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Anesth Analg 2002;94:421-426
© 2002 International Anesthesia Research Society

PAIN MEDICINE

The Correlation Between Dietary Soy Phytoestrogens and Neuropathic Pain Behavior in Rats After Partial Denervation

Yoram Shir, MD*, James N. Campbell, MD{dagger}, Srinivasa N. Raja, MD{ddagger}, and Ze’ev Seltzer, DMD§

*Department of Anesthesiology and Pain Relief Unit, Hadassah University Hospital, Jerusalem, Israel; Departments of {dagger}Neurosurgery and {ddagger}Anesthesiology, Johns Hopkins Medical Institutions, Baltimore, Maryland; and §Department of Physiology, Faculties of Medicine and Dental Medicine, Hebrew University, Jerusalem, Israel

Address correspondence and reprint requests to Yoram Shir, MD, Department of Anesthesiology and Pain Relief Unit, Hadassah University Hospital, Jerusalem 91120, Israel. Address e-mail to yshir{at}hadassah.org.il


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Soy diets suppress the development of neuropathic pain behavior in rats undergoing partial sciatic nerve ligation (PSL) injury. Phytoestrogens, plant isoflavones and lignans, abundantly found in soy products, have powerful estrogenic properties. Because, in some preparations, steroid estrogens were found to exert antinociception, we examined whether the analgesic effect of dietary soy is mediated by phytoestrogens. Male Wistar rats were fed five different diets containing 8–180 µg of phytoestrogens per gram. These diets were administered 2 wk before and 2 wk after PSL injury. Levels of tactile allodynia and mechanical and heat hyperalgesia of these rats were determined on Days 3, 8, and 14 after PSL injury. Plasma levels of two major phytoestrogens (genistein and daidzein) and two daidzein metabolites (equol and dihydrodaidzein) were assessed on Day 14 postoperatively. We found that the plasma concentration of these phytoestrogens and the levels of allodynia and hyperalgesia varied highly among dietary groups. Average plasma concentrations of phytoestrogens were associated with reduced levels of tactile allodynia and mechanical hyperalgesia, but not with reduced heat allodynia. Low and high plasma phytoestrogen levels were not analgesic in these tests. This report is the first to show that, at certain plasma concentrations, phytoestrogens reduce neuropathic pain in rats.

IMPLICATIONS: Dietary soy suppresses neuropathic pain in rats after partial sciatic nerve ligation. Some of the pain-suppression properties of soy can be attributed to phytoestrogens, isoflavones abundantly found in soy products. Average, but not low or high, plasma levels of phytoestrogens are associated with analgesia.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Previous animal experiments showed that diet modifies acute (1), inflammatory (2), and chronic pain in animal models (3). In our previous studies, we identified soy as a novel dietary ingredient that markedly suppresses allodynia and hyperalgesia in a model of neuropathic pain produced in rodents after partial sciatic nerve injury (the PSL model) (4). This effect of soy is a generalized phenomenon, not specific to a certain laboratory, rat strain, or pain-testing instrument, and is not correlated with calorie intake, weight gain, or dietary concentration of fat and carbohydrates (5).

The identity of the active ingredient in commercial soy products that blunts neuropathic pain after PSL injury is unknown. Of the various ingredients in soy that could play a role in pain suppression, phytoestrogens emerge as a plausible candidate. These isoflavones and lignans are abundantly found in legumes and soy products and, among other functions, influence steroid hormone metabolism (6), inhibit various types of protein-kinase enzymes (7), and have antioxidative properties (8). The structure and molecular weight of phytoestrogens are similar to those of steroid estrogens, and they possess functionally potent estrogenic activity (9). Because steroid estrogens have been implicated as antinociceptive agents (10), in this study we tested whether soy phytoestrogens are the analgesic ingredient suppressing neuropathic pain after PSL injury.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
Experiments conformed with institutional regulations for animal experimentation and those of the International Association for the Study of Pain. We used seven groups of male Wistar rats (n = 9–18 per group) supplied by Harlan (Indianapolis, IN), weighing 225–275 g at the beginning of the experiment. Males were used because all our previous studies on the role of soy feeding in blunting neuropathic pain after PSL injury were performed with male rats. Rats were housed under standard colony conditions (three rats per cage; ambient temperature kept at 22°C ± 0.5°C; water and food supplied ad libitum; day/night cycle with lights switched on at 7:00 AM and off at 7:00 PM). Tests were done between 10:00 AM and 5:00 PM.

Rats consumed one of five diets containing increasing levels of phytoestrogens (Table 1). Four of these diets contained various amounts of soy products (SOY-A, -B, and -C and RMH), whereas one diet (noSOY) was devoid of soy. RMH (RMH-1000; PMI Feeds, St. Louis, MO) is a standard rat chow that is based on a balanced formula and provided at the vivaria of Johns Hopkins University. Rats were fed RMH diet from weaning until the beginning of the experiment, and then they were switched to one of the experimental diets. Fourteen days later, baseline sensitivity to noxious and innocuous stimuli was determined (see below). All rats then underwent the PSL nerve injury. Levels of tactile allodynia and mechanical and heat hyperalgesia were determined on Days 3, 8, and 14 postoperatively (PO). The noSOY and RMH groups were replicated. Because their results were not significantly different from the first run, data of the two runs were pooled. On day 14 PO, the last day of the experiment, blood samples were taken from the heart for determination of phytoestrogen plasma concentration.


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  		Table 1. Composition of the Diets Compared in the Study
 
Nerve injury was performed under inhaled anesthesia. The right sciatic nerve was exposed near the trochanter, and an 8-O silk suture was inserted into the middle of the nerve, trapping in a tight ligation the dorsal one third to one half of the nerve thickness. The wound was closed layer by layer with muscle sutures and skin staples (11).

Behavioral tests were done by an experimenter who was unaware of the type of diet consumed by rats being tested. Withdrawal threshold to touch was measured with a set of eight calibrated von Frey hairs (measuring 0.3, 1.1, 2.8, 4.4, 6.4, 9.5, 11, and 20 g). The tested hair was indented five times (at a rate of two times per second) in the midplantar skin of the paw until the hair bowed. If below threshold, the stimulus intensity was increased by using the next hair. At threshold, rats responded by paw elevation. Response to pinprick was tested by pricking the midplantar area once with a sharpened wooden stick. Duration of paw lifting was recorded using a stopwatch, with a cutoff of 30 s. Response to noxious heat was determined with a Hargreaves device. We recorded the time elapsed from stimulus onset until paw lifting ("withdrawal latency") and the duration of paw lifting until it was replaced on the floor ("response duration"), with a cutoff of 30 s. Each paw was tested three times, allowing 2 min between tests to avoid sensitization. Withdrawal latency and response duration of individual rats were calculated as the average of three trials.

Plasma levels of two major phytoestrogens (genistein and daidzein) and two daidzein metabolites (equol and dihydrodaidzein) were determined (12). Blood samples of one or two rats of each diet group were pooled to create 4–13 samples per diet group. Each sample was run in duplicate, and measurements were averaged. Isoflavone concentration was determined by adding 1.0 mg of ß-glucoronidase/sulfatase to 1.0 mL of serum. The pH was adjusted to 5.0 with 1.0 M ammonium acetate buffer and incubated overnight at 37°C. The isoflavone mixture was dissolved in 4 volumes of hexane and then extracted twice, each time with 3 volumes of ethyl ether. Extracts were pooled, evaporated to dryness, and redissolved in one tenth of the original volume. Analyses were performed on a Hewlett-Packard (Palo Alto, CA) 1050 high-performance liquid chromatography system and a PE Sciex (Ontario, Canada) API III triple quadrapole mass spectrometer. A linear gradient of 0%–50% acetonitrile in 10 mM ammonium acetate, pH 6.5, over 10 min at a flow rate of 1.0 mL/min, was used to separate the isoflavones on a 10-cm-long, 4.6-mm-inner-diameter, 300 pore size, Aquapore C8 (Varian, Walnut Creek, CA) reversed phase column.

The sensitivity of intact rats to noxious and innocuous stimuli was calculated for each group as the average of both hindpaws, creating a single score. One-way analysis of variance (ANOVA) for main effect of diet type on the withdrawal threshold to touch was done with the Kruskal-Wallis test. Post hoc differences between the two diet groups were calculated with the Mann-Whitney U-test. Differences in the withdrawal threshold to heat and the response duration to pinprick and noxious heat were assessed with ANOVA, and Student’s t-tests were used for post hoc analyses.

The levels of allodynia and hyperalgesia after PSL injury were determined for the partially denervated hindpaw. For each diet group, a grand average (±SEM) was calculated over the three PO testing sessions (Days 3, 8, and 14), creating a single PO score per group. We calculated the average (±SEM) plasma levels of each phytoestrogen for each diet. The main effect of diet was determined with one-way ANOVA.

Plasma phytoestrogen concentrations were correlated with the levels of allodynia and hyperalgesia. We first explored the type of correlation that best fitted the data by calculating the correlation coefficient for linear, exponential, logarithmic, power, and second-order polynomial functions. This was done separately for each phytoestrogen and then grand averaged across all four phytoestrogens over the baseline and PO periods. The best correlation type was then identified with an ANOVA test comparing the correlation coefficients for each sensory test, followed by a post hoc analysis. P < 0.05 was regarded as significant and was corrected when appropriate with the Bonferroni adjustment.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
The plasma levels of the four phytoestrogens were highly variable across the five diet types, ranging from 13.8 ± 1.1 to 1094.5 ± 53.3 nmol/L for genistein, 4.1 ± 0.3 to 1353.5 ± 63.4 nmol/L for daidzein, 5.1 ± 0.4 to 1568.3 ± 45.0 nmol/L for equol, and 0 to 131.1 ± 17.2 nmol/L for dihydrodaidzein (P < 0.0001; Fig. 1). Compared with noSOY, the RMH diet contained 79-, 330-, 307-, and 1311-fold higher concentrations of these phytoestrogens, respectively.



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  		Figure 1. Average (±SEM bars) plasma levels of equol, daidzein, genistein, and dihydrodaidzein (DHD) in rats fed four diets containing soy protein (RMH and SOY-A, -B, and -C) and a diet devoid of soy (noSOY). Diet groups are presented from left to right on the basis of levels of phytoestrogens in plasma (RMH > SOY-C > SOY-B > SOY-A > noSOY).

 
Figure 2A–D shows the average levels of allodynia and hyperalgesia normalized relative to the baseline levels. Rats fed a noSOY diet developed tactile allodynia (decreased withdrawal threshold to tactile stimuli, Fig. 2A), heat allodynia (decreased withdrawal latency and increased response duration to noxious heat; Fig. 2, B and D, respectively), and mechanical hyperalgesia (increased response duration to pinprick; Fig. 2C). Rats fed diets containing soy (RMH and SOY-A, -B, and -C, pooled as "SOY") developed mechanical hyperalgesia and increased response duration to heat after the PSL injury (Fig. 2, C and D, respectively), but not tactile and heat allodynia (Fig. 2, A and B, respectively). Reaffirming our previous reports, rats fed the noSOY diet developed a significantly reduced withdrawal threshold to tactile stimulation and reduced withdrawal latency to heat stimulation compared with rats fed the SOY diets (P < 0.0001, respectively), and they developed an increased response duration to pinprick (P = 0.03). The response duration to noxious heat was not significantly different between the SOY and noSOY groups (Fig. 2D).



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  		Figure 2. Levels of sensory disorders produced by partial sciatic nerve ligation (PSL) injury in rats fed diets containing soy (RMH or SOY-A, -B, or -C, pooled as SOY) or devoid of soy protein (noSOY). Post-PSL responses to noxious and innocuous stimuli were normalized relative to the baseline levels of intact animals (Baseline = 100%). A, The withdrawal threshold (g) to von Frey hair indentation in the plantar area of the hindpaw after PSL injury. The withdrawal threshold decreased significantly only in rats fed the noSOY diet (P < 0.0001). B, The heating time until paw withdrawal (s) was significantly shorter in rats fed the noSOY diet (P < 0.0001). C, The response duration (s) to a single pinprick applied to the midplantar area of the hindpaw. Mechanical hyperalgesia developed in rats fed SOY and noSOY diets but was more pronounced in rats fed the noSOY diet (P = 0.037). D, The response duration (s) to noxious heat applied to the midplantar area of the hindpaw. SOY and noSOY diet groups developed heat allodynia, more in the latter group, but this difference was not significant.

 
Figure 3 shows the grand average coefficients for the correlation between plasma phytoestrogen levels and sensory responses for the various correlation types. A second-order polynomial function yielded the highest coefficients (P < 0.0001). Using this function, Figure 4A–D shows the correlation between plasma levels of the phytoestrogens and baseline sensibility of intact rats and their post-PSL sensory abnormalities. A U-shaped correlation characterizes the baseline sensitivity to touch, pinprick, and noxious heat stimuli. Thus, midrange, but not large or small, plasma phytoestrogen concentrations were associated with reduced sensitivity. Likewise, midrange plasma phytoestrogen concentrations reduced tactile allodynia and mechanical hyperalgesia. Mid- and large-range plasma phytoestrogen concentrations were analgesic for the latency to withdrawal from a noxious heat stimulus (Fig. 4C). However, this effect was not evident for the response duration to noxious heat (Fig. 4D).



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  		Figure 3. The grand average (±SEM) of the coefficients of correlation between plasma levels of equol, daidzein, genistein, and dihydrodaidzein and responses of intact and partial sciatic nerve ligation-injured animals to tactile, noxious mechanical, and heat stimuli. For each behavioral response we plotted a curve that best fitted the data, using the following correlation types: second-order polynomial (Poly), linear (Line), logarithmic (Log), power, and exponential (Exp). The average correlation coefficients of a second-order polynomial function were significantly better in characterizing the data than the other correlation types (P < 0.0001).

 


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  		Figure 4. The second-order polynomial correlation between plasma levels of equol, daidzein, genistein, and dihydrodaidzein (DHD) and the responses of intact (broken lines) and partial sciatic nerve ligation (PSL)-injured rats (solid lines) to nonnoxious and noxious mechanical and heat stimuli. A, The correlation between phytoestrogen plasma levels and the withdrawal threshold to touch (g), using repeated von Frey hair indentation at the hindpaw plantar area. A second-order polynomial function shows an inverted U-shape for this correlation (with R2 ranging from 0.63 to 0.94 for intact rats and from 0.47 to 0.6 for PSL-injured rats). B, The correlation between plasma levels of the four tested phytoestrogens and the response duration (s) to a single pinprick. The ordinate on the right side relates to intact rats and the ordinate on the left to PSL-injured rats. A second-order polynomial function shows a U-shaped curve for this correlation, with coefficients ranging from 0.75 to 0.94 for intact rats and 0.2 to 0.56 for PSL-injured rats. C, The correlation coefficients for plasma levels of phytoestrogens versus the heating time (s) until paw withdrawal were 0.21–0.53 for intact rats and 0.2–0.41 for PSL-injured rats. D, The correlation coefficients for plasma levels of phytoestrogens versus the response duration (s) to noxious heat were 0.14–0.69 for intact rats and 0.006–0.05 for PSL-injured rats.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
We have reported that consumption of soy is associated with blunting of neuropathic pain disorders after partial denervation in the PSL model (4). These results reaffirm these observations because variable concentrations of soy in the diet suppressed the levels of allodynia and hyperalgesia after partial hindpaw denervation. Soy products contain large concentrations of various phytoestrogens. These compounds bind to estrogen receptors and possess a significant estrogenic effect in animals and humans. Previous studies have shown that estrogens play a role in acute and chronic pain in animals. For example, the administration of ovarian sex steroids caused antinociception in females and orchidectomized male rats (10,13). Autotomy (self-mutilation) levels after hindpaw denervation were reduced in estradiol-treated ovariectomized female rats (14). In contrast, more robust tactile allodynia developed in female than in male rats after PSL injury in Sprague-Dawley rats (15), and intact female rats were more susceptible to develop tactile allodynia than ovariectomized rats (16). Thus, estrogen has complex effects on nociception, depending on the type of pain model and perhaps also the animal species and strain under study.

In this study we correlated plasma phytoestrogen levels with the responses of partially denervated rats to sensory stimuli. The main results of this study show that midrange plasma levels of phytoestrogens were associated with reduced pain behavior in response to innocuous and noxious mechanical, but not heat stimuli. In contrast, low and high plasma phytoestrogen levels had no analgesic properties. Thus, like estrogen, soy phytoestrogens play a complex role in the development of neuropathic pain levels in rats.

In this study, rats were fed the RMH diet from weaning until they were switched to one of the tested diets. Because compared with these diets, RMH feeding was associated with the highest plasma levels of phytoestrogens, our results may reflect a response to the withdrawal from the levels provided by RMH.

In four of the five diet groups, the concentration of phytoestrogens in plasma correlated with phytoestrogen levels in the diet. However, rats consuming the RMH diet had the highest plasma levels of phytoestrogens (Fig. 1), but only average levels in the diet (Table 1). Rats of all five groups consumed similar amounts of diet, and weight gain in all five groups was not significantly different (data not shown). Thus, the high plasma levels of phytoestrogens in the RMH-Fed group did not result from a larger consumption of this diet. Although we have no explanation for this result, it is possible that certain ingredients in the RMH diet enhanced production of phytoestrogens by intestinal flora (17).

A rapidly growing body of data indicates that dietary phytoestrogens can reach the central nervous system (CNS) (18), exerting powerful neuroactive properties that may augment or suppress neuropathic pain. For example, phytoestrogens increase the levels of brain-derived neurotrophic factor (19) and inhibit tyrosine kinase (20), all of which play a role in processing pain sensation. In addition, some phytoestrogens provide neuroprotective effects, as demonstrated, for example, in the murine model of amyotrophic lateral sclerosis and after oxygen singlet-induced cerebral damage (21). This protective property of phytoestrogens may be relevant to pain. It has been suggested that chronicity of pain may result from neurodegeneration of inhibitory CNS neurons (22). The reduction in {gamma}-aminobutyric acid (GABA) neurons in the spinal dorsal horn and supraspinally is compatible with this putative mechanism. We recently reported that the analgesic effect of dietary soy is apparent only when consumed before, but not after, PSL injury (23). Our results are compatible with the hypothesis that, at a certain concentration range, phytoestrogens may protect inhibitory neurons when present in the CNS at the time of nerve injury and during the first days thereafter. However, genistein and daidzein block GABAA receptors (20). It is possible that at certain concentrations, lack of antinociception by phytoestrogens may be mediated by their interference with GABA antinociception.

These putative mechanisms may account for the analgesic effect of phytoestrogens in small-range and midrange concentrations. However, the reduced analgesic effect of phytoestrogens at large concentrations needs to be further investigated.

Could these results be of value in the treatment of chronic pain in humans? The median plasma levels of genistein and daidzein in Japanese middle-aged women consuming a traditional soy diet based on tofu, natto, and miso were approximately 280 nmol/L (24). These levels are within the range of plasma levels of phytoestrogens in rats in this study. However, it is difficult to extrapolate from our results in rats to the possibility of pain suppression in humans experiencing chronic pain. Because phytoestrogens possess estrogen-like activity, caution should be exercised when considering clinical trials using large doses of these compounds (25).

In summary, we report that dietary phytoestrogens exerted a complex U-shaped effect on baseline sensibility of intact rats and on tactile allodynia and mechanical hyperalgesia after partial nerve injury. Each of the four tested phytoestrogens exerted its analgesic effect at midplasma levels. Low and high plasma levels of phytoestrogens were not associated with decreased pain behavior.


   Acknowledgments
 
Supported in part by grants from the US-Israel Binational Science Foundation (93-00257 and 96-00350), National Institutes of Health (NS26363), and the Blaustein Foundation for Pain Research.

We are grateful to ADM Co. (Decatur, IL) for a gift of soy products and to Bio-Serve, Inc. (Frenchtown, NJ), for the rat diets.


   References
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Accepted for publication October 2, 2001.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2002 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press