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REGIONAL ANESTHESIA AND PAIN MEDICINE

Glucocorticoid Inhibition of Neuropathic Hyperalgesia and Spinal Fos Expression

Wade S. Kingery, MD^*, Geeta S. Agashe, MD, Shigehito Sawamura, MD, M. Frances Davies, PhD, J. David Clark, MD, PhD, and Mervyn Maze, MB, ChB

*Department of Functional Restoration, Stanford University School of Medicine, Stanford, California, and Physical Medicine and Rehabilitation Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, California; Department of Anesthesia, Stanford University School of Medicine, Stanford, California, and Anesthesiology Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, California; and Magill Department of Anaesthetics, Imperial College School of Medicine, London, UK

Address correspondence and reprint requests to Wade S. Kingery, MD, Physical Medicine and Rehabilitation Service 117, Veterans Affairs Palo Alto Health Care System, 3801 Miranda Ave., Palo Alto, CA 94304. Address e-mail to wkingery{at}leland.stanford .edu.

	Abstract

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Glucocorticoids are used to treat patients suffering from neuropathic pain and complex regional pain syndromes (CRPS). Previously we found that once-daily injections of the glucocorticoid methylprednisolone had no antihyperalgesic effect in the rat sciatic nerve transection model for CRPS, but on the basis of CRPS clinical data, we hypothesized that a continuous infusion of methylprednisolone might prove effective. We further postulated that the antihyperalgesic effects of glucocorticoids were mediated by the inhibition of spinal neuron hyperactivity and by the depletion of substance P or its NK₁ receptor. This study tested the effects of continuously infused methylprednisolone in sciatic nerve-transected rats. Continuous infusion of methylprednisolone (3 mg · kg^-1 · d^-1 for 21 days), started after the development of neuropathic hyperalgesia, reversed both heat and mechanical hyperalgesia over 2 wk, and this effect persisted for at least 1 wk after discontinuing methylprednisolone. In addition, continuous methylprednisolone infusion partially reversed nerve injury-evoked Fos expression in the dorsal horns, suggesting that glucocorticoids can inhibit the spinal neuron hyperactivity induced by chronic sciatic nerve transection. Finally, no changes were observed in spinal substance P or NK₁ immunoreactivity after chronic methylprednisolone infusion, suggesting that the depletion of this neuropeptide or its receptor does not contribute to the antihyperalgesic actions of glucocorticoids.

Implications: Chronic continuous infusion of the glucocorticoid, methylprednisolone, relieved pain in a rodent model of nerve injury, and this effect persisted after discontinuing the drug. Methylprednisolone may be a curative treatment for some types of neuropathic pain when administered in divided daily doses over several weeks.

	Introduction

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Complex regional pain syndrome type II (CRPS II or causalgia) has been defined as a syndrome that starts after a nerve injury and is not necessarily limited to the distribution of the injured nerve. The diagnosis requires pain, allodynia, or hyperalgesia disproportionate to injury; evidence at some time of edema, changes in skin blood flow, or abnormal sudomotor activity in the region of pain; and no other conditions that would otherwise account for the degree of pain and dysfunction (1). There is no consensus on the pathophysiology of this condition and whether any treatment for CRPS is effective; hence, current therapeutic management tends to adopt a trial-and-error approach (2). Two small randomized controlled trials have reported that a 4–12-wk course of large-dose glucocorticoids, administered orally three or four times daily, can alleviate pain, hyperalgesia, and edema in CRPS patients (3,4). Interestingly, this effect can be curative, frequently persisting after the medication is discontinued (3,5). Despite these promising clinical findings, glucocorticoids are rarely used as a first-line treatment for CRPS in pain clinics, and there are no data regarding the mechanisms of action or physiologic responses to glucocorticoids in a CRPS model.

Previously we demonstrated that sciatic nerve transection in rats caused the gradual development of spontaneous pain behavior (autotomy), limb edema, and the development of hyperalgesia in a territory outside that of the injured nerve, a syndrome resembling CRPS (6). With this model, we examined the effects of once-daily methylprednisolone injections (3 mg · kg^-1 · d^-1 for 21 days); this regimen was predicated by pharmacodynamic data derived from surrogate effect marker studies. Although this methylprednisolone regimen prevented the development of autotomy pain behavior and hindpaw edema, it had no effect on heat or mechanical hyperalgesia (6). The lack of methylprednisolone antihyperalgesic effect in this CRPS model was discordant with the positive outcomes observed in randomized clinical CRPS trials that use large-dose methylprednisolone or prednisone administered orally every 6–8 h (3,4). Because of this discrepancy with the human studies, we wondered whether a single daily injection of methylprednisolone may be associated with troughs of concentrations that prevented a concerted therapeutic effect. To test this possibility, we continuously infused methylprednisolone in the same CRPS animal model. After 2 wk of infusion, methylprednisolone reversed heat and mechanical hyperalgesia, and this effect persisted after discontinuing the infusion.

Noxious stimulation leads to the induction of the neuronal immediate early gene c-fos, resulting in the rapid and transient translation of Fos protein in nuclei of spinal cord neurons. Fos immunohistochemistry has been used extensively to quantify neural responses to nociceptive stimuli. Measuring analgesic effects on noxiously evoked Fos expression allows studies in awake, intact, unrestrained animals and permits both neuroanatomical localization and quantitation of analgesic effects. Sciatic nerve transection triggers long-term spontaneous discharges in the injured neurons, and it has been proposed that this ectopic firing causes a chronic central sensitization of nociceptive spinal neurons, resulting in the persistent increase of spinal Fos (7). In the current study, we used spinal Fos immunoreactivity to demonstrate that chronic methylprednisolone infusion (3 mg · kg^-1 · d^-1 for 21 days) inhibited spinal neuronal hyperactivity in the sciatic section CRPS model.

We recently determined that a 4-wk course of methylprednisolone almost completely blocked the hindpaw neurogenic dye extravasation evoked by saphenous nerve stimulation (6). Neurogenic extravasation is mediated primarily by substance P, which is released after electrical stimulation of the peripheral nerve and binds to NK₁ receptors on the postcapillary venules. This induces the formation of intercellular gaps in the endothelium venules, thus allowing the extravasation of large protein molecules and perhaps inducing limb edema. Substance P also contributes to the development and maintenance of neuropathic hyperalgesia (8–10) and has also been proposed as a mediator of pain and edema in CRPS patients. Because substance P mediates neurogenic extravasation and is an important transmitter for neuropathic hyperalgesia, and because chronic glucocorticoid treatment inhibited both these processes, we postulated that these effects were caused by the depletion of spinal substance P or its receptor. We then tested this hypothesis by measuring substance P and NK₁ receptor immunostaining in the dorsal horns of rats after chronic methylprednisolone (3 mg · kg^-1 · d^-1 for 21 days) or saline infusion. No differences were observed in spinal immunoreactivity between the treatment groups, indicating that the antihyperalgesic effects of chronic glucocorticoid infusion were not caused by changes in spinal substance P or the NK₁ receptor.

	Methods

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These experiments were approved by our institute’s Subcommittee on Animal Studies. Adult (300–350 g) male Sprague-Dawley rats (B&K Universal, Fremont, CA) were used in all experiments. The animals were housed after surgery in groups of two in clear plastic cages with solid floors covered with 3–6 cm of soft bedding and were fed and watered ad libitum.

Sciatic nerve transections were performed under isoflurane anesthesia. The nerve was exposed at the middle of the thigh, a 1-cm segment of the nerve was excised, and the proximal stump was tightly ligated with 4-0 silk. The incision was then closed with wound clips, which were removed 10 days later. In another group of rats, sham sciatic section surgery was performed with the same procedure, but the nerve was not transected or ligated. Infusion pumps were surgically placed subcutaneously over the thoracic spine, and the skin was closed with wound clips. Methylprednisolone sodium succinate (Upjohn Company, Kalamazoo, MI) was diluted in normal saline for infusions.

Heat nociceptive thresholds were determined from the mean of three consecutive hindpaw withdrawal thresholds to a Peltier device (4 x 4-cm surface, CP1: 4-127-06L; Melcor, Trenton, NJ) applied to the medial dorsum of the hind paw. A linear ramped temperature (1°C/s, starting at 40°C and with a cutoff of 52°C) was used as previously described (6). The examiner controlled the Peltier with a foot pedal switch.

Mechanical nociceptive withdrawal responses were measured with calibrated von Frey fibers (North Coast Medical, San Jose, CA) applied over the medial dorsum of the hind paw, between the second and third metatarsals. Each fiber was applied three consecutive times by pushing down on the hind paw until the rat withdrew its paw or the fiber bowed. Four different fibers were used in graduating sequence (10, 23, 57, and 85 g) for 12 consecutive fiber applications. The withdrawal threshold was the smallest fiber size that evoked at least two hindpaw withdrawal responses during three consecutive applications with the same fiber (6). Each fiber was applied for approximately 1 s, and the interstimulus interval was approximately 5 s.

Animals were tested weekly, and before baseline measurements were taken, the animals were trained with two sessions of Peltier and von Frey testing. The testing procedure always followed the same sequence: first we measured the von Frey thresholds and then did the Peltier testing. The testing room was dimly lit, and the room temperature was maintained between 22°C and 24°C. The rats were gently held during the nociceptive testing, and testing was performed only when the rats were quietly resting in the investigator’s hand. The investigator performing the measurements was blinded to treatment.

Rats were transcardially fixed and the spinal cords removed and postfixed. Then 40-µm-thick sections were cut on a coronal plane by using a freezing cryostat. Fos immunostaining was performed as previously described (11). Because the sciatic nerve projects heavily to the L-5 segment of the spinal cord, we analyzed the numbers of Fos immunoreactive neurons at that level. Only those cells with nuclear staining that was easily identified at 10x objective magnification were counted. The dorsal horns ipsilateral and contralateral to the side of surgery were scored separately by an examiner who was blinded as to treatment.

Substance P immunoreactivity was measured in thoracic spinal sections by using an antibody for substance P (Peninsula Laboratories, San Carlos, CA). The NK₁ receptor immunoreactivity was measured in cervical spinal sections by using an antibody for the carboxyl terminus of the rat NK₁ receptor (12). The substance P antibody was diluted to 1:30,000, the NK₁ receptor antibody was diluted to 1:20,000, and immunostaining was performed as described above for Fos. To compensate for the variable density of staining between incubation wells, the cord sections from one methylprednisolone- and one saline-treated rat were placed together in the same well for all incubations (the saline-treated sections were identified by a small incision in the ventral cord). Immunoreactivity was measured in the superficial dorsal horn of the spinal cord with a computer-assisted image analysis system (NIH Image software; National Institutes of Health, Bethesda, MD). Images of the spinal cord were captured with a 4x objective and a charge-coupled device camera and converted to a digital image with a gray value ranging from 0–255. To quantify staining density, a threshold was established above which the number of pixels was counted; the threshold was the same for all cord sections.

For all behavioral data, a repeated-measures analysis of variance was performed on the data for each test date, comparing treatment groups. The repeated measure was time. Fisher’s protected least significant difference test was used to determine the source of differences among groups. Wilcoxon’s signed rank test was used to compare the source of differences for the von Frey fiber thresholds. Differences in the means of the Fos data were tested with a one-way analysis of variance and post hoc comparisons by the Fisher’s protected least significant difference test. All data are presented as the mean ± SEM, and differences are considered significant at P < 0.05.

Experiment 1
The antihyperalgesic effect of chronic methylprednisolone infusion was measured in this experiment. We had previously established that methylprednisolone did not alter nociceptive thresholds in normal rats and that sham-operated rats did not develop mechanical or heat hyperalgesia (6,13). After baseline Peltier and von Frey threshold testing, all the rats had their right sciatic nerve sectioned, and then the nociceptive thresholds were tested weekly for 8 wk. Four weeks after sciatic section, all rats were implanted with infusion pumps (ALZET 2 mL4; Alza, Palo Alto, CA). One group of rats received normal saline, and the other group had methylprednisolone (3 mg · kg^-1 · d^-1). After 3 wk of infusion (7 wk after sciatic transection), the pumps were removed. The final nociceptive threshold testing was performed 8 wk after the sciatic transection and 1 wk after removal of the pumps.

Experiment 2
This experiment examined the effect of chronic sciatic section on dorsal horn Fos immunoreactivity and then determined whether this effect was inhibited by chronic methylprednisolone infusion. There were three experimental groups: sham right sciatic section with saline pump, right sciatic section with saline pump, and right sciatic section with methylprednisolone pump (3 mg · kg^-1 · d^-1). The infusion pumps were inserted at the time of nerve injury. After 21 days of methylprednisolone or saline infusion, all the rats were perfused with fixative, Fos immunostaining was performed, and positive nuclei were counted in the bilateral dorsal horns of the L-5 segment.

Experiment 3
The effect of chronic methylprednisolone infusion on spinal substance P and NK₁ receptor immunoreactivity was evaluated in this experiment. Normal unoperated rats received either methylprednisolone (3 mg · kg^-1 · d^-1) or saline via infusion pumps for 21 days, then all the rats were transcardially perfused with fixative, and substance P and NK₁ immunostaining was performed on cervical and thoracic spinal cord sections.

	Results

Top Abstract Introduction Methods Results Discussion References

 
Experiment 1
Continuously infused methylprednisolone had an antihyperalgesic effect in neuropathic rats. After sciatic section, the nociceptive withdrawal thresholds for heat and mechanical stimuli applied over the saphenous innervated medial dorsum of the hind paw gradually dropped over several weeks ( Fig. 1). Significant hyperalgesia appeared by 2 wk for both assays. At Week 4, a continuous methylprednisolone infusion (3 mg · kg^-1 · d^-1) or normal saline was started, continuing for the next 21 days. Nociceptive thresholds gradually increased during infusion in the methylprednisolone group but not the saline group. Compared with saline, the methylprednisolone treatment reversed both heat and mechanical hyperalgesia after 2 wk of treatment. One week after stopping the infusion, the antihyperalgesic effect of the methylprednisolone treatment persisted for both nociceptive assays.

View larger version (24K): [in this window] [in a new window]   Figure 1. Methylprednisolone infusion reversed both heat and mechanical hyperalgesia. Nociceptive thresholds were tested over the saphenous innervated medial dorsum of the hind paw. After baseline testing, the sciatic nerve was transected, which caused the Peltier (A) and von Frey fiber (B) withdrawal thresholds to gradually decline, achieving hyperalgesia within 1–2 wk after nerve injury. Starting at 4 wk after sciatic transection, methylprednisolone (3 mg · kg-1 · d-1, n = 17) or saline (n = 17) was continuously infused for 21 days (black bar above x axis). Methylprednisolone gradually reversed both heat and mechanical hyperalgesia, an effect reaching significance (versus saline) after 2 wk of infusion. One week after stopping the infusions (Week 8), the reversal of heat and mechanical hyperalgesia persisted in methylprednisolone-treated animals, and the mechanical nociceptive thresholds had returned to baseline levels. Saline-treated animals remained hyperalgesic at the completion of the study. *P < 0.05 and **P < 0.01 vs saline treatment.

View larger version (37K): [in this window] [in a new window]   Figure 2. Methylprednisolone infusion inhibited the sciatic section evoked increase in spinal Fos. Sham-operated rats that underwent constant saline infusion for 21 days (sham/saline) had very few Fos-immunoreactive neurons in their dorsal horns ipsilateral or contralateral to the sham surgery (n = 6). After sciatic nerve section and 21 days of saline infusion (section/saline), there was more than a 200% increase in Fos-positive neurons in the dorsal horn ipsilateral to the nerve injury (n = 6). Contralateral to the sciatic section there was also a large increase in Fos immunoreactivity after 21 days, but this was significantly less than in the ipsilateral dorsal horn (37 ± 4 vs 47 ± 3, respectively; P < 0.05). Sciatic-sectioned rats treated with methylprednisolone infusion (3 mg · kg-1 · d-1) for 21 days after surgery (section/methylprednisolone) had a slightly smaller increase in Fos expression than the sectioned saline-treated rats, and this effect was seen only on the side ipsilateral to nerve injury (n = 7). The mean number of Fos-positive neurons counted in the dorsal horn were averaged from three sections taken from each animal. ###P < 0.001 vs sham/saline and *P < 0.05 vs section/saline treatment.

View larger version (87K): [in this window] [in a new window]   Figure 3. Fos immunostaining in the L-5 dorsal horns ipsilateral to surgery in (A) sham-operated rats treated with saline infusion for 21 days, (B) sciatic-transected rats treated with saline infusion for 21 days, and (C) sciatic-transected rats treated with methylprednisolone infusion (3 mg · kg-1 · d-1) for 21 days. There was a diffuse increase in Fos-positive neurons 21 days after sciatic section (A and B), and this increase was partially blocked by chronic methylprednisolone infusion (B and C).

View larger version (121K): [in this window] [in a new window]   Figure 4. The top two photomicrographs show dense immunostaining for substance P in the superficial dorsal horn laminae of the cervical cord. There was no obvious difference in the density of staining in normal rats treated with a 21-day infusion of saline (A) or methylprednisolone (B). The bottom two photomicrographs show the immunostaining for NK1 receptors in the superficial dorsal horn laminae of the thoracic cord. There was no difference in the density of staining in normal rats treated with a 21-day infusion of saline (C) or methylprednisolone (D). Within each incubation well, the staining density of six sections from the methylprednisolone-treated rat and six sections from the saline-treated rat were compared. The dosage of methylprednisolone was 3 mg · kg-1 · d-1 (n = 4 rats for each treatment cohort).

	Discussion

Top Abstract Introduction Methods Results Discussion References

It is difficult to predict effect-time relationships with glucocorticoids because there is no clear correlation between the magnitude and temporal course of the surrogate effect marker response and the serum concentration of methylprednisolone (14). The pharmacokinetic half-life of oral, IV, and IM administered methylprednisolone sodium succinate is 2.5 hours, but the pharmacodynamic latency of peak effect for surrogate markers (serum glucose, leukocytes, lymphocytes, endogenous hydrocortisone) is 4–6 hours, and the half-life for therapeutic effects on joint inflammation is 12–36 hours (14–16). Glucocorticoids transduce their action after binding to intracellular glucocorticoid receptors; the ligand-receptor complex binds to the glucocorticoid-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. Glucocorticoid activity is based on the modulation of de novo protein biosynthesis, and until the proteins mediating the therapeutic effects of glucocorticoids are identified, the pharmacodynamics cannot be defined.

Several previous studies have examined the analgesic efficacy of glucocorticoids in a different neuropathic model. Systemic (17) and topical glucocorticoids applied to the sciatic injury site (18) prevented or reversed hyperalgesia in a sciatic nerve loose ligation model. Because the chromic gut suture used in this neuropathic model creates a chemical inflammatory neuritis, the antihyperalgesic effects of glucocorticoids in this model may have been caused by their rapidly developing antiinflammatory properties. Significantly, glucocorticoids reversed inflammatory neuritis evoked hyperalgesia within 1–2 days (17,18), whereas the antihyperalgesic effects of methylprednisolone took two weeks to develop in our sciatic section model of CRPS. The gradual onset of glucocorticoid antihyperalgesic action in the sciatic section model suggests that this effect is not caused by an antiinflammatory mechanism.

We found that chronic sciatic transection increased Fos immunoreactivity in the spinal dorsal horn neurons both ipsilateral and contralateral to the nerve lesion. Other investigators, reporting similar findings, have demonstrated that a local anesthetic blockade of the sciatic neuroma inhibited the increase in dorsal horn Fos, suggesting that hyperactivity generated in the injured nerve evokes spinal Fos (7). We found that methylprednisolone infusion reduced Fos expression on the side of the spinal cord ipsilateral to the sciatic transection, but not contralaterally, an indication that this inhibitory effect was not caused by a generalized glucocorticoid inhibition of Fos biosynthesis but was specific to spinal activity evoked by nerve injury. Collectively, our results suggest that glucocorticoid inhibition of spinal neuron hyperactivity may play a role in its antihyperalgesic effects.

Previously we observed that chronic methylprednisolone treatment almost completely blocked the hind paw neurogenic extravasation evoked by nerve stimulation (6). Because substance P mediates neurogenic extravasation and is an important transmitter for neuropathic hyperalgesia, and because chronic glucocorticoid treatment inhibited both these processes, we postulated that these effects were caused by the depletion of spinal substance P or its receptor. Some investigators have observed a modest inhibition of substance P expression and release by glucocorticoids (19–21). Glucocorticoids also have mild postjunctional inhibitory effects on neurogenic extravasation, suggesting the possibility that the effect is caused by a down-regulation of NK₁ receptors (22–24). We found no reductions in substance P and NK₁ receptor immunoreactivity in the dorsal horns of rats chronically infused with methylprednisolone, even though antihyperalgesic effects with chronic glucocorticoid infusion were noted. Therefore, these effects are not mediated by substance P or its receptor NK₁. The immunohistochemistry methods we have used in this investigation have limited sensitivity for quantification, but clearly the ablation of neurogenic extravasation after chronic methylprednisolone administration that we observed in our previous study (6) would require large reductions in substance P or NK₁ receptor density, which we failed to observe with spinal cord immunostaining.

In conclusion, we have demonstrated that methylprednisolone, when administered by continuous infusion, has antihyperalgic effects in a CRPS model based on sciatic nerve transection. In addition, continuous methylprednisolone infusion partially reversed nerve injury-evoked Fos expression in the dorsal horns, suggesting that glucocorticoids can inhibit the spinal neuron hyperactivity induced by chronic sciatic nerve transection. Finally, no changes were observed in spinal substance P or NK₁ immunoreactivity after chronic methylprednisolone infusion, suggesting that depletion of this neuropeptide or its receptor does not contribute to the antihyperalgesic actions of glucocorticoids.

	Acknowledgments

 
This study was supported by National Institutes of Health Grant GM30232, a VA Merit Review, and the Medical Research Council.

We thank Drs. Allan Basbaum and Bradley Taylor for their invaluable advice and assistance with this investigation.

	References

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