Soy-Containing Diet Suppresses Chronic Neuropathic
Sensory Disorders in Rats
Yoram Shir, MD*, Rishi Sheth,
Ze’ev Seltzer, MD§
MD†,
James N. Campbell,
MD†,
Srinivasa N. Raja,
DMD‡,
and
*Department of Anesthesiology and Pain Relief Unit, Hadassah University Hospital, Jerusalem, Israel; †Department of
Neurosurgery, Johns Hopkins Medical Institutions, Baltimore, Maryland; ‡Department of Anesthesiology, Johns Hopkins
Medical Institutions, Baltimore, Maryland; and §Department of Physiology, Faculties of Medicine and Dental Medicine,
Hebrew University, Jerusalem, Israel
Partial sciatic nerve ligation (PSL) in rodents produces
chronic neuropathic sensory disorders resembling neuropathic pain in humans. We previously reported that
levels of allodynia and hyperalgesia after PSL injury
were markedly attenuated by consumption of soycontaining diets. Here we aimed to show that dietary
effect on pain behavior is not specific to a certain laboratory. For this purpose, experiments were conducted
in a different laboratory (Baltimore rather than Jerusalem) and a different rat strain (Wistar rather than Sabra), with additional and different testing methods (radiant heat from a lamp rather than a CO2 laser). Rats
were fed two soy-free diets and a soy-containing one for
P
artial sciatic nerve ligation (PSL) in rats produces
chronic neuropathic sensory disorders (CNSD)
(1). Levels of allodynia and hyperalgesia in this
model vary considerably across laboratories. Attempting to identify the variable at play, we found that diet
markedly modifies levels of CNSD in this model (2).
Specifically, consumption of a diet containing soy protein suppressed CNSD after PSL injury. We also found
that diet affects CNSD levels in another neuropathic
model produced in rodents by total hindpaw denervation (3). However, it is possible that these observations were idiosyncratic to a particular experimental
design and not a generalized phenomenon. Indeed,
differences in modes of behavior other than pain were
found across different laboratories (4). Therefore, here
we examined whether the effect of diet on CNSD was
demonstrable across two laboratories, differing in
Accepted for publication December 12, 2000.
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
[email protected].
©2001 by the International Anesthesia Research Society
0003-2999/01
28 days. The sensitivity of rats to nonnoxious and noxious stimuli was determined before PSL injury, and levels of neuropathic sensory disorders were determined
after it. We found that consuming the soy-containing
diet prevented development of tactile and heat allodynia, but not mechanical hyperalgesia. This dietary effect was not correlated with calorie intake and weight
gain or dietary concentration of fat and carbohydrates.
We conclude that, regardless of experimental site, diet
markedly affects chronic neuropathic sensory disorders in rats and should be standardized in animal models of pain.
(Anesth Analg 2001;92:1029 –34)
their vivaria, rat strain, composition of diet, and sensory testing methods used to determine levels of sensory disorders. We also examined whether diet has an
effect on baseline touch and acute pain sensitivity in
intact animals (5). Finally, food palatability and calorie
intake affect acute (6,7) and persistent inflammatory
pain (8). Therefore, we examined whether the calorie
intake of a certain diet under test is responsible for
suppression of the sensitivity of intact rats to noxious
stimuli and of CNSD in the PSL model.
Methods
Experiments were conducted at Johns Hopkins University, Baltimore, MD, and conformed to institutional
regulations for animal experimentation and those of
the International Association for the Study of Pain (9).
We used eight groups of male Wistar rats (n ⫽ 6 –11
rats per group) (Harlan, Indianapolis, IN) weighing
225–275 g at the beginning of the experiment. Rats
were housed under standard colony conditions (3 rats
per cage; ambient temperature kept at 22°C ⫾ 0.5°C;
water and food supplied ad libitum; day/night cycle
was lights switched on at 7:00 am and off on 7:00 pm).
Tests were performed between 10:00 am and 5:00 pm.
Anesth Analg 2001;92:1029–34
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CHRONIC PAIN IS SUPPRESSED BY DIETARY SOY
We tested three diets:
1. RMH (RMH-1000; PMI Feeds, St. Louis, MO), a
balanced diet comprising 14% protein (85% from
soy), 67.5% carbohydrates, 6% fat, 4.5% fiber, 8%
ash, vitamins, and trace elements. This diet contained 70 ␮g phytoestrogen per gram of diet and
provided 3.3 kcal/g.
2. CAS (Bio-Serv Co., Frenchtown, NJ), an artificial
balanced diet (10) comprising 16% casein protein,
65% carbohydrates (50% starch, 15% sucrose),
5% canola oil (composed of 6% saturated, 36%
polyunsaturated, and 58% monounsaturated
fatty acids), 5% fiber, 3.5% ash, vitamins, and
trace elements. This diet contained 8 ␮g phytoestrogen per gram of diet and provided 3.8
kcal/g.
3. BC, an unbalanced diet made of white bread and
fresh cucumbers from a local store. The caloric
and nutritional values of cucumbers were considered to be negligible. White bread is 8.2%
protein, 50% carbohydrates (43% starch, 7%
sucrose), 3.6% fat (composed of 30% saturated,
15% polyunsaturated, and 55% monounsaturated fatty acids), 3.4% fiber, 2.1% ash, vitamins, and trace elements. This diet contained
16 ␮g phytoestrogen per gram and provided
2.7 kcal/g.
Rats were fed RMH diet from weaning until the
beginning of the experiment, then switched to one of
the experimental diets for 28 days. Three Control
groups of rats (n ⫽ 6 per group) were fed RMH, CAS,
and BC and designated CON-RMH, CON-BC, and
CON-CAS. Five rat groups, fed RMH, CAS, or BC
diets, underwent a PSL injury on Day 14 (PSL-RMH,
PSL-CAS, and PSL-BC groups). The former two
groups were replicated. Because their results were not
significantly different from the first run, data of the
two runs were pooled.
Daily dietary consumption of each cage was calculated by weighing the diet remaining in the food hopper and subtracting it from the amount given the day
before (no allowance was made for spillage). Daily
calorie intake per rat was calculated by multiplying
the daily weight of consumed diet per cage by its
caloric value and dividing it by the number of rats per
cage. Rats’ weights were recorded at the beginning of
experiment, before nerve injury, and at the end of the
experiment.
With the rats under inhaled anesthesia, the right
sciatic nerve was exposed near the trochanter (1). By
using a minineedle, an 8-0 silk suture was inserted in
the middle of the nerve, trapping in a tight ligation the
dorsal 1⁄3–1⁄2 of the nerve thickness. The wound was
closed with muscle sutures and skin staples.
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The responses of PSL-injured rats to mechanical and
thermal stimuli were determined bilaterally 1 day before PSL surgery (Day 13 of experimental feeding) and
repeated on Days 3, 8, and 14 thereafter (1). Intact rats
were tested on Days 13, 16, 22, and 28 of the experiment, matching those of PSL-injured rats. The experimenter was unaware of the type of diet consumed by
rats under testing.
Withdrawal threshold to touch was measured with
a set of eight calibrated von Frey hairs (weighing 0.3,
1.1, 2.8, 4.4, 6.4, 9.5, 11, and 20 g). Each rat was placed
in a chamber with a mesh metal floor, covered by an
opaque plastic dome. After 5 min of acclimation, the
tested hair was indented five times, at a rate of two per
second, in the midplantar skin of the paw until it
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 in the same chamber by a single pricking of the midplantar area with a
sharpened wooden stick. Duration of paw lifting was
recorded with a stopwatch, with a cutoff of 30 s.
Response to noxious heat was tested with the
Hargreaves method (11). Rats were tested in a chamber with a glass floor kept at 32°C. Heat was emitted
from a 150 W lamp, automatically shutting off when
the animal withdrew. We recorded the time lapsing
from stimulus onset until paw lifting (“withdrawal
threshold”) 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 an interval of 2 min between tests to avoid sensitization. Withdrawal threshold and response duration
of individual rats were calculated as the average of
three trials.
Weight gain of individual rats and mean calorie
intake per rat were calculated separately for 14 days
before nerve injury and for 14 days after surgery.
Sensitivity of intact rats to noxious and innocuous
stimuli was calculated as the average of both hindpaws for each testing day. A grand average of the four
testing sessions was performed for each group, creating a single score. One-way analysis of variance
(ANOVA) for main effect of diet on the withdrawal
threshold to touch was done by using the KruskalWallis test. Post hoc differences between two diets
were calculated with the Mann-Whitney U-test. Differences in the withdrawal threshold to heat and the
response duration to pinprick and heat were assessed
by using ANOVA, and t-test for post hoc analyses.
Behavioral scores of PSL-injured rats were calculated for each hindpaw separately. For each group, a
grand average was calculated for the three postoperative testing sessions, creating a single score per
group. P ⬍ 0.05 was used as the level of significance,
corrected when appropriate by using the Bonferroni
adjustment.
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CHRONIC PAIN IS SUPPRESSED BY DIETARY SOY
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Results
The average variance in the weight gain per cage,
along the experiment, was small (5.5% of the average
rat weight). Weight gain of PSL-BC, PSL-CAS, and
PSL-RMH rats significantly differed a day before
nerve injury (P ⬍ 0.0001) and at the end of the experiment (P ⬍ 0.0001). Weight gain of PSL-BC rats was
significantly smaller than that of the PSL-RMH or
PSL-CAS groups, before (P ⬍ 0.0001) and after nerve
injury (P ⬍ 0.0001) (Fig. 1). Weight gain and calorie
consumption of PSL-RMH and PSL-CAS groups were
not significantly different before (P ⫽ 0.1) or after PSL
injury (P ⫽ 0.1). PSL-BC rats consumed more calories
but gained less weight than the PSL-CAS or PSL-RMH
groups (Fig. 1).
Tactile withdrawal threshold and response duration
to pinprick or noxious heat of intact rats were not
significantly different among the three diet groups (P
⬎ 0.3 for all three comparisons) (Figs. 2, 3, 5). Withdrawal threshold to heat was significantly affected by
type of diet (P ⬍ 0.0001) (Fig. 4). Consumption of
bread and cucumbers for 28 days produced significant
hypoalgesia compared with RMH and CAS diets
(CON-BC versus CON-CAS or CON-RMH, P ⬍
0.0001).
Nerve injury produced sensory abnormalities in all
three dietary groups, lasting at least 14 days after
surgery.
Compared with intact rats, all three PSL-injured
groups developed a significant tactile allodynia, because their withdrawal threshold to touch was significantly lower after nerve injury (PSL-RMH versus
CON-RMH, P ⫽ 0.0004; PSL-CAS versus CON-CAS, P
⫽ 0.0002; PSL-BC versus CON-BC, P ⫽ 0.001) (Fig. 2).
Diet significantly affected levels of tactile allodynia
after PSL injury (P ⫽ 0.017). Consumption of RMH, a
diet containing soy, produced significantly lower levels of tactile allodynia than diets devoid of soy (PSLRMH versus PSL-CAS, P ⫽ 0.01; PSL-RMH versus
PSL-BC, P ⫽ 0.039). Levels of allodynia to touch in rats
fed diets devoid of soy were not significantly different
(PSL-CAS versus PSL-BC, P ⫽ 0.9).
Compared with intact rats, all three PSL-injured
groups developed a significant mechanical hyperalgesia, because their response duration to pinprick was
significantly prolonged after nerve injury (PSL-RMH
versus CON-RMH, P ⫽ 0.001; PSL-CAS versus CONCAS, P ⫽ 0.0002; PSL-BC versus CON-BC, P ⫽ 0.01)
(Fig. 3). Levels of mechanical hyperalgesia did not
depend on the type of diet (P ⫽ 0.2).
Compared with intact rats, a significant heat allodynia developed in the two groups fed a diet devoid
of soy (CAS and BC), because their withdrawal threshold to heat was significantly lower after nerve injury
(PSL-CAS versus CON-CAS, P ⫽ 0.0003; PSL-BC versus CON-BC, P ⬍ 0.0001). However, consuming RMH
Figure 1. Relative weight gain and calorie intake of intact rats and
rats undergoing partial sciatic nerve ligation (PSL injury). BC, a diet
made of white bread and fresh cucumbers; RMH, a diet containing
soy; CAS, a diet devoid of soy, based on casein. Baseline, first day
rats were switched to one of the three tested diets; pre-PSL, Day 14
of feeding on an experimental diet, just before PSL nerve injury;
post-PSL, Day 14 after PSL nerve injury. Although consuming significantly more calories than the other two groups, BC fed rats
gained significantly less weight throughout the experiment (*P ⬍
0.05).
had not changed the time needed to elicit paw withdrawal (PSL-RMH versus CON-RMH, P ⫽ 0.08) (Fig.
4). Diet had a significant effect on withdrawal threshold to heat after PSL injury (P ⬍ 0.0001). This effect
was more robust in rats consuming diets devoid of soy
compared with rats fed a diet containing soy (PSL-BC
versus PSL-RMH, P ⫽ 0.0002; PSL-CAS versus PSLRMH, P ⫽ 0.0006). Levels of heat allodynia in the two
groups fed diets devoid of soy did not differ significantly (PSL-CAS versus PSL-BC, P ⫽ 0.5).
A significantly prolonged response duration to heat
developed in all nerve-injured groups, compared with
intact rats (PSL-RMH versus CON-RMH, P ⫽ 0.0005;
PSL-CAS versus CON-CAS, P ⫽ 0.0001; PSL-BC versus CON-BC, P ⫽ 0.0004) (Fig. 5). The response duration did not depend on the type of diet (P ⫽ 0.3).
Of PSL-CAS and PSL-BC rats, 43% and 36%, respectively, expressed tactile allodynia on the contralateral
intact hindpaw, compared with only 17% of PSL-RMH
rats. In addition, 44% and 20% of PSL-BC and PSLCAS rats, respectively, presented heat allodynia on the
intact hindpaw, whereas none of the rats of the PSLRMH group did so. Thus, consumption of soycontaining diet prevented development of allodynia
on the mirror image side as well.
Discussion
Surprisingly, very little is known about the effect of
diet on chronic pain in animals (3,12) or humans (13).
The main results of this experiment were that the type
of diet rats consumed played an important role in
neuropathic pain levels after partial denervation. Specifically, we found that a soy-containing diet significantly blunted tactile and heat allodynia after PSL
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Figure 2. The effect of diet on touch sensitivity of intact rats and tactile allodynia in
nerve-injured rats. Left panel, intact rats fed
a tested diet for 28 days. Right panel, nerveinjured rats (PSL) fed the same diets for
14 days before nerve injury and 14 days
thereafter. Withdrawal threshold of intact
rats to von Frey hair indentation did not
differ significantly across the three diets.
However, after PSL injury, rats fed bread
and cucumbers (BC) and rats fed soy-free
diet (CAS) presented significantly more tactile allodynia than rats fed soy-containing
diet (RMH) (P ⫽ 0.04 and P ⫽ 0.001,
respectively).
Figure 3. The effect of diet on noxious mechanical sensitivity of intact rats (left panel)
and mechanical hyperalgesia in nerve injured rats (PSL) (right panel). BC, a diet
made of white bread and fresh cucumbers;
RMH, a diet containing soy; CAS, a diet
devoid of soy, based on casein. Response
duration to pinprick of intact rats fed three
different diets did not differ significantly.
All three dietary groups developed significant mechanical hyperalgesia that was not
significantly different among groups.
injury, but not mechanical hyperalgesia. The analgesic
properties of soy were not limited to a single laboratory because we reaffirmed its effect in a different
laboratory and experimental design.
The only difference between our previous results in
Jerusalem (2) and this study in Baltimore is that soy
diet did not prevent the development of increased
response duration to heat in the latter. This difference
may be caused by the different rat strain used in the
two studies (Sabra and Wistar, respectively). Genetic
effects in the PSL and related models have been demonstrated in rats and mice (14 –16). In addition, the
differing results could be caused by different methods
for production of heat (CO2 laser versus the Hargreaves method). Because in the latter method, rats
withdraw from the stimulus at threshold, the level of
sensitization it produces is lower compared with the
CO2 laser.
In agreement with other reports, heat pain sensitivity of intact rats was significantly affected by diet.
Increased amounts of dietary sucrose reportedly attenuated heat pain (6,7,17) and paw inflammation (8),
an effect putatively mediated by endogenous opioids
(18). However, in this experiment, RMH and casein
diets contained equal concentrations of carbohydrates
(67.5% and 65%, respectively), yet PSL-injured rats fed
these diets differed significantly in their tactile and
heat allodynia. Moreover, BC diet contained 15%–17%
fewer carbohydrates than CAS or RMH, but levels of
allodynia and hyperalgesia in rats fed BC did not
differ significantly from CAS. Thus, carbohydrates did
not affect the reduction in tactile and heat threshold in
the two soy-free groups.
Increasing fat content in the diet attenuates acute
heat pain (5). It is unlikely, however, that in this
experiment, dietary fat content affected levels of
CNSD. The CAS and BC diets differed both in their
fatty acids concentration and composition. Yet similar
levels of CNSD developed in these two groups after
nerve injury. Moreover, CAS and RMH contained similar fat levels but expressed significantly different levels of allodynia.
Consumption of highly palatable foods increases
calorie intake (19) and attenuates responses of rodents
to acute pain (6,7). In this experiment, rats fed BC
consumed significantly more calories than rats fed the
RMH or CAS diets. It is not clear whether the increased calorie consumption of rats fed the BC diet
was caused by its increased palatability or to its being
an unbalanced diet. Nevertheless, similar to previous
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CHRONIC PAIN IS SUPPRESSED BY DIETARY SOY
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Figure 4. The effect of diet on heat sensitivity of intact rats (left panel) and heat
allodynia in rats undergoing partial sciatic ligation (PSL) (right panel). Withdrawal threshold of intact rats fed bread
and cucumbers (BC) was significantly
higher compared with the other two diet
groups. When fed soy-free diets (CAS
and BC), PSL-injured rats developed significantly higher heat allodynia than rats
fed a soy-containing diet (RMH) (*P ⫽
0.0002 and P ⫽ 0.0006, respectively).
Figure 5. The effect of diet on the response duration to noxious heat stimuli
of intact rats (left panel) and rats undergoing partial sciatic ligation (PSL) (right
panel). BC, a diet made of white bread
and fresh cucumbers; RMH, a diet containing soy; CAS, a diet devoid of soy,
based on casein. Response duration of
intact rats fed three different diets did
not differ significantly. All three dietary
groups developed significant heat allodynia that was not significantly different
among groups.
studies, the withdrawal threshold to noxious heat of
intact BC rats was significantly higher compared with
the other two groups (Fig. 4) (6,7). Higher calorie
intake had no effect, however, on the development of
the PSL model, because BC and CAS rats, significantly
differing in their calorie intake, developed similar
neuropathic pain levels.
Younger rats tend to develop more pain in other
models of neuropathy, arguably because of lower
body weight [reviewed by Zeltser and Seltzer (20) and
Bennett et al. (21)]. This was never examined, however, in the PSL model. BC-fed rats gained significantly less weight than the other two groups, but their
levels of CNSD after PSL injury were not significantly
different than CAS-fed rats. Thus, body weight in
Wistar rats is not associated with levels of neuropathic
disorders in this model.
It is likely that soy is the dietary ingredient responsible for suppression of CNSD in the PSL model. RMH
and CAS diets differed mainly in the protein source,
i.e., soy protein in RMH versus casein protein in CAS.
Nevertheless, these diets were not identical, suggesting that other ingredients could suppress CNSD in
this model. However, when rats were fed identical
diets differing only in their protein, i.e., soy versus
casein, soy-based diet was associated with suppressed
levels of allodynia and hyperalgesia (2). Of the various
ingredients in soy protein that could prevent the development of CNSD, phytoestrogens and certain
amino acids are the most plausible candidates. Phytoestrogens are plant compounds possessing estrogenic properties (22). Because estrogens may augment
antinociception (23), soy phytoestrogens could mediate the suppression of CNSD after PSL injury. Our
recent results in Wistar rats partially support this suggestion (unpublished data). However, the correlation
between dietary and plasma levels of amino acids in
rats fed the RMH, CAS, and BC diets—and CNSD in
these rats—was not significant for any amino acid
(unpublished data). Thus, a possible role for certain
amino acids in the suppression of CNSD in the PSL
model has yet to be found.
We conclude that the effect of diet on the development of CNSD in the PSL model was evident across
two different laboratories, rat strains, heat-producing
stimulators, diet types, diet providers, and vivaria.
Food vendors supply rat chows standardized for the
relative content of basic nutritional ingredients, but
not for the source and type of these ingredients. Therefore, standardized, artificial balanced diets are recommended for rat experiments that use the PSL model,
and probably for other pain models. Neuropathic pain
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CHRONIC PAIN IS SUPPRESSED BY DIETARY SOY
in humans is only partially understood and many
times is refractory to treatment. Future studies will
show whether dietary manipulation can alleviate pain
in humans with these syndromes.
We are grateful to Marshall Devor for commenting on this manuscript. This project was supported in part by the US-Israel Binational
Science Foundation 98203, NIH grant 26363, and the Blaustein
Foundation for Pain Research.
References
1. Seltzer Z, Dubner R, Shir Y. A novel behavioral model of neuropathic pain disorders produced in rats by partial sciatic nerve
injury. Pain 1990;43:205–18.
2. Shir Y, Ratner A, Raja SN, et al. Neuropathic pain following
partial nerve injury in rats is suppressed by dietary soy. Neurosci Lett 1998;240:73– 6.
3. Shir Y, Ratner A, Seltzer Z. Diet can modify autotomy behavior
in rats following peripheral neurectomy. Neurosci Lett 1997;236:
71– 4.
4. Crabbe JC, Wahlsten D, Dudek B. Genetics of mouse behavior:
interactions with laboratory environment. Science 1999;284:
1670 –2.
5. Yehuda S, Carraso RL. Modulation of learning, pain thresholds
and thermoregulation in the rats by preparations of free purified alpha linolenic and linolenic acids: determination of their
optimal ratio. Proc Natl Acad Sci U S A 1993;90:10345–9.
6. Blass E, Fitzgerald E, Kehoe P. Interactions between sucrose,
pain and isolation distress. Pharmacol Biochem Behav 1987;26:
483–9.
7. Zhang T, Reid K, Acuff CG, et al. Cardiovascular and analgesic
effects of a highly palatable diet in spontaneously hypertensive
and Wistar-Kyoto rats. Pharmacol Biochem Behav 1994;48:
57– 61.
8. Ren K, Blass EM, Zhou Q, Dubner R. Suckling and sucrose
ingestion suppress persistent hyperalgesia and spinal Fos expression after forepaw inflammation in infant rats. Proc Natl
Acad Sci U S A 1997;94:1471–5.
ANESTH ANALG
2001;92:1029 –34
9. Zimmermann M. Ethical guidelines for investigations of experimental pain in conscious animals. Pain 1983;16:109 –10.
10. Anastasia JV, Braun BL, Smith KT. General and histopathological results of a two-year study of rats fed semi-purified diets
containing casein and soya protein. Food Chem Toxicol 1990;
28:147–56.
11. Hargreaves K, Dubner R, Brown F, et al. Hargreaves: a new and
sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain 1988;32:77– 88.
12. Abbott FV, Young SN. The effect of tryptophan supplementation on autotomy induced by nerve lesions in rats. Pharmacol
Biochem Behav 1991;40:301– 4.
13. King RB. Pain and tryptophan. J Neurosurg 1980;53:44 –52.
14. Seltzer Z, Shir Y. Sympathetically-maintained causalgiform disorders in a model of neuropathic pain: a review. J Basic Clin
Physiol Pharmacol 1991;2:18 –56.
15. Devor M, Raber P. Heritability of symptoms in an experimental
model of neuropathic pain. Pain 1990;42:51– 68.
16. Mogil JS, Wilson SG, Bon K, et al. Heritability of nociception. I.
Responses of 11 inbred mouse strains on 12 measures of nociception. Pain 1999;80:67– 82.
17. Frye CA, Bock BC, Kanarek RB. Hormonal milieu affects tailflick latency in female rats and may be attenuated by access to
sucrose. Physiol Behav 1992;52:699 –706.
18. Marks-Kaufman R, Hamm MW, Barbato GF. The effects of
dietary sucrose on opiate receptor binding in genetically obese
(ob/ob) and lean mice. J Am Coll Nutr 1989;8:9 –14.
19. Jakubczak LF. Age differences in the effects of palatability of
diet on regulation of calorie intake and body weight of rats.
J Gerontol 1977;32:49 –57.
20. Zeltser R, Seltzer Z. A practical guide for the use of animal
models for neuropathic pain. In: Boivie J, Hansson P, Lindblom
U, eds. Touch, temperature and pain. Seattle: IASP Publications,
1994:337–79.
21. Bennett GJ, Chung JM, Seltzer Z. Animal models for painful
neuropathies. Protocols Neurosci. In press.
22. Aldercreutz H, Mazur W. Phytoestrogens and western diseases.
Ann Med 1997;29:95–120.
23. Wardlaw S, Thompson L, Frantz A. Effects of sex steroids on
brain beta-endorphin. Brain Res 1982;245:327–31.