effects of curcumin on pain threshold and on the expression of nuclear factor κ b and cx3c receptor...

• 1 •Chin J Integr Med

Neuropathic pain is one of the common and chronic syndromes in clinic caused by tissue injury, inflammation and nerve system injury. Hyperalgesia, al lodynia and spontaneous pain are the main syndromes of this disease.(1) Nuclear factor κB (NF-κB) is the key signal transduction molecule to regulate immunogenes and inflammatory genes and is usually activated at the early phase of neuropathic pain.(2) CX3C chemokine receptor 1 (CX3CR1) localized in microglia exerts crucial effects in immunogenes and inflammatory reaction of spinal cord, is directly involved in the development of neuropathic pain because its expression is significantly increased in the process of neuropathic pain.(3,4) Activation NF-κB induced by nerve injury may up-regulate the expression of CX3CR1 in the spinal cord, which was involved in the occurrence of neuropathic pain, while the inhibitor of NF-κB can delay this process.(5,6) Our previous study showed

that curcumin can ameliorate the neuropathic pain of diabetic rats, down-regulate the expression of NF-κB(7) and relieve thermal hyperalgesia and mechanic abnormal pain of chronic constrictive injury (CCI) rats.(8) Therefore, this study aimed to investigate the effects of curcumin on the nociceptive behavior of rats with CCI and the expressions of NF-κB and CX3CR1 in spinal

ORIGINAL ARTICLEEffects of Curcumin on Pain Threshold and on the

Expression of Nuclear Factor κB and CX3C Receptor 1 after Sciatic Nerve Chronic Constrictive Injury in Rats

CAO Hong (曹红), ZHENG Jin-wei (郑晋伟 ), LI Jia-jia (李佳佳), MENG Bo (孟波), LI Jun (李军), and GE Ren-shan (葛仁山)

©The Chinese Journal of Integrated Traditional and Western Medicine Press and Springer-Verlag Berlin Heidelberg 2013Supported by National Natural Science Foundation of China (No. 81073125), Natural Science Foundation of Zhejiang Province (No. Y2090252), International Cooperation Project of Wenzhou Science and Technology Bureau (No. H20070035)Department of Anesthesiology, The Second Affiliated Hospital of Wenzhou Medical College, Wenzhou, Zhejiang Province (325027), ChinaCorrespondence to: Prof. CAO Hong, Tel: 86-577-86699767, Fax: 86-577-86699767, E-mail: [email protected]: 10.1007/s11655-013-1549-9

ABSTRACT Objective: To investigate the effects of curcumin on pain threshold and the expressions of nuclear factor κB (NF-κB) and CX3C chemokine receptor 1 (CX3CR1) in spinal cord and dorsal root ganglion (DRG) of the rats with sciatic nerve chronic constrictive injury. Methods: One hundred and twenty male Sprague Dawley rats, weighing 220–250 g, were randomly divided into 4 groups. Sham surgery (sham) group: the sciatic nerves of rats were only made apart but not ligated; chronic constrictive injury (CCI) group: the sciatic nerves of rats were only ligated without any drug treatment; curcumin treated injury (Cur) model group: the rats were administrated with curcumin 100 mg/(kg•d) by intraperitoneal injection for 14 days after CCI; solvent control (SC) group: the rats were administrated with the solvent at the same dose for 14 days after CCI. Thermal withdrawal latency (TWL) and mechanical withdrawal threshold (MWT) of rats were respectively measured on pre-operative day 2 and post-operative day 1, 3, 5, 7, 10 and 14. The lumbar segment L4–5 of the spinal cord and the L4, L5 DRG was removed at post-operative day 3, 7 and 14. The change of nuclear factor κB (NF-κB) p65 expression was detected by Western blotting while the expression of CX3CR1 was determined by immunohistochemical staining. Results: Compared with the sham group, the TWL and MWT of rats in the CCI group were significantly decreased on each post-operative day (P<0.01), which reached a nadir on the 3rd day after CCI, and the expressions of NF-κB p65 and CX3CR1 were markedly increased in spinal cord dorsal horn and DRG. In the Cur group, the TWL of rats were significantly increased than those in the CCI group on post-operative day 7, 10 and 14 (P<0.05) and MWT increased than those in the CCI group on post-operative day 10 and 14 (P<0.05). In addition, the administration of curcumin significantly decreased the positive expressions of NF-κB p65 and CX3CR1 in spinal cord and DRG (P<0.05). Conclusion: Our study suggests that curcumin could ameliorate the CCI-induced neuropathic pain, probably through inhibiting CX3CR1 expression by the activation of NF-κB p65 in spinal cord and DRG.KEYWORDS curcumin, neuropathic pain, microglia, nuclear factor κB, CX3C chemokine receptor 1

• 2 • Chin J Integr Med

cord to explore the possible mechanisms of curcumin in treating CCI.

METHODSAnimals and Regents

One hundred and twenty specific-pathogen free Sprague Dawley (SD) rats, weighting 220–250 g, were provided by Animal Center of Wenzhou Medical College [license No. SCXK (Zhejiang) 2005-0019]. All animal research were allowed and performed conformed to the guidelines of Animal Center of Wenzhou Medical College. Model 33 Analgesia Meter and Model 2390 Electrovonfrey Anesthesiometer were purchased from ⅡTC/Life Science Instruments, USA. NF-κB p65 antibody, CX3CR1 antibody and curcumin were purchased by Sigma, USA. Rabbit two-step kit and diaminobenzidine (DAB) developer were purchased from Beijing Zhongshan Golden Bridge Company, China. Curcumin was disposed into 100 mg/kg stock solution with 1% Tween80 and 1% sodium carboxymethycellulose and stored at 4 ℃ refrigerator away from light.

Animal Model In accordance with the method of Bennett and

Xie,(9) the rats were anesthetized by the intraperitoneal injection with 5％chloral hydrate (300 mg/kg). Under disinfect, the skin on the right leg of rat was cut off and subcutaneous muscle was segregated to make sciatic nerve exposed. Then skin and muscle of rats were sutured with # 4 surgical suture and each interval of ligation is about 1 mm. It is appropriate that ligation of calf muscle strength can cause mild vibration response. Paw adduction, hindfoot valgus and mild claudication in the operated side of rats can be used to test whether the model is created successfully.

Animal GroupingThe rats were randomly divided into 4 groups

with 30 rats in each group: (1) sham surgery (sham) group: the sciatic nerves of rats were only made apart but not ligated; (2) CCI model group: the sciatic nerves of rats were only ligated without any drug treatment; (3) curcumin treated (Cur) group: the rats were administrated with curcumin 100 mg/(kg•d) by intraperitoneal injection for 14 days after CCI; (4) solvent control (SC) group: the rats were administrated wi th the solvent (1% Tween80 + 1% sodium carboxymethycellulose) at the same dose for 14 days after sciatic nerve CCI.

Determination of Ethology The ethology of rats were determined at

10:00–14:00 and 24.0±0.5 ℃ in room pre-operative day 2 and post-operative day 1, 3, 5, 7, 10 and 14.

Determination of Thermal Withdrawal Latency

To assess the sensitivity to thermal withdrawal latency (TWL) of rat, the right plantar surface of mice was tested individually using model 33 Analgesia Meter.(10) Parameter settings: heat emission intensity of the laser head is 20% and 60% when heating. The cut-off time is 25 s, and the triggering temperature is 30 ℃.

The rats were placed in transparent glass plate, sole of rat's foot in operated side was exposed with heated head, the leg-raising time was defined as TWL. The interval of each stimulation is 5 min, and the average was determined after measured 3 times.

Determination of Mechanical Withdrawal Threshold

The rats were placed in a transparent plexiglass box, whose bottom consists of the wire at 1 cm×1 cm. The rats need the adaption of 15 min before test. The ipsilateral plantar skin and smooth was stimulated vertically from bottom to top by using the Model 2390 Electrovonfrey Anesthesiometer,(10) and the intensity of stimulation was gradually increased. The stimulus intensity value is defined as mechanical withdrawal threshold (MWT) when foot retraction response such as licking and shaking legs were observed. The interval of each stimulation was 10 s, 3 times were measured and the average was chosen.

Western Blot AnalysisAt 3, 7 and 14 days after CCI, the rats were

injected with chloral hydrate to cause anesthesia, the spinal cord lumbar enlargement and the L4, L5 and DRG was rapid taken on the saline ice, and washed with pre-cooling 4 ℃ artificial cerebrospinal fluid blood. After fully grinding and ultrasonicating, the lysates were allowed to stand for 30 min, before being centrifuged at 12,000 r/min at 4 ℃ for 15 min. The supernatant was then collected, and the protein concentration was determined using the bicinchoninic acid (BCA) method. Take 50 μg in 100 g/L sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) separation, proteins transferred to polyvinylidene fluoride (PVDF) membrane. The membrane was blocked for 2 h with 50 g/L skim


milk, before membranes were incubated with anti-NF-κB p65 (1:100) and glyceraldehyde phosphate dehydrogenase (GAPDH, 1:1000) antibodies at 4 ℃ for 18 h, then incubated with the second anti-mouse anti-Rabbit IgG (1:500) for 1 h. ECL luminescent reagent was added, and the membranes were exposed. The Quantity One-4.4.0 software was used to analysis the average optical density of protein and internal reference.

ImmunohistochemistryAt 3, 7 and 14 days after surgery, the rats were

anesthetized with 5% chloral hydrate at 400 mg/kg and the aorta was perfused with 100 mL normal saline, and followed by perfusion of 400 mL 4% paraformaldehyde to make the paraffin sections in L4–5 dorsal horn of the spinal cord and DRG of rats. The sections were deparaffined in xylene and rehydrated in graded ethanol. The antigen of slides was repaired under high pressure and slightly boiling citrate retrieval solution (pH 6.0), and blotted by 3% hydrogen peroxide for 10 min. Then anti-NF-κB p65 or CX3CR1 primary antibody (1:200) was added to the sections using a drop-wise technique and incubated at 4 ℃ for 24 h. Sections were then incubated with the appropriate secondary antibodies for 2 h at 37 ℃. Finally, all the slides were counterstained with hematoxylin after DAB color development. The positive cells were observed in light microscope after mounting. The 20 dorsal horn of the spinal cord slices and DRG slices were collected from each animal.

Statistical Analysis All data are expressed as mean ± standard

deviation and were analyzed by SPSS16.0 software followed by One-way analysis of variance. P values less than 0.05 were considered significant.

RESULTSEffect of Curcumin on TWL and MWT of Sciatic Nerve CCI Rats

Infection and self-mutilation was not observed in rats during the experiment. There was no significant difference on TWL and MWT in each group at baseline. The rats on the sham group after surgery did not appear claw adduction and movement disorders. There was no significant difference in TWL and MWL at each time point after excluding the effect of the skin incision and other surgical procedures on pain behavior of rats with CCI. Moreover, there was also no significant difference in TWL and MWL at each time point between the SC group and the CCI group (Tables 1 and 2).

The TWL and MWT of the CCI group began to decline 1 day after surgery, while reached a minimum value 3 days after surgery, and was 54.6% and 45.8% of baseline value, respectively, with significant difference compared with the baseline value (P<0.01). Compared with that of the sham group, the TWL and MWT on the CCI group at each time point was significantly decreased (P<0.01). In addition, the TWL and MWT of the Cur group after surgery also began to decrease and reached a minimum 3 days after surgery. Compared with that of the CCI group, the TWL in the Cur group from day 7 after surgery was significantly increased (P<0.05), while the MWT began to significantly increase 10 days after surgery (P<0.05, Tables 1 and 2).

Table 1. Comparison of TWL of Rats among Groups ( ±s)

Group n Pre-operative day 2

Post-operative day 1






Sham 6 11.9±1.8 11.8±1.5 11.7±1.5 11.9±1.8 12.1±1.7 11.8±1.8 11.9±1.5

CCI 6 11.9±2.0 7.8±1.3 6.5±1.1 6.6±1.2 7.0±1.7 6.9±1.0 7.1±1.1

Cur 6 12.2±1.2 8.1±1.3 7.2±0.9 7.7±1.0 8.7±0.9△ 8.8±1.2△ 8.7±0.7△

SC 6 12.1±1.8 8.0±0.9 6.7±1.5 7.1±1.8 7.0±1.0 7.1±1.0 7.1±1.2

Notes: P<0.01, compared with the sham group; △P<0.05, compared with the CCI group; the same below

Table 2. Comparison on MWT of CCI Rats among Groups ( ±s)

Group n Pre-operative day 2







Sham 6 49.1±3.7 48.3±4.4 47.7±4.8 49.3±4.4 48.0±3.4 49.1±4.0 47.7±5.1

CCI 6 49.3±5.9 36.6±3.7 22.6±5.1 26.1±5.1 24.9±4.1 24.6±3.1 26.2±4.3

Cur 6 50.3±5.4 37.7±4.9 26.0±3.5 26.7±3.4 29.1±3.7 30.3±4.3△ 32.5±3.9△

SC 6 50.5±5.1 37.5±3.0 24.1±5.4 25.3±3.9 25.2±4.1 25.7±3.2 26.4±4.5


NF-κB p65 Expression in Lumbar Spinal Cord and DRG of Rats

In this experiment, only a small amount of protein of NF-κB p65 was expressed in lumbar spinal cord and DRG in the sham group. As shown in Table 3 and Figure 1, compared with that of the sham group, NF-κB p65 protein expression in lumbar spinal cord of postoperative CCI rats was significantly increased (P<0.01), and rised up to the peak on 3 days after surgery. Compared with that of the CCI group, the NF-κB p65 protein expressions in lumbar spinal cord and DRG of the Cur group rised up to the peak on 3 days after surgery and began to decrease on 7 days after surgery (P<0.05). There was no significant difference between the SC and CCI groups (Table 3 and Figure 1).

the cells with CX3CR1 positive expression can be observed in spinal dorsal horn of the operated side on the sham group rat. As shown in Table 4, Figures 2 and 3, in spinal dorsal horn and DRG, compared with that of the sham group, the number of the cells with CX3CR1 positive expression in the operated side of the CCI group was significantly increased (P<0.01), and rised up to the peak 3 days after surgery. Compared with that of the CCI group, the number of the cells with CX3CR1 positive expression in the operated side of the Cur group reached the peak 3 days after operation and began to decrease 7 days after surgery (P<0.01), and there was no significant difference on the number of the cells with CX3CR1 positive expression on the operated side between the SC and the CCI groups.

DISCUSSIONThe experimental data from the pain behavior

in rats showed that the TWL and MWT of rats after CCI were significantly decreased than those before surgery and continuous intraperitoneal injection of 100 mg/kg curcumin can effectively reduce the CCI-induced hyperalgesia andmaintain for a certain time, which is consistent with our previous results.(7) The expressions of NF-κB p65 and chemokine receptor CX3CR1 in spinal cord of rats was significantly increased at the beginning to the 3rd day after CCI, which is consistent with the progress of neuropathic pain. In addition, the expression of NF-κB p65 and CX3CR1 in spinal cord of rats were reduced significantly on the 7th day after intraperitoneal injection of curcumin, which is consistent with improved hyperalgesia in rats. Therefore, the above results suggest that NF-κB and CX3CR1 may play a crucial role in the early inflammation in spinal cord and the formation of pain.

Neuropathic pain is an intractable and chronic pain and one of clinical obstinate illnesses, and its pathogenesis is much too complex. Nowadays, the research of neuropathic pain focused on small glial

Table 3. Expression of NF-κB p65 Protein in Lumbar Spinal Cord and DRG after Surgery ( ±s)

Group nLumbar spinal cord DRG







Sham 4 0.54±0.07 0.42±0.09 0.35±0.07 0.19±0.03 0.07±0.01 0.04±0.01

CCI 4 0.80±0.08 0.75±0.11 0.69±0.12 0.32±0.06 0.19±0.03 0.15±0.03

Cur 4 0.70±0.10 0.58±0.08△ 0.53±0.09△ 0.27±0.03 0.13±0.03△ 0.10±0.03△

SC 4 0.79±0.09 0.73±0.10 0.70±0.10 0.28±0.04 0.18±0.03 0.14±0.03

Figure 1. Curcumin Suppressed the Expression of NF-κB p65 Protein in CCI Injury Rats

Notes: NF-κB p65 protein Western blot analyses of lumbar spinal cord (A) and DRG (B) in sham, CCI, Cur and SC groups on 3, 7, 14 days after CCI

NF-κB p65 →

GAPDH →

NF-κB p65 →

GAPDH →

NF-κB p65 →

GAPDH →

Sham CCI Cur SCA

NF-κB p65 →

GAPDH →

NF-κB p65 →

GAPDH →

NF-κB p65 →

GAPDH →

Sham CCI Cur SCB







CX3CR1 Expression in Spinal Dorsal Horn and DRG of Rats

In this experiment, only a small amount of


Figure 3. CX3CR1 Expression in DRG of Rats among Groups (Immunohistochemical staining, ×400)

Sham CCI Cur SC




Figure 2. CX3CR1 Expression in Spinal Cord of Rats among Groups (Immunohistochemical staining, ×400)

Sham CCI Cur SC




Table 4. Comparison of the Count of Positive Cells Labelling CX3CR1 in Spinal Cord Dorsal Horn and DRG of Rats among Groups after Surgery ( ±s)

Group nSpinal dorsal horn Dorsal root ganglia







Sham 4 18.3±4.4 17.9±5.0 17.3±4.0 10.7±2.9 9.3±1.8 9.0±1.4

CCI 4 45.0±6.1 41.8±6.0 39.9±6.6 28.8±3.5 27.8±2.3 24.8±2.3

Cur 4 39.0±6.3 32.9±6.2△ 28.7±4.9△ 26.3±3.3 22.5±2.9△ 20.5±3.1△

SC 4 43.9±5.2 40.2±5.0 38.8±7.2 28.7±3.1 28.2±2.6 25.3±3.1

Notes: P<0.01, compared with the sham group, △P<0.01, compared with the CCI group

cells. A growing number of studies have shown that microglia in spinal cord plays an important role in the process of neuropathic pain. Microglial cells are the

primary cells in central nervous system (CNS) immune surveillance, when the injured CNS, inflammation, ischemia and neurodegeneration stimulated, microglial


cells will be quickly activated and the shape, number, function and gene expression of microglial cells will have a series of changes, including retraction of cell processes, hyperplasia and upregulation of various receptors, the release of a large number of active medium, the antigen-presenting and participating in immune and inflammatory processes.(11) Specific inhibitor of microglia minocycline can inhibit its activation, and further block or delay the development of neuropathic pain.(12) Peripheral inflammation and injury can result in the activation of glial cells with a facilitated effect in pain, but the the mechanism how the glial cells at rest in the spinal cord are induced and activated is not fully understood.

One possibility is that damage induces neuronal activation, then releases neurotransmitter from afferent neurons, directly binding to non-neuronal cells to make activation. Among them, the neurons release chemokines Fractalkine (Fkn) and small glial cells express the chemokine receptor CX3CR1 binding specifically to participate in neurons and microglia signaling. Intrathecal CX3CR1 receptor antagonist, can delay CCI, mono-arthritis single arthritis animal model of neuropathic pain caused by mechanical and thermal hyperalgesia.(13,14) Further studies in early injury or inflammation Fkn binding to its unique receptor CX3CR1 can activate p38MAPK pathway, then activates microglia, and CX3CR1 neutralizing antibody can inhibit the activation of p38MAPK, reduce neuropathic pain, suggesting that microglia CX3CR1/ p38MAPK signaling pathway may play a key role in the development of neuropathic pain.(15,16)

NF-κB is a transcription factor which is widely present in the cytoplasm of variety of cells as a format of p65/p50 dimer, and forms a trimer by binding to the inhibitory protein IκB to result in inactivation. NF-κB is involved in the activation reaction of many cells in CNS, and translocated to the nucleus after NF-κB and IκB dissociation. p65 phosphorylation containing the transcriptional activation domain can induce and regulate a large number of genes expression, which led to its control of producing a large number of reactants. In addition, NF-κB is an important signaling molecule that CNS regulates immune and inflammatory gene expression. It is also the signal molecules in the painful area, and inflammatory mediators, neurotransmitters in the spinal cord synapses and chemokines results in the

occurrence and maintenance of pain. Nerve injury led to production of inflammatory factors, such as TNF-α, interleukin-1β and other inflammatory factors in neuropathic pain animal models which promote the development of pain.(17,18) NF-κB regulates gene expression of these cells through the NF-κB enhancer binding sequence-based. Therefore, the recognition and inhibition of neuropathic pain can trigger the transcription factor and can be used for pain therapy or to minimize the generation of pain-related symptoms. In recent years, the activation of NF-κB pathway is found in partial ligation, completely cut off, or CCI model of sciatic nerve or animal models of spinal cord compression injury in animals,(19,20) Inhibition of NF-κB pathway, or reducing its gene expression can alleviate chronic pain.(21,22) In addition, NF-κB pathway plays a role in the activation of the spinal cord CX3CR1/p38MAPK pathway, and regulates the gene transcription of CX3CR1, which may be involved in the regulation of expression in microglia.(23)

Curcumin, a phenolic pigment extracted from turmeric roots, has anti-inflammatory and antioxidant effects, can inhibit the activation of NF-κB. Research has shown that curcumin can inhibit the activation of NF-κB and regulate its gene expression by downregulating the activity of IκBα kinase and Akt,(24) moreover, curcumin reduced the the high reactivity of inflammation by inhibiting NF-κB.(25) On the other hand, active NF-κB induced by nerve injury may upregulate the expression of CX3CR1 in the spinal cord, which was involved in the occurrence of neuropathic pain, while the inhibitor of NF-κB can delay this process.(4,5)

This study found that NF-κB is rapidly activated at early-stage after CCI in spinal cord of rats, and curcumin can inhibit the expression of NF-κB at the spinal cord of rats after CCI. In addition, this inhibitative effect has some correlation of the inhibition of CX3CR1 expression at spinal dorsal horn and DRG. Therefore, we hypothesized that curcumin may alimerate the pain through inhibiting the activation of NF-κB in the spinal cord and furtherly reducing the expression of CX3CR1 in dorsal horn of the spinal cord and DRG.

REFERENCESCostigan M, Scholz J, Woolf CJ. NeuroPathic pain: a 1.

maladaptive response of the nervous system to damage.

Annu Rev Neurosci 2009;32:1-32.


Ledeboer A, Gamanos M, Lai W, Martin D, Maier SF, 2.

Watkins LR, et al. Involvement of spinal cord nuclear factor B

activation in rat models of proinflammatory cytokine-mediated

pain facilitation. Eur J Neurosci 2005;22:1977-1986.

Verge GM, Milligan ED, Maier SF, Watkins LR, Naeve GS, 3.

Foster AC. Fractalkine (CX3CL1) and fractalkine receptor

(CX3CR1) distribution in spinal cord and dorsal root

ganglia under basal and neuropathic pain conditions. Eur J

Neurosci 2004;20:1150-1160.

Pan YD, Guo QL, Wang E, Ye Z, He ZH, Zou WY, et al. 4.

Intrathecal infusion of pyrrolidine dithiocarbamate for the

prevention and reversal of neuropathic pain in rats using a

sciatic chronic constriction injury model. Reg Anesth Pain

Med 2010;35:231-237.

Ji RR, Strichartz G. Cell signaling and the genesis of 5.

neuropathic pain. Sci STKE 2004(252), reE14.

Shen BL, Yu XD, Cao H. Effect of curcumin on diabetic 6.

neuropathic pain in rats. Chin J Anesthesiol (Chin)

2009;29:626-629.

Li X, Cao H, Lian QQ. The effect of p-ERK, p-CREB, c-fos 7.

in curcumin treat neuropathic pain of rats. Chin J Appl

Physiol (Chin) 2009;25:418-422.

Narita M, Kaneko C, Miyoshi K, Nagumo Y, Kuzumaki 8.

N, Nakajima M, et al. Chronic pain induces anxiety

with concomitant changes in opioidergic function in the

amygdale. Neuropsychopharmacol 2006;31:739-750.

Clark AK, Yip PK, Grist J, Gentry C, Staniland AA, 9.

Marchand F, et al. Inhibition of spinal microglialcathepsin

S for the reversal of neuropathic pain. Proc Natl Acad Sci

USA 2007;104:10655-10660.

Bennett GJ, Xie YK. A peripheral mononeuropathy in rat 10.

produces disorders of pain sensation like those seen in

man. Pain 1988;33:87-107.

Hu P, Bembrick AL, Keay KA, McLachlan EM. Immune cell 11.

involvement in dorsal root ganglia and spinal cord after

chronic constriction or transection of the rat sciatic nerve.

Brain Behav Immun 2007;21:599-616.

Hanisch UK. Microglia as a source and target of cytokines. 12.

Glia 2002;40:140-155.

Raghavendra V, Tanga F, DeLeo JA. Inhibition of microglial 13.

activation attenuates the development but not existing

hypersensitivity in a rat model of neuropathy. J Pharmacol

Exp Ther 2003;306:624-630.

Milligan ED, Zapata V, Chacur M, Schoeniger D, Biedenkapp 14.

J, O'Connor KA, et al. Evidence that exogenous and

endogenous fractalkine can induce spinal nociceptive

facilitation in rats. Eur J Neurosci 2004;20:2294-2302.

Sun S, Cao H, Han M, Li TT, Pan HL, Zhao ZQ, et al. New 15.

evidence for the involvement of spinal fractalkine receptor

in pain facilitation and spinal glial activation in rat model of

mono-arthritis. Pain 2007;129:64-75.

Tsuda M, Mizokoshi A, Shigemoto-Mogami Y, Koizumi 16.

S, Inoue K. Activation of p38 mitogen-activated protein

kinase in spinal hyperactive microglia contributes to pain

hypersensitivity following peripheral nerve injury. Glia

2004;45:89-95.

Zhuang ZY, Kawasaki Y, Tan PH, Wen YR, Huang J, Ji RR. 17.

Role of the CX3CR1/p38 MAPK pathway in spinal microglia

for the development of neuropathic pain following nerve

injury-induced cleavage of fractalkine. Brain Behav Immun

2007;21:642-651.

Manning DC. New and emerging pharmacological targets for 18.

neuropathic pain. Curr Pain Headache Rep 2004;8:192-198.

Sommer C, Kress M. Recent findings on how proinflammatory 19.

cy tok ine cause pa in : per iphera l mechan isms in

inflammatory and neuropathic hyperalgesia. Neurosci Lett

2004;361:184-187.

Sakaue G, Shimaoka M, Fukuoka T, Hiroi T, Inoue T, 20.

Hashimoto N, et al. NF-kappa B decoy suppresses cytokine

expression and thermal hyperalgesia in a rat neuropathic

pain model. Neuroreport 2001;24:2079-2084.

Pollock G, Pennypacker KR, Mémet S, Israël A, Saporta S. 21.

Activation of NF-kappa B in the mouse spinal cord following

sciatic nerve transection. Exp Brain Res 2005;165:470-477.

Lee HL, Lee KM, Son SJ, Hwang SH, Cho HJ. Temporal 22.

expression of cytokines and their receptors mRNAs in a

neuropathic pain model. Neuroreport 2004;15:2807-2811.

Tegeder I, Niederberger E, Schmidt R, Kunz S, Gühring 23.

H, Ritzeler O, et al. Specific inhibition of Ikappa B kinase

reduces hyperalgesia in inflammatory and neuropathic pain

models in rats. J Neurosci 2004;24:1637-1645.

Ji RR. Suter MR. p38 MAPK, microglial signaling, and 24.

neuropathic pain. Mol Pain 2007;3:33-42.

Aggarwal S, Ichikawa H, Takada Y, Sandur SK, Shishodia S, 25.

Aggarwal BB. Curcumin down-regulates expression of cell

proliferation and antiapoptotic and metastatic gene products

through suppression of IκBα kinase and Akt activation.

Mol Pharmacol 2006;69:195-206.

Oh SW, Cha JY, Kim DY. Curcumin attenuates allergic airway 26.

inflammation and hyper-responsiveness in mice through NF-

kappaB inhibition. J Ethnopharmacol 2010; Jul 17.

Pan YD, Guo QL, Wang E, Ye Z, He ZH, Zou WY, et al. 27.

Intrathecal infusion of pyrrolidine dithiocarbamate for the

prevention and reversal of neuropathic pain in rats using a

sciatic chronic constriction injury model. Reg Anesth Pain

Med 2010;35:231-237.

(Received June 10, 2011)Edited by YUAN Lin

effects of curcumin on pain threshold and on the expression of nuclear factor κ b and cx3c receptor...

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