifenprodil, specific NMDA receptor subunit NR2B antagonist, may show better separation between efficacy and side effects.
ABSTRACT
Objective To investigate whether blocking NR2B receptor can reverse the process of cytotoxicity to spiral ganglion neurons induced by sodium salicylate in guinea pig by applying ifenprodil (a NR2B antagonist) at the round window niche .Methods Sixty healthy guinea pigs provided by the experimental animal center of Guangxi medical university were randomly and evenly divided into a control group (Group I ,no treatment) ,an APL group (Group II ,60μl APL directly applied to the round window ) ,a sodium salicylate group (Group III ,60 μl APL di-rectly applied to the round window and then be given intraperitoneal sodium salicylate injection ) ,and an ifenprodil group (Group IV ,60μl of 10μmol/l ifenprodil in APL directly applied to the round window and then be given intra-peritoneal sodium salicylate injection ) .Sodium salicylate was given at 400 mg · kg -1 · d-1 for 7 days .Auditory brainstem responses (ABRs) were recorded before animal sacrifice by decapitation .The left cochlea was removed and prepared for detection of caspase -3 expression in spiral ganglion neurons via immunohistochemistry .From each group ,6 cochleae were used to test apoptosis index in spiral ganglion neurons using the TUNEL technique .Results Before salicylate administration ,the ABR threshold was less than 40 dB SPL in all animals .After salicylate ad-ministration ,the ABR threshold was 33 .33 ± 5 .17 dB SPL in Group II ,64 .17 ± 7 .36 dB SPL in Group III and 49 .17 ± 5 .85 dB SPL in Group IV ,in contrast to 31 .67 ± 5 .16 dB SPL in Group I (controls) .The caspase -3 ex-pression was not changed obviously in Group I and Group II ,but was significantly changed in Group III and Group IV (P<0 .01) .The caspase-3 expression appeared to be decreased in Group IV compared to those in Groups III (P<0 .05) ,but still increased compared to those of in Group I and II (P<0 .05) .The apoptosis index among spiral ganglion neurons in Groups III and IV increased significantly compared to those of in Group I and II (P<0 .001) .It was however ,lower in Group IV than in Group III (P<0 .01) .Conclusion Blocking NR2B receptor with specificity can reverse the process of cytotoxicity to spiral ganglion neurons induced by sodium salicylate in guinea pig .
ABSTRACT
Objective To investigate the effect of ifenprodil in the mice of bone cancer pain.Methods 96 male C3H/HeJ mice were divided randomly into tumor group( Group T),control group( Group C) and sham group( Group S).The α-minimal essence media(ct-MEM) with 2 × l05 osteosarcoma NCTC 2472 cells were implanted into the intramedullary space of the right femurs of mice to induce ongoing bone cancer related pain behaviors.The sham group was inoculated by α-MEM without any cells.On the 14th d after inoculation,pain ethology indexes such as the spontaneous lifting behaviors,the paw withdrawal mechanical threshold(PWMT) and the paw withdrawal thermal latency (PWTL)were observed on 1 d before inoculation and on 3 d,5 d,7 d,10 d,14 d,17 d,19 d,23 d after inoculation.Lumbar intumescentia of mice in each group were taken out to investigate the expression level of NR2B western blot after pain behaviors tests at the same time point after intrathecal injection.Results ( 1 ) At day14 after the operation,the obvious increasing of spontaneous lifting behaviors ( ( 12.88 ±1.64) ) and the expression of NR2B (2.12 ±0.13),the significant decreasing of PWMT( (0.39 ±0.17)g) and PWTL( ( 11.59 ± 1.67 ) s ) were observed in group T compared with group S and preoperative base level (P ＜ 0.05 ).(2) At day 17,day 19 and day 23 after the operation,compared with the basal level of dayl4 before administration and group C,the spontaneous lifting behaviors ( (5.13 ± 1.38),(4.70 ± 1.58),(5.64 ± 1.17) ) of group T were obviously decreased,PWMT ( ( 1.10 ± 0.65 ) g,( 0.95 ± 0.56 ) g,( 1.05 ± 0.26 ) g) and PWTL ( ( 15.17 ± 1.27) s,( 15.93 ± 2.18 ) s,( 16.28 ± 1.48 ) s ) were increased,the expression of NR2B ( ( 1.42 ± 0.17),(1.67 ±0.53),(1.14 ±0.79) ) were significantly decreased(P＜0.05).Conclusion Repeated intratheal injection of ifenprodil can efficiently relieve spontaneous lifting behaviors,mechanical hyperalgia and thermal hyperalgia and decrease the expression of lumbar intumescentia NR2B in the mouse model of bone cancer pain.