Antinociceptive effects of oxymatrine from Sophora flavescens, through regulation of NR2B-containing NMDA receptor-ERK/CREB signaling in a mice model of neuropathic pain.
Oxymatrine from Sophora flavescens
Chronic constrictive injury
Purpose: In this study we investigated a ntinociceptive effects of oxymatrine through regulation of NR2B-containing NMDA receptor-ERK/CREB signaling in a chronic neuropathic pain model induced by chronic constrictive injury (CCI) of the sciatic nerve.
Methods: The von Frey and plantar tests were performed to assess the degree of mechanical and thermal changes respectively. Immunohistochemistry assay was used to evaluate the expressions of NR2B. Western blotting assay were used to evaluate the expressions of NR2B, tERK, p-ERK, tCREB and p-CREB. Results: The intraperitoneal administration of OMT (160, 80 mg/kg) could prevent the development of mechanical allodynia, thermal hyperalgesia induced by CCI. Intraperitoneal administration of OMT decreased the mean IOD of NR2B in the dorsal horn and expression of NR2B, p-ERK and p-CREB protein.
Conclusion: Regulation of NMDA NR2B receptor-ERK/CREB signaling maybe the targets for the antinoci-ceptive effects of OMT on a chronic neuropathic pain model induced by chronic constrictive injury of the sciatic nerve.
[c] 2013 Elsevier GmbH. All rights reserved.
Neuropathic pain associated with peripheral nerve injury is particularly debilitating and characterized by allodynia, hyperalgesia and spontaneous pain (Dworkin et al. 2003). It is a major chronic pain condition that is severe and intractable and continues to pose a major challenge clinically (Carlton et al. 2009). The traditional analgesics and nonpharmacological treatments have only achieve clinically significant (greater than 50%) pain relief in less than 50% of patients and are associated with sub-optimal side effect profiles (Attal et al. 2010; Dworkin et al. 2003; Bridges et al. 2001). Oxymatrine (OMT), a natural quinolizidine alkaloid, is the main basic constituents derived from the root of Sophora flavescens, a Chinese traditional medicine (Fig. 1). Recent study has been reported that OMT protects neurons through down-regulation of NR2B-containing NMDARs (Zhang et al. 2012). Previous studies in our laboratory found that OMT through down-regulate the expression of GAT-1 and up-regulate the expression of GABAAR[alpha]2 mediate its effect on neuropathic pain (Liu et al. 2012). However, little is known regarding the antinociceptive effect of OMT with glutamate, which is a principal excitatory neurotransmitter in the central nervous system (CNS).
The excitatory amino acid glutamate is the major excitatory neurotransmitter released at the central terminals of primary afferent nociceptive neurons after noxious stimulation (Bridges et al. 2001). Glutamate accumulation and excessive stimulation of its receptors induce potent excitotoxicity in the CNS (Fundytus 2001). N-methyl-D-aspartate receptors (NMDARs) play a key role in mediating glutamate excitotoxicity because their high calcium permeability (Hardingham and Bading 2003). Indeed, excitotoxicity is triggered by the selective activation of NMDARs containing the NR2B subunits (von Engelhardt et al. 2007). NMDA-induced [Ca.sup.2+] influx, which activates various [Ca.sup.2+]-dependent kinases to initiate the MAPK signaling cascade in the spinal dorsal horn neurons (Wang et al. 2007: Ji et al. 2009). Additionally, NMDARs activate ERK via both PKA and PKC, which contributes to central sensitization through the cAMP response element-binding protein (CREB)-mediated transcriptional or non-transcriptional regulation (Ji et al. 2009; Kawasaki et al. 2004).
In this study, we tested the hypothesis that the antinociceptive effects of OMT on neuropathic pain through regulation of NR2B-containing NMDA receptor-ERK/CREB signaling.
Materials and methods
Animals and neuropathic pain model
All experimental procedures were conducted in accordance with the recommendations of the International Association for the Study of Pain and the National Institute of Health Guide for the Care and Use of Laboratory Animals. All experimental protocol was duly reviewed and approved by the institutional animal ethics committee. Male ICR mice weighing between 21 and 25g were purchased from the Experimental Animal Center of Ningxia Medical University (Certificate number was SYXK Ningxia 2005-0001). Neuropathic pain was induced by the chronic constriction of the sciatic nerve (CCI), which was employed according to methods described by Bennett and Xie (1988). Briefly, mice were anaesthetized by an intraperitoneal (i.p.) injection of sodium pentobarbital (1%). The biceps femoris and the gluteus superficialis were separated by blunt dissection, and the right sciatic nerve was exposed. Close to the bifurcation, about 7 mm of the nerve was freed, and three the ligatures (4/0 silk) were tied loosely around the nerve with 1 mm spacing. After performing nerve ligation, the muscular and skin layer was immediately sutured with thread and a topical antibiotic was applied at once. In sham-operated controls, an identical surgical procedure was performed, except that the sciatic nerve was not ligated (Hervera et al. 2010).
OMT was purchased from Zi Jin Hua Pharmaceutical Co., Ningxia, China (purity >98.3%). Sodium pentobarbital was obtained from Sigma-Aldrich Co. OMT was prepared freshly everyday immediately before administration and was diluted in 0.9% saline. Both OMT and sodium pentobarbital were injected intraperitoneally (i.p.) in an application volume of 0.1 ml/10 g body weight. N-Methyl-D-aspartic acid (NMDA, purity >98%), dizocilpine (MK801, purity>98%) and ifenprodil (purity >98%) were obtained from Sigma-Aldrich Co. For intrathecal administration, NMDA, MK801 and ifenprodil were in a 5-[micro]l volume of solution, or vehicle (normal saline or 5% DMSO) in an equal volume. The doses of OMT (35-160 mg/kg) were selected based on the results of our preliminary experiments (Liu et al. 2012).
The mouse was held firmly by pelvic girdle in one hand while the syringe was held in the other hand at an angle of about 20 above the vertebral column. The microinjector was inserted into one side of the tissue of the L5 spinous process so that the injector slipped into the groove between L5 and L6. The microinjector was then moved carefully forward to the intervertebral space as the angle of the syringe was decreased to about 10[degrees]. About 0.5cm of the microinjectors tip was inserted into the vertebral column, and 5[micro]l was injected. Then the microinjector was withdrawn with a rotation after 10s of injection (Hylden and Wilcox 1980).
Measurements of mechanical allodynia
Mechanical allodynia was assessed by using von Frey filaments. In brief, mice were placed in Plexiglas[R] box (20 cm high, 9 cm diameter) with a wire mesh grid that allowed their paws access to the von Frey filaments (North Coast Medical, Inc., San Jose, CA, USA). Bending forces ranging from 0.008 to 3.5g were applied by using a modified version of the up-down paradigm, as previously reported by Chaplan et al. (1994). Beginning with the 0.4g force, the filament was vertically stimulated between the third and fourth metatarsus or lateral plantar until it bowed slightly. The 4.0g filament was used as a cut-off. Each filament was tested 5 times, at an interval of at least 3s. Nociceptive behavior responses appearing three or more times were record as a positive reaction. Then, the strength of the next filament was decreased or increased according to the response (Hervera et al. 2010). The baseline values were between 1.3 and 1.5g.
Measurements of thermal hyperalgesia
Thermal hyperalgesia were assessed with the paw withdrawal latency (PWL) to radiant heat according to the protocol of Hervera et al. (2010). Mice were placed in a PL-200 Plantar Analgesia Tester (Chengdu Technology & Market CO., Ltd., Sichuan, China) positioned on a glass surface, and were allowed to adapt to the apparatus for at least 10 min before measurements every time. The radiant heat lamp source was positioned under the plantar surface of the hind paw and was adjusted vertically to project a light spot of 5-mm in diameter onto the glass plate. The mean paw withdrawal latencies from the operated side hind paws were determined from the average of 3 separate trials, taken at 5 min intervals to prevent thermal sensitization and behavioral disturbances. The cut-off time was 12 s to prevent tissue damage.
The experiments were divided into -five groups with 10 mice in each group, as follows: sham-operate group, animals treated with saline i.p.: CCI group, animals treated with saline i.p.; different OMT dosage groups, animals treated with OMT i.p. 40, 80, and 160 mg/kg, respectively. OMT was administered for 7 consecutive clays in mice subjected to CCI, starting from the 8th day after the surgery. The behavior tests were performed one day prior to surgery as referred to day 0 and 7, 8, 10, 12 and 14 days thereafter, 60 min after injection. Both OMT and saline were given in an application volume of 0.1 ml/10g body weight.
Effects of a specific NMDAR agonist NMDA, a noncompetitive NMDA receptor antagonist MK801 and a selective antagonist of NMDA receptors containing the NR2B subunit ifenprodil on the antinociception of i.p. OMT
Mice were divided into nine groups with 10 mice in each group: NMDA (50 ng/site, ith) + NS (i.p.) group, NM DA (50 ng/site, ith) + OMT (160 mg/kg, i.p.)group, MK801 (1.5 [micro]g/site, ith) + NS(i.p.) group, MK801 (1.5 [micro]g/site, ith) + OMT (35 mg/kg, i.p.) group, ifenprodil (1.5 [micro]g/site, ith) + NS (i.p.)group, ifenprodil (1.5 [micro]g/site, ith) + 0MT (35 mg/kg, i.p.) group, NS (ith) + OMT (35 mg/kg, i.p.) group, NS (ith) + OMT (160 mg/kg, i.p.) group and NS (ith) + NS (i.p.) as a control group. All the agonists and antagonists were given 45 min on the 14th day after OMT i.p.: OMT (35 mg/kg and 160 mg/kg, i.p.) and NS (i.p.) were given in an application volume of 0.1 ml/10 g body weight, while NS (ith) was given in a 5-[micro]1 volume. Paw withdrawal threshold was measured and recorded in each group as described in measurements of mechanical allodynia.
In this test, 21 mice were divided into three groups with 7 mice in each group: OMT, CCI, and sham-operated group. OMT group was treated i.p. OMT 160 mg/kg, the sham-operated and CCI groups received a similar volume of 0.9% NaCl solution (10 ml/kg). On the 14th day after the surgery, 60 min after injection, animals were deeply anaesthetized i.p. in a volume of 0.1 ml/10g pentobarbital sodium (1%). Immunohistochemistry studies were performed as previously described (Zhou et al. 2010). Briefly, the lumbar spinal cord was cut into 4 [micro]m-thick segments. After washing in phosphate buffer saline, the tissue sections were incubated in phosphate-buffered saline containing 5% normal goat serum at room temperature for 30 min, followed by primary polyclonal rabit-anti-NMDAR2B antibody (1:400 in PBS, Abcam, Inc., USA), at 4 [degrees]C for 24h. The sections were then incubated at 37 [degrees]C for 2h with the secondary antibody (goat anti-rabbit IgG) and avidin-biotin complex (ABC) Specimens were then washed as before and visualized in 3, 3'-diaminobenzidine (DAB; Boster, Ltd., China). Finally, sections were rinsed in phosphate-buffered saline to stop the reaction, mounted on gelatin-coated slides, air-dried, dehydrated with 70-100% alcohol, cleared with xylene, and cover-slipped for microscopic examination.
Western blot analysis
Animals, preparatory drugs, and groups of experiments were as described for the test of Immunohistochemistry. On the 14th day after the surgery, 60 min after injection, mice were killed immediately and the lumbar spinal cord segments (L4-L5) were taken out. Samples were frozen in liquid nitrogen. To quantify temporal changes of the protein levels of N-methyl-D-aspartate (NMDA) receptor subtypes NR2B, extracellular signal-regulated kinases (ERK), cyclic adenosine monophosphate (cAMP) response element-building (CREB) in rat spinal cord, whole-cell protein extract lysates were used. Membrane extracts from the lumbar spinal cord were prepared using cell lysis buffer for Western (Biotype Institute of Biotechnology, Jiang Su, China). Tissue was homogenized in a Dounce homogenizer in 600[micro]l cell lyses buffer with 6[micro]l of 1[micro]M PMSF for 60 mg tissue. Homogenates were centrifuged at 12,500 x g for 60 min at 4 [degrees]C. Protein content was assayed using the BCA protein assay (Beyotime Institute of Biotechnology). 15[micro]g of total protein was separated in 7.5% SDS-PAGE polyacrylamide gels at 60 V for 150 min. Following the transfer onto PVDF membranes, the membranes were blocked by Tris--buffered saline containing 7.5% nonfat dry milk, 10 mmol/L Tris--HCI (pH 7.5), and 0.15% Tween-20 for 2 h, then incubated over night at 4 [degrees]C with primary antibodies: NMDAR2B, 1:100 from Abcam, p44/42 MAPK (Erkl /2) (137F5) 1:500; phosphorylation of ERK (pERK)(Thr202/yr204), 1:500; CREB (48H2) 1:500; Phospho-CREB (Ser133) (87G3) 1:500, from Cell Signaling Technology (Danvers, MA, USA); the membranes were washed with PBS-Tween and then incubated with a peroxidase-conjugated secondary antibody (1:2000; ZSGB-B10) at 37 [degrees]C for 3h. Supersignal West Pico chemiluminescent substrate (Pierce Biotechnology) was used for chemiluminescent detection. To ensure the analysis in a linear range, films were exposed for various times. The quantification of immunoreactive bands was performed using Quantity One 4.31 software (Bio-Rad).[beta]-actin expression was used as an internal control all the time. Relative protein expression was analyzed: relative protein expression = (optical density value of gen band of the object protein)/(optical density value of gel band of [beta]-actin).
The analyses were performed using SPSS 11.5 software. For behavioral studies, the data of paw withdrawal thresholds and paw withdrawal latency passed normality tests, thus were suitable for parametric statistics. The data were analyzed by two-way ANOVA followed by the Turkey's test for post hoc analysis. The immunohistochemistry and Western blot data were analyzed with one-way ANOVA followed by LSD post hoc test. All the data were presented as mean [+ or -] SD, and p-value < 0.05 or less was considered statistically significant in all cases.
OMT treatment on CCI-induced mechanical allodynia and thermal hyperalgesia
Seven days after surgery, when compared with sham operated group, mice subjected to CCI produced long-lasting and rapid-onset mechanical allodynia and thermal hyperalgesia. When compared with the CCI group treated with saline, the development of mechanical allodynia and thermal hyperalgesia was significantly attenuated by intraperitoneal administration of OMT 160 mg/kg from on Day 8 (F (1, 18) = 38.668, p<0.001 and F (1, 18) = 63.343, p < 0.001) to Day 14 (F (1. 18)=40.203, p <0.001 and F (1, 18) = 166.577, p < 0.001). To a lesser extent, OMT (80 mg/kg) treatment prevented CCI-associated decreases in paw withdrawal threshold and increased paw withdrawal latency from on day 7 to day 14 in CCI rats (Fig. la and b). OMT (40 mg/kg) treatment did not reduce analgesic effects on mechanical allodynia, which was similar to that on the thermal hyperalgesia (Fig. 2a and b). These results indicate that OMT treatment, applied in the seventh day after nerve injury for seven consecutive days can effectively attenuate severity and shorten duration of neuropathic pain.
To test our hypothesis that the antinociceptive effect of OMT could affect NMDAR in neuropathic pain, we administered NMDA, a specific agonist of the NMDAR, MK-801, a noncompetitive NMDAR antagonist, ifenprodil which was a selective antagonist of NMDAR containing the NR2B subunit. Behavioral tests in Fig. 3 a revealed that intraperitoneal treatment with OMT (160 mg/kg) produced a significant increase in the paw withdrawal threshold, while NMDA (50 ng/site, ith) significantly reduced the OMT-induced antinociception, F (3, 36) = 55.377, p <0.001. The results presented in Fig. 3b and c show that OMT (35 mg/kg, i.p.), MK801 (1.5 [micro]g/site, ith), and ifenprodil (1.5 [micro]g/site, ith) did not affect the paw withdrawal thresholds alone, but the combination of OMT and MK801 caused significant inhibition of the nociceptive response induced by von frey filaments, F (3, 36) = 14.252, p < 0.001. The paw withdrawal threshold after the combination of OMT and infenprodil also showed a significantly larger increase than that seen after OMT alone, F (3, 36) = 10.491, p < 0.001. These data suggested that OMT could successfully prevent CCI-induced mechanical allodynia in the spinal dorsal horn through blocking NMDAR, more precisely, NR2B-containing NMDAR.
Effect of OMT on CCI-induced NR2B expression in the spinal cord
The effect of OMT treatment on NR2B expression was determined in the superficial dorsal horn Laminae I-III of the lumbar enlargement, areas involved in the transmission of nociceptive inputs and control of sympathetic outflow (Furst 1999). NR2B expression was weak in the sham group. The expression of NR2B in the superficial dorsal horn of the CCI group was increased significantly when compared to the sham group. The expression of OMT group obviously decreased when compared with the CCI group (Fig. 4A). Similar to the results of the immunohistochemical studies, the Western blot results showed that CCI significantly increased the expression of NR2B protein in the spinal cord when compared with sham group. Intraperitoneal injection of OMT 160 mg/kg significantly inhibited the increase of NR2B protein expression (Fig. 4B). These data further confirmed that NR2B-containing NMDAR plays an important role in antinociceptive effects of OMT in CCI-induced neuropathic pain.
Effects of OMT on CCI-induced pERK and pCREB expression in the spinal cord
CCI-induced ERK activation was confirmed by Western blot analysis. Compared with sham group mice, the levels of phospho-ERK, not unphospho-ERK, were increased on the 14th day after CCI (Fig. 5A). Intraperitoneal injection of OMT 160 mg/kg markedly inhibited the increase in pERK expression. The Western blot results further showed that pCREB was highly expressed on CCI. Intraperitoneal injection of OMT 160 mg/kg significantly inhibited the increase of pCREB expression (Fig. 5B). These data suggest that activation of FRK contributes to increased pCREB expression in the spinal cords of CCI rats.
In the present study, the mice subjected to CCI showed significant mechanical allodynia and thermal hyperalgesia, which became observable on postoperative day 7 and continued until postoperative day 14. The Bennett chronic constriction injury model is one of the most commonly employed neuropathic animal model of nerve damaged-induced allodynia/hyperalgesia that closely mimic many features of clinical neuropathic pain (Jaggi and Singh 2010; Decosterd and Woolf 2000). Our study demonstrates that OMT therapy can significantly attenuate neuropathic pain in animals with peripheral nerve injury. OMT therapy produces a long-lasting and rapid-onset inhibition of mechanical allodynia and thermal hyperalgesia in mice after nerve injury.
The role that central sensitization and the NMDA receptor have in pathological pain is highlighted by studies that show blocking of central sensitization with NMDA antagonists abolishes pain hypersensitivity in patients with neuropathic pain. (Nelson et al. 1997). The evidence of involvement of excitatory amino acids in neuropathic pain has also prompted studies on drugs with an NMDA-antagonistic effect (Max et al. 1995; Felsby et al. 1996). Clinical trial of the identified NR2B-selective NMDAR antagonists showed that the compound did not produce the side effects seen with non-selective NMDAR blockers (Gogas 2006). Our results show that the antinociceptive effects produced by intraperitoneal injection OMT is reversed by NMDA, and were potentiated by coad-ministered MK801 and ifenprodil, while both alone in subthreshold doses did not show any effects on antinociception in mechanical allodynia test. Taken together, these data suggest that the glutamatergic system is involved in the mechanism of OMT, and the activation of NMDA receptors, more precisely, NR2B-containing NMDAR may potentiate the nociceptive transmission at the spinal level.
The spinal NMDARs, which are known to contribute to excitatory synaptic transmission within the spinal cord when evoked by nociceptive primary afferent stimuli, play important roles in hyper-excitability of spinal dorsal neurons and nociceptive transmission (Gao et al. 2005; Wilson et al. 2005). Functional NMDARs like NR2B subunit has a relatively restricted distribution in the superficial spinal dorsal horn which has more important correlations with nociceptive transmission (Paoletti and Neyton 2007; Laurie et al. 1997). Our results suggest that the antinociceptive action induced by OMT inhibit the NMDAR related ERK/CREB activation as OMT could block nerve injury-induced NR2B expression. In the present study, we did not exclude the role of other subunits of NMDAR in OMT-induced antinociceptive effects. However, together with previous reports, antinociceptive action induced by OMT contributes to NMDAR related ERK/CREB activation following nerve injury.
The transcription factor cAMP response element binding protein (CREB), which can be phosphorylated by multiple intracellular kinases in response to a vast range of physiological and pathological stimuli (Chen et al. 2003), has been suggested to contribute to the central sensitization associated with persistent pain states (Hoeger-Bement and Sluka 2003; Ma et al. 2003; Ma and Quirion 2001). It has been proposed that NMDA activation-induced [Ca.sup.2+] influx can trigger an early phase of CREB phosphorylation and a persistent phase of CREB phosphorylation is mediated by a delayed extracellular signal-regulated kinase (ERK) signal cascade, which is important to the development and maintenance of chronic pain (Song et al. 2005). In addition, ERK phosphorylation by glutamate receptor contributes to central sensitization through post-translational and CREB or Elk-1-mediated transcriptional regulation in dorsal horn neurons (Kawasaki et al. 2004; Ji et al. 1999). In the present study, phosphorylation of ERK induced by CCI was arrested by treatment with OMT. Furthermore, OMT suppressed CCI-evoked CREB phosphorylation in the spinal cord.
In conclusion, intraperitoneal injection of OMT could beneficially decrease the CCI-induced mechanical allodynia and thermal hyperalgesia, antagonize the effect of NMDA, synergistic enhance the effect of MK801 and infenprodil, led to a marked decrease in NMDA NR2B, pERK and pCREB induced by CCI in the spinal cord in mice. Our observations indicate that regulation of NMDA NR2B receptor-ERK/CREB signaling maybe the targets for the antinociceptive effects of OMT. These findings encourage further pharmacological and chemical studies to evaluate if there are other mechanisms responsible for the antinociceptive action induced by OMT. Our findings may be helpful to develop effective drugs for the treatment of neuropathic pain.
Conflict of interest
There is no conflict of interest.
This research was supported by the National Natural Science Foundation (Grant No. 81160524), the Key Scientific Research Projects of Ningxia Health Department (2012049), and the Key Project of Ningxia Medical University (XZ200803, XM2011001).
* Corresponding author at: Department of Pharmacology. Ningxia Medical University, Yinchuan 750004, Ningxia. PR China. Tel.: +86 951 6980879.
E-mail address: firstname.lastname@example.org (J. Yu).
(1.) These authors contributed equally to this work.
0944-7113/$--see front matter [c] 2013 Elsevier GmbH. All rights reserved.
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Wang Haiyan (a), (d), (1), Li Yuxiang (b), (e), (1), Dun Linglu (a), Xu Yagiong (a), Jin Shaojv (a), Du Juan (a), Ma Lin (c), Li Juan (a), Zhou Ru (a), He Xiaoliang (a), Sun Tao (c), Yu Jianqiang (a), *
(a) Department of Pharmacology, Ningxia Medical University, Yinchuan, China
(b) College of Nursing, Ningxia Medical University, Yinchuan, China
(c) Ningxia Key Laboratory of Craniocerbral Diseases of Ningxia Hui Autonomous Region, Yinchuan, China
(d) Xin Hua Hospital affiliated to Shanghai Jiao Tong University School of Medicine Chongming branch, China
(e) Shanghai Pudong New Area Gough Hospital, China
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|Author:||Haiyana, Wang; Yuxiang, Li; Linglu, Dun; Yaqiong, Xu; Shaojv, Jin; Juan, Du; Lin, Ma; Juan, Li; Ru,|
|Publication:||Phytomedicine: International Journal of Phytotherapy & Phytopharmacology|
|Date:||Aug 15, 2013|
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