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Betamethasone Affects Cerebral Expressions of NF-B and Cytokines that Correlate with Pain Behavior in a Rat Model of Neuropathy

Address correspondence to Jianguo Xu, Ph.D., Department of Anesthesiology, Jinling Hospital, 305 East Zhongshan Road, Nanjing 210002, P.R.China; tel 86 25 8480 6839; fax: 86 25 8480 6839; e-mail: xwyxieweiying{at}hotmail.com.

	Abstract

Top Abstract Introduction Materials and Methods Results Discussion Acknowledgements References

 
The objective of this study was to investigate whether corticosteroids modulate neuropathic pain by altering cerebral expression of nuclear factor-kappa B (NF-B) and specific cytokines. The effects of topical betamethasone on neuropathic pain and cerebral expression of NF-B and cytokines were studied in a rat model of L5 spinal nerve transaction. Behavioral testing was undertaken on days 1, 3, 7, 14, and 21 post-operation using the von Frey and Hargreaves tests. NF-B activation in the brain was investigated by an electrophoretic mobility shift assay (EMSA), and cerebral expressions of tumor necrosis factor- (TNF), interleukin-1ß (IL-1ß), and interleukin-10 (IL-10) were quantified using enzyme-linked immunosorbent assays (ELISA). Spinal nerve transection induced mechanical allodynia and thermal hyperalgesia, which were significantly ameliorated by topical injection of betamethasone around the site of injury. In addition, betamethasone reduced the activation of NF-B and elevation of TNF and IL-1ß, and induced the expression of IL-10 in the brain, all of which correlated with the changes of pain thresholds in rats. The results suggest that topical betamethasone injection inhibits the development and maintenance of neuropathic pain. Betamethasone may act by regulating the expression of NF-B, TNF, IL-1ß and IL-10 in the brain. This study yields new insight into the mechanisms of corticosteroid action in neuropathic pain and may provide a basis for clinical pain control.

Keywords: betamethasone, neuropathic pain, hyperalgesia, allodynia, NF-B, TNF, IL-1ß, IL-10

	Introduction

Top Abstract Introduction Materials and Methods Results Discussion Acknowledgements References

 
Neuropathic pain is a persistent pain state that arises from intense, prolonged noxious stimulation or from nerve injury, and leads to long-term functional changes in the pain sensory system. It is often associated with the appearance of abnormal sensory signs, such as hyperalgesia (increased responsiveness to noxious stimuli) and allodynia (painful responses to normally innocuous stimuli). Mechanisms of the development and maintenance of neuropathic pain are elusive, although the problem has been under study for decades.

Corticosteroid injections have been clinically used for neuropathic pain for more than 50 years [1]. Systemic corticosteroids have appeared to be effective in the treatment of complex regional pain syndromes (CRPS) [2]. A recent clinical study showed that intrathecal injection of methylprednisolone reversed postherpetic neuralgia (PHN) [3]. In rat models of neuropathic pain, systemic and intrathecal corticosteroid treatments inhibited the development and maintenance of pain states induced by spinal nerve ligation [4]; epidural injections of betamethasone in a model of lumbar radiculopathy showed a significant effect on thermal hyperalgesia [5]; and topical corticosteroids applied to the sciatic ligation site reversed hyperalgesia and allodynia in animals with peripheral mononeuropathy [6].

The current literature strongly implicates a role for proinflammatory cytokines such as tumor necrosis factor- (TNF) and interleukin-1ß (IL-1ß) in the genesis, persistence, and severity of neuropathic pain following nerve injury. These cytokines were associated with pain and hyperalgesia in a host of painful diseases [7]. Elevated TNF activity in the brain was found necessary for the development of hyperalgesia during neuropathic pain [8]. Increases in TNF and IL-1ß immunoreactivities were observed in the spinal cord in two rat models of mononeuropathy [9]. The expressions of TNF and IL-1ß genes were up-regulated in the rat chronic constriction injury (CCI) model, associated with hyperalgesia and allodynia [10]. In addition, central administration of IL-1 receptor antagonist (IL-1ra) combined with soluble TNF receptor was found to attenuate pain-associated behavior in rats with neuropathic pain [11]. In injury-free animal models, peripheral [12–15] or central [16,17] administration of TNF and IL-1ß have been shown to induce allodynia and/or hyperalgesia, which suggests that TNF and IL-1ß can modulate pain responses both peripherally and centrally.

Nuclear factor-kappa B (NF-B) plays a pivotal role in regulating gene expression of these proinflammatory cytokines and NF-B is reported to be crucially involved in the signaling in the nervous system [18]. Compared with the well-studied function of NF-B in inflammation, its role in neuropathic pain is still elusive, although various cytokines are known to be involved in the development of hyperalgesia and allodynia after nerve injury. Evidence is emerging for involvement of NF-B in pathological pain. The activation of NF-B was detected in dorsal root ganglia in several animal models of neuropathic pain [19]. NF-B decoy alleviated hyperalgesia induced by spinal nerve ligation injury [20], while inhibition of inhibitor kappaB (IB) kinase (which phosphorylates IB to activate NF-B) reduced hyperalgesia in inflammatory and neuropathic pain models of rats [21]. In contrast to the inflammatory cytokines, interleukin-10 (IL-10) is considered an anti-inflammatory cytokine that offers a potentially new approach for clinical pain control [22]. Expression of IL-10 was increased gradually in the rat CCI model [10], and its administration inhibited the hyperalgesic responses to proinflammatory cytokines [23] and attenuated hyperalgesia caused by CCI injury [24].

In the present study, we tested the hypothesis that there is a connection between neuropathic pain and cerebral production of NF-B and cytokines through corticosteroid modulation. Corticosteroids are known to down-regulate NF-B and proinflammatory cytokines (eg, TNF, IL-1ß) and to up-regulate anti-inflammatory cytokines (eg, IL-10), but these actions have been considered related to the effects of corticosteroid treatments on acute pain or inflammatory pain, and have seldom been connected with their effects on chronic neuropathic pain, especially in animal models. us, using a rat model of spinal nerve ligation and transection (modified from Kim and Chung [25]), we investigated the effects of topical injection of betamethasone on neuropathic pain and the relations between pain behavior and expressions of NF-B, TNF, IL-1ß, and IL-10 in the brain.

	Materials and Methods

Top Abstract Introduction Materials and Methods Results Discussion Acknowledgements References

 
Animals.  Male Sprague-Dawley rats (body wt 250–300 g at the time of surgery) were used in this study. The rats were housed in an approved vivarium and maintained on a 12-hr light/12-hr dark cycle, with food and water available ad libitum. Seventy-five rats were divided randomly into 3 groups: (i) spinal nerve transection with topical injection of betamethasone (n = 30), (ii) spinal nerve transection with topical injection of saline (n = 30), and (iii) sham surgery (n = 15). All animal experiments were performed in accordance with national legislation and with the National Institutes of Health Guidelines regarding the care and use of animals for experimental procedures. The rats maintained good health and had normal weight gain throughout the experiment.

Surgical procedure.  Neuropathic pain was induced following the method of Kim and Chung [25]. All surgical procedures were performed with the rats under deep sodium pentobarbital anesthesia (50 mg/kg, ip). A midline incision was made on the back, and the left paraspinal muscles were separated from the spinous processes at the L4–S1 levels. The L6 transverse processes were partially removed, and the left L4 and L5 spinal nerves were exposed by carefully teasing the underlying fascia. The L5 nerve was identified, tightly ligated with a 3-0 silk thread, and transected distal to the ligature without damage to the dorsal root ganglion or other nerves. After ligation and transection of the nerve, the site of injury was injected with 0.05 ml of betamethasone (Diprospan, 1 mg/L in saline), or with 0.05 ml of saline alone. After surgery, the wound was irrigated with saline and was closed in two layers with 3-0 silk ligatures.

Drug.  Diprospan (betamethasone dipropionate + betamethasone disodium phosphate) was purchased from Schering-Plough (Schering-Plough Labo N.V., Brussels, Belgium) and was diluted in sterile saline. The dosage of topical diprospan was based on a previous study [6] and our preliminary trials.

Mechanical sensitivity.  Measurements of rat paw withdrawal latency were collected on post-operation days 1, 3, 7, 14, and 21. The surgery day was regarded as post-operation day 0. All behavioral experiments were conducted between 8:00 and 11:00 a.m. To quantify mechanical sensitivity of the paw, the threshold of paw withdrawal in response to normally innocuous mechanical stimuli was determined by using an ElectroVonFrey aneshesiometer (Model 2390CE, IITC Life Science, Inc.). Each rat, under non-restrained conditions, was placed singly beneath an inverted ventilated Plexiglas cage with a metal-mesh floor allowing access to the plantar surface of the hind paw and was habituated to this environment for 10 min. The von Frey hair was pressed perpendicular to the plantar surface of the hind paw, and mechanical stimulation was increased in a graded manner until the hind paw was withdrawn. The percentage of decrease of the mechanical paw withdrawal threshold was calculated as:MPWT= (left paw-baseline)/baseline.

Thermal withdrawal latency.  The threshold of rat paw withdrawal to noxious heat stimuli was measured using a paw stimulator analgesia meter (Model 390, IITC Life Science, Inc) [26]. Rats were placed on a 6-mm-thick glass floor under an inverted clear Plexiglas cage and were allowed to acclimatize for 10 min before testing. The movable radiant heat source beneath the glass floor was focused on the plantar surface of the hind paw when it was in contact with the glass floor. Withdrawal latencies were measured automatically and a cutoff time was set at 20 sec to avoid tissue damage. The percentage of decrease of thermal paw withdrawal threshold was calculated as: TPWT= (left paw-baseline)/baseline.

Tissue harvest.  Animals were allowed to survive for 1, 3, 7, 14, or 21 days following the surgery, respectively. After each survival time, the animals were deeply anesthetized with sodium pentobarbital (50 mg/kg, ip) and killed by rapid decapitation (n = 6 per group). The brain was excised and quickly frozen in liquid nitrogen.

Electrophoretic mobility shift assay (EMSA) of NF-B expression in brain.  Nuclear protein was extracted and quantified as described [27]. EMSA was performed using a kit (Gel Shift Assay System; Promega, Madison, WI, USA). NF- B consensus oligonucleotide (AGT-TGA-GGG-GAC-TTT-CCC-AGG) was labelled with [-³²P] ATP (Free Biotech, Beijing, China) with T4 polynucleotide kinase. Equal amounts of nuclear extract (60 µg) were added to 9 µl of gel shift binding buffer (Tris-HCl 10 mM, pH 7.5, NaCl 50 mM, EDTA 0.5 mM, MgCl₂ 1 mM, DTT 0.5 mM, glycerol 4%, poly-dIdC 0.05 mg/ml). After 15 min at room temperature, the mixture was incubated for 30 min with 1 µl of the ³²P-labelled oligonucleotide probe. One µl of loading buffer was added and the sample electrophoresed in a 4% polyacrylamide gel. The dried gel was exposed to X-ray film (Fuji Hyperfilm) at –70°C. The intensity of the NF-B complex was quantified by densitometry.

Enzyme-linked immunosorbent assay (ELISA) of cytokine expressions in brain.  Cerebral expressions of TNF, IL-1ß and IL-10 protein were quantified using ELISA kits specific for rat cytokines according to the manufacturer’s instructions (Diaclone USA for TNF; Biosource USA for IL-1ß and IL-10). Values were expressed as pg/mg protein. Protein concentrations in the supernatant samples were assayed as previously described [28].

Statistics.  Data were expressed as mean ± SD and compared by one-way analysis of variance (ANOVA) and Tukey’s test or Student’s t-test (SPSS 10.0) (p value <0.05 was significant).

	Results

Top Abstract Introduction Materials and Methods Results Discussion Acknowledgements References

 
Mechanical allodynia.  Animals with L5 nerve transection displayed marked mechanical allodynia that increased to a maximum on day 3 (Fig. 1A). Compared to saline, the diprospan administration caused significant reduction of mechanical allodynia (p <0.01), although there were still significant differences between the diprospan-treated and the sham-operated groups (p <0.01).

View larger version (19K): [in this window] [in a new window]   Fig. 1. Changes in the (A) mechanical (B) thermal paw withdrawal threshold post-transection. Circles: nerve transection + saline; triangles: nerve transection + diprospan; squares: sham operation. Diprospan ameliorated the development of mechanical and thermal hyperalgesia, although there were still differences between the diprospan-treated and the sham-operated groups (*p <0.05, **p <0.01 versus saline; p <0.05, p <0.01 versus sham operation).

NF-B activation.  EMSA experiments examined the effect of diprospan on the activation of NF-B induced by L5 nerve transection. As shown in Fig. 2 and Table 1, NF-B activation in the brain was markedly increased after spinal nerve injury compared with the unoperated control. The activity of NF-B varied with time after operation, and peaked on day 3. Diprospan significantly inhibited NF-B activation compared to the saline-treated group on days 1, 3, 7, and 14 post-transection (p <0.01).

View larger version (24K): [in this window] [in a new window]   Fig. 2. Activation of nuclear factor kappa B (NF-B) in the brain. NF-B activation in the brain was detectable at a low level in unoperated control (lane 11) and was markedly increased on days 1, 3, 7, 14, and 21 post-transection (lanes 1, 3, 5, 7, and 9). In the diprospan-treated group, NF-B activations were significantly reduced compared to the saline-treated group on days 1, 3, ,7 and 14 post-transection (lanes 2, 4, 6, 8, and 10).

View this table: [in this window] [in a new window]   Table 1. Expression of NF-B, TNF, IL-1ß, and IL-10 in the brain on days 1, 3, 7, 14, and 21 post-transection.

Production of proinflammatory cytokines(TNF, IL-1ß).

Production of anti-inflammatory cytokine (IL-10).  In contrast to TNF and IL-1ß, IL-10 levels showed a progressive increase with time after operation, reaching maximum at the last time point of 21 days (Table 1). Diprospan significantly induced IL-10 expression compared to the saline-treated group on days 3, 7, 14, and 21 post-transection (p <0.01).

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion Acknowledgements References

 
The present study provides a new viewpoint on the mechanism of action of corticosteroids in neuropathic pain. Since few studies in the literature have focused on the relation between neuropathic pain and cerebral expression of NF-B and cytokines through corticosteroid regulation, the present results may provide the basis for a clinical approach to pathological pain control. Our study showed that topical injection of betamethasone inhibited mechanical allodynia and thermal hyperalgesia in rats after spinal nerve transection, and suppressed the protein expressions of NF-B and specific cytokines in the brain, which were coincident with the development of neuropathic pain. Diprospan (compound betamethasone injection) was selected as the experimental agent because it is a long-acting corticosteroid whose effect can last for 3–4 weeks clinically after a single dose.

In the present study, spinal nerve transection resulted in elevation of NF-B, TNF, and IL-1ß levels in the brain, and the timing of these increases positively correlated with the mechanical allodynia and thermal hyperalgesia in rats. Expression of IL-10 was gradually increased, which seemed to be associated with the relief of allodynia and hyperalgesia. Diprospan administration significantly reduced behavioral responses and cerebral levels of NF-B and cytokines, and the changes of NF-B and cytokines expression seemed coincident with pain behavior post-transection. Taken together, the results suggest that NF-B and these specific cytokines may be mediators of neuropathic pain, and that betamethasone may alleviate neuropathic pain via regulation of cytokine production in the central nervous system.

The mechanisms of the genesis and maintenance of neuropathic pain are complicated and they are still only partially understood. The molecular and cellular mechanisms may include the induction of sensitization by posttranslational regulation of molecules in peripheral and central neurons involved in sensation, and the maintenance of sensitization by transcriptional regulation, all through the action of multiple protein kinases [29]. Besides, male and female rats respond differently in the pathological pain states [30]. In our experiment only male rats were used, so we need more studies to investigate the differences of pathological pain threshold between male and female rats. We used the whole brain for extraction, not specific regions, to observe the general changes of NF-B and specific cytokine expression in the brain. Other studies have shown that expression of pain-related cytokines varies in different brain regions [8,31].

TNF is regarded as the prototypic proinflammatory cytokine due to its principal role in initiating the cascade of activation of other cytokines in the inflammatory responses. TNF induces IL-1ß, and they are both produced under pathological conditions that are associated with increased pain and hyperalgesia in human and animal models. Activation of TNF and IL-1ß may indirectly induce the release of catecholamines from sympathetic fibers [32], as well as the expression of final common mediators in pain transmission, such as substance P, glutamate, nitric oxide, COX-2 [33], and PGE2 [31]. These proinflammatory cytokines were postulated to contribute to central sensitization [34,35], which resulted in lower thresholds and spontaneous ectopic neuronal firing, manifested as allodynia and hyperalgesia [36].

Since NF-B is considered one of the most important transcription factors that link early signaling with changes in gene expression of proinflammatory cytokines [37], special attention was paid to how diprospan affected NF-B activation during the development of neuropathic pain. Recently, evidence has been emerging that NF-B acts as a crucial signal in synaptic transmission and neuronal plasticity in the CNS [38]. us, activated NF-B may be involved in the initiation and exacerbation of neuropathic pain via neuron-mediated central sensitization. Moreover, activated NF-B in the glia may induce many products including proinflammatory cytokines and classic pain mediators [29,39], modulating the development of neuropathic pain.

Anti-inflammatory cytokine IL-10 may inhibit a positive feed-forward loop occurring between proinflammatory cytokines and NF-B in both inflammation and neuropathic pain states. Diverse pathological pain states are controlled by intra-thecal gene therapy that drives the production and release of anti-inflammatory cytokine IL-10 in cerebrospinal fluid (CSF) [40], which suggests that IL-10 could attenuate neuropathic pain by inhibiting proinflammatory cytokines. IL-10 suppresses the production and activity of proinflammatory cytokines at multiple levels, including transcription, translation, and release. Besides, it can take effect by inhibiting p38 mitogen-activated protein kinase (MAPK) [41,42] and NF-B activation, translocation, and DNA binding. In our study, the sustained increase in IL-10 expression suggests a compensatory drive to counterbalance the elevation of a number of potential proinflammatory cytokines. Recently, unknown proteins have been reported to be involved in neuropathic pain and they need to be investigated [43].

Corticosteroids are widely used for their anti-inflammatory and immunosuppressive properties. They transduce their action after binding to intracellular corticosteroid receptors; then the ligand-receptor complex binds to the corticosteroid-responsive element of DNA in the promoter region of the gene being regulated, either stimulating or inhibiting the transcription of that gene and hence the expression of proteins and transcription factors. Corticosteroids have been postulated to act by inhibiting NF-B and proinflammatory cytokines in inflammation, stress, allergy, and other diseases, but this action is seldom considered in regard to the effect of corticosteroids on neuropathic pain.

We found that in the diprospan-treated group, mechanical allodynia and thermal hyperalgesia induced by spinal nerve transection correlated well with the reduction of NF-B and proinflammatory cytokines in the brain; expression of IL-10 was up-regulated and seemed to be consistent with the relief of pain behavior. Taken together, these data suggest that beta methasone may inhibit neuropathic pain by modulation of NF-B, proinflammatory, and anti-inflammatory cytokines in the CNS. In addition, the analgesic action of corticosteroids may include inhibition of prostaglandin by blockade of phospholipase A2 activity [44], inhibition of spinal Fos synthesis [45], prolonged suppression of ongoing neuronal discharge, and suppression of sensitization of dorsal horn neurons. Recent evidence suggests that glia in the CNS contribute to a number of pathologic pain states [22], and that corticosteroids may inhibit the development and maintenance of neuropathic pain via a glia-mediated mechanism [4].

In conclusion, we have demonstrated that topical application of betamethasone (diprospan) inhibited the development of neuropathic pain in a rat model of spinal nerve transection. In addition, betamethasone administration reduced the elevations of NF-B, TNF, and IL-1ß, and induced the expression of IL-10 in the brain, all of which were coincident with pain behavior in rats, suggesting that betamethasone may produce analgesic effects by modulation of NF-B and these specific cytokines.

	Acknowledgements

Top Abstract Introduction Materials and Methods Results Discussion Acknowledgements References

 
We are grateful to Feng Genbao for invaluable advice and excellent technical assistance. This work was supported by grants from Jinling Hospital.

	References

Top Abstract Introduction Materials and Methods Results Discussion Acknowledgements References

 

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