PAIN MEDICINESECTION EDITOR

CHRISTOPH STEIN

Dietary Omega-3 Fatty Acids May Be Associated withIncreased Neuropathic Pain in Nerve-Injured RatsJordi Perez, MD*†, Mark A. Ware, MBBS†‡, Stephanie Chevalier, PhD§,Rejeanne Gougeon, PhD§, and Yoram Shir, MD*†‡

*Anesthesia Research Unit and †Pain Centre, Department of Anesthesia, ‡Centre for Research on Pain and §the Nutritionand Food Science Centre, McGill University Health Centre, Montreal, Canada

Certain dietary proteins and oils are capable of decreasingchronic neuropathic pain levels in rats after partial sciaticnerve ligation injury. We tested, for the first time, the roleof dietary polyunsaturated fatty acids in suppressing painin partial sciatic nerve ligation-injured rats. Six groups ofmale Wistar rats were fed an identical casein-based, fat-free diet for 1 wk preceding partial sciatic nerve ligationinjury and for 1 wk thereafter. In addition, rats received,via gavage, 1 mL/day of pure canola, corn, hemp, soy, orsunflower oil, differing significantly in their �-3 and �-6polyunsaturated fatty acid content, or 1 mL of plain water.Responses to tactile and noxious heat stimuli were re-cordedbeforeandaftersurgeryandadifferencescorewascalculated for each group by subtracting the preoperativefrom the post-partial sciatic nerve ligation values. Heathyperalgesia, but not tactile allodynia, was significantly

different among the dietary groups (P � 0.005). Heat hy-peralgesia of rats fed hemp oil, developing the most ro-bust response, was significantly larger compared withrats fed corn oil, developing the least pain model (differ-ence score: 24.3 � 4.1 s versus 6.1 � 3.1 s, respectively; P �0.001). These oils contain similar levels of �-6 polyunsatu-rated fatty acids (hemp, 60%; corn, 58%) but their �-3 lev-els are 28-fold different (20% versus 0.7%, respectively). Asignificant correlation was found among dietary levels of�-3, but not �-6 or the �-3/�-6 ratio, of the six dietarygroups and heat hyperalgesia (P � 0.006). We concludethat dietary oil might predict levels of neuropathic pain inrats and that this effect may be associated with dietary �-3levels.

(Anesth Analg 2005;101:444–8)

D iet can modify the response of rodents to acuteand chronic nociceptive stimuli. Most researchhas been done on the role of diet in acute pain

tests (1–3), while there is only sparse evidence on theeffect of diet in attenuating chronic pain in experimen-tal animals (4,5). Most data on the effect of diet onchronic pain come from our work on the partial sciaticnerve ligation (PSL) model (6). Using this model wehave shown that levels of neuropathic pain after PSLdepended significantly on the type of dietary proteinrats consumed. For example, consumption of soy-richdiets significantly suppressed the development of tac-tile and heat allodynia and hyperalgesia after a PSLinjury (7–9), whereas albumin-rich diets enabled thedevelopment of significant sensory disorders (10).

Recently, we (10) found that dietary fat could alsosuppress chronic neuropathic pain in PSL-injured ratsand that this effect is augmented by an interactionbetween dietary fat and protein. Dietary fatty acids,especially polyunsaturated fatty acids (PUFA), havebeen shown to significantly affect multiple physiolog-ical and pathological processes in experimental ani-mals (11) and humans (12). Moreover, dietary fat pos-sessed analgesic properties in acute experimental heatpain tests in rats (3). No previous studies, however,considered a possible role of fat in attenuating exper-imental chronic pain states that could be more rele-vant in clinical situations. Indirect support for a pos-sible role for fatty acids in attenuating chronicneuropathic pain derives from data showing that di-etary PUFAs suppress the production and function ofinflammatory cytokines (13), whose role in the devel-opment of neuropathic pain in PSL rats is welldemonstrated.

Our aims in this study were to verify that dietary fathas antinociceptive properties in PSL-injured rats in-dependently of other dietary components and to learnwhether this effect could be attributed to levels of �-3or �-6 PUFA in the diet. For that purpose we tested six

Supported, in part, by the Research Institute of the McGill Uni-versity Health Centre and the Louise Edwards Foundation.

Accepted for publication January 19, 2005.Address correspondence and reprint requests to Yoram Shir, MD,

MUHC Pain Centre, Montreal General Hospital, Room E19–133,1650 Cedar Ave., Montreal, QC, H3G 1A4, Canada. Address e-mailto yoram.shir@muhc.mcgill.ca.

DOI: 10.1213/01.ANE.0000158469.11775.52

©2005 by the International Anesthesia Research Society444 Anesth Analg 2005;101:444–8 0003-2999/05

PSL rat groups fed identical diets, differing solely intheir fat source.

MethodsThis study was approved by the McGill UniversityInstitutional Animal Care and Use Committee andconducted according to its regulations. Experimentsadhered to the guidelines for animal experimentationof the International Association for the Study of Pain.

Six groups of male Wistar rats (Charles River Lab-oratories, Montreal, Canada; 10–11 rats/group),weighing 225–250 g at the beginning of the experimentwere used. Rats were housed in standard colony con-ditions (three rats per cage; ambient temperature of22°C � 0.5°C; water and food supplied ad libitum;day-night cycle with lights switched on at 7 am and offat 7 pm). Surgery and behavioral tests were done be-tween 10 am and 5 pm, by a single investigator blindedas to the rats’ group allocation. Rats underwent 215-min acclimatization periods in the testing chamberbefore the first sensory test.

From the time they were weaned until the begin-ning of experiment rats were fed a regular commercialrodent chow (as per Charles River routine; Purina5075®). Starting 1 wk before PSL injury and for 1 wkthereafter, rats were fed the tested diet. A presurgicalfeeding period of 1 wk was considered to suffice forthe purpose of this study based on our previous re-sults (9). All rats received a commercially availablefat-free diet (AIN 93G; Bio-Serv CO, Frenchtown, NJ).This diet comprised 52.7% cornstarch, 17% sucrose,20% protein (�85% casein), 5% cellulose, and 3.5%minerals, vitamins and trace elements, and it con-tained �0.15% fat. Over the same time period, fivegroups of rats were supplemented daily at noon with1 mL of commercially available oil via gavage. The oilswere corn, soy, canola, sunflower, or hemp bought inlocal stores. The amount of fat was calculated based on5% fat content in most commercial rodent chows andan average daily food consumption of 20 g per adultrat. These oils were chosen for their availability fordaily use, their high levels of PUFAs, and the signifi-cant differences in their �-3 and �-6 content (Table 1).The sixth group of rats served as a control and re-ceived 1 mL of plain water via gavage. An investigatorblinded as to their identity supplemented oil andwater.

Daily consumption of food was calculated per cageby subtracting the food remaining in the cage from theamount given the day before (no allowance was madefor spillage). Daily intake per rat was calculated bydividing by the number of rats per cage. Rats’ weightswere recorded before PSL and at the end of the exper-iment 1 wk later.

PSL was done under inhaled anesthesia with2%–3% isoflurane. The right sciatic nerve was exposed

high on the thigh, near the trochanter. Using a mini-needle, an 8-0 silk suture was inserted in the middle ofthe nerve, trapping in a tight ligation the dorsal one-third to one-half of the nerve thickness. The woundwas closed layer by layer with absorbable sutures (6).

The responses of rats to tactile and thermal stimuliwere determined before surgery and on days 3 and 7thereafter. The withdrawal threshold to repetitivetouch was measured with von Frey hairs (1, 2, 4, 6, 8,10, 15, and 26 g; North Coast Medical, San Jose, CA).The tested hair was indented 5 times, at a rate of 2 persecond, in the midplantar skin of the hindpaw untilthe hair bowed. If subthreshold, the stimulus intensitywas increased by using the next hair. At threshold,rats responded by hindpaw elevation. Groups wereconsidered to develop tactile allodynia if their meanpost-PSL thresholds were significantly lower com-pared with their baseline means.

Heat pain was tested with the Hargreaves device(Ugo Basile, Comerio, VA, Italy). The time elapsedfrom stimulus onset until hindpaw lifting (withdrawalthreshold) and the duration of hindpaw lifting until itwas placed again on the floor (response duration)were recorded. Each hind paw was tested 3 times,2 min apart, and the response of individual rats wascalculated as the average of 3 trials. Based on previousexperiments with the PSL and other partial nerve in-jury models (e.g., the chronic constriction injury [CCI]model), groups were considered to develop heat hy-peralgesia if their post-PSL thresholds were signifi-cantly lower or if their post-PSL response durationswere significantly longer compared with their baselinemeans.

Only post-PSL injury data from the ipsilateral, op-erated, side were used in the analysis. Levels of post-operative sensory abnormalities were calculated byaveraging the responses at days 3 and 7 after PSL,creating a single post-PSL score/rat. An average post-PSL score was calculated for each dietary group. Todemonstrate the development of tactile allodynia andheat hyperalgesia after PSL, the postoperative sensorylevels were compared with preoperative levels withineach dietary group using paired Student’s t-tests. Adifference score was computed for every rat by sub-tracting the preoperative value from the average post-PSL value, and results were summarized across di-etary groups. To investigate the differences amonggroups one-way analysis of variance was performedwith post hoc Student’s t-tests. Mean daily food con-sumption and weight gain were also compared amonggroups using analysis of variance.

The association between experimental pain behav-ior and dietary �-3 and �-6 (including �-6/�-3 ratio)intake was explored using linear and nonlinear regres-sion analyses. Significance was set at the 5% level, andall tests were two-sided.

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ResultsThe experimental dietary groups did not differ in theirdaily solid food consumption (average, 17.6 � 0.42g/rat) and weekly weight gain (average, 34.4 � 1.74g/rat). There was a 200-fold difference in �-3 intakebetween groups consuming hemp and sunflower oils,containing the highest and lowest levels of �-3, respec-tively (Table 2). Similarly, there was a 3.2 fold differ-ence in �-6 consumption between rats fed sunflowerand canola oils, containing the highest and lowestlevels of �-6, respectively. A 295-fold difference in the�-6/�-3 ratio has been calculated for the sunflowerversus the canola oils (Table 2).

All six groups of rats developed a significant tactileallodynia after PSL (P � 0.001). There was no signifi-cant difference in threshold response, however,among groups (P � 0.41, analysis of variance) (Fig. 1).Dietary content of �-3 or �-6 had no effect on tactileallodynia, and no correlation was observed betweenthe dietary �-3/�-6 ratio and tactile allodynia.

There was no significant difference in the thresholdresponse to heat among groups (mean � sem differ-ence: canola �0.8 � 1.2 s; water 0.4 � 1.3 s; corn 0.7 �1.4 s; hemp 1.0 � 1.1 s; soy 1.2 � 1.5 s; sunflower 3.0� 1.6 s; P � 0.44). The dietary content of �-3 or�-6 had no effect on the threshold response to heatafter PSL, and there was no relationship betweenthreshold response and �-3/�-6 ratio.

Significant heat hyperalgesia developed in the 5experimental groups receiving the soy (P � 0.05),sunflower (P � 0.008), canola (P � 0.001), and hemp (P� 0.001) oils and water (P � 0.004) (Fig. 1). Rats fed thecorn oil did not develop heat hyperalgesia after PSL (P� 0.09). The response duration to heat was signifi-cantly different among groups (P � 0.005; analysis ofvariance). Heat hyperalgesia of rats fed hemp oil, de-veloping the most robust response, was significantlylarger compared with rats fed corn oil, developing theleast pain model (difference score: 24.3 � 4.1 s versus6.1 � 3.1 s, respectively; P � 0.001). Although reachingonly marginally significant differences, rats supple-mented with water only developed suppressed heathyperalgesia compared to hemp-fed rats (P � 0.07)and increased heat response compared to corn-fed rats

(P � 0.06). No correlation was found between dietary�-6 consumption or the �-3/�-6 ratio and levels ofheat hyperalgesia. However, a highly significant cor-relation between the �-3 dietary intake and durationof withdrawal response was found (r2 � �0.35, P �0.006) (Fig. 2).

DiscussionThis study shows that levels of neuropathic pain inrats undergoing PSL could depend on dietary oil mod-ification. The consumption of corn and soy oil wasassociated with decreased neuropathic pain levels,whereas canola and hemp oils enabled the develop-ment of a significant heat hyperalgesia. In addition,we unexpectedly found that the tendency to developneuropathic pain may correlate with dietary levels of�-3, but not �-6, PUFA. The effect of oil was indepen-dent of other dietary constituents because except forthe supplemented oil, all six tested groups consumedthe same amounts of identical diet during the entirestudy period. Together with our preliminary findings(10) these data show that common dietary oils couldbe associated with reduced pain levels after PSL inrats.

Choosing the appropriate basic diet for this experi-ment was not trivial because both dietary fat andprotein could play an analgesic role in PSL rats. Con-sequently, most purified diets could deviate the re-sults of this study, depending on their specific fat/protein composition. We have chosen to use a casein-based, fat-free diet that eliminated the possibility offatty components, other than those tested, to affect

Table 1. Polyunsaturated Fatty Acid Composition of the Five Tested Oils

Fat *Corn *Soy *Sunflower *Canola †Hemp

% Saturated 12.7 14.4 10.3 7.1 8.0% Monounsaturated 24.2 23.3 16.0 58.9 12.0% Polyunsaturated 58.7 57.9 69.0 29.6 80.0% �-Linolenic acid �3 (18:3n-3) 0.7 6.8 �0.1 9.3 20.0% Linoleic acid �6 (18:2n-6) 58.0 51.0 65.0 20.3 60.0Ratio linoleic n-6/linolenic n-3 82.0 7.5 650.0 2.1 3.0

* United States Department of Agriculture: USDA book #8-1, 1976.† Erasmus U. Fats That Heal, Fats That Kill: The Complete Guide to Fats, Oils, Cholesterol and Human Health. Alive Publishing Group Inc. Burnaby, B.C.,

1993.

Table 2. Daily Dietary �-3 and �-6 Polyunsaturated FattyAcid Intake by Oil Type (mg)

Oil �-3 �-6 �-6/�-3 ratio

Corn 5.6 464.0 82.9Soy 61.2 459.0 7.5Sunflower 0.9 585 650.0Canola 83.7 182.7 2.2Hemp 180.0 540 3.0

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rats’ pain behavior. A casein-based diet has been cho-sen because it has been safely used in rodent experi-ments of long-term feeding (14) and consistently en-abled the development of a significant neuropathicpain model after PSL (7–9). Thus, we believe that

supplementing rats with this diet optimized ourchances to discriminate among oils in accordance withtheir pain-relieving properties. The oils for this exper-iment have been chosen considering their availabilityfor daily use and their possible relevance for clinicalpain states, their high levels of PUFA, and the signif-icant differences in their �-3 and �-6 content. Al-though supplemented as pure products, a possibleeffect on pain behavior of other vitamin and traceelements in these oils cannot be excluded.

In accordance with our previous results (7) a casein-based diet enabled the development of significant tac-tile allodynia and heat hyperalgesia (Fig. 1). Choosingthe casein/water diet as a control group enabled theclear differentiation between the pro-analgesic (cornand soy) and the pro-nociceptive (canola and hemp)dietary oils (Fig. 1B). Feeding rats a fat-free diet for alimited period of time has been shown to be safe inexperimental rats and was not associated with signif-icant deleterious effects (15).

The oils used in the current study were effective inreducing one type of neuropathic pain behavior, heathyperalgesia, but not tactile allodynia. Several lines ofevidence support the assumption that these two sen-sory abnormalities could be mediated via differentpathophysiological mechanisms. It has been shownthat the number of damaged nerve fibers after PSLcould predict the development of either tactile or heathyperalgesia or both (16). A variety of drugs withproven analgesic potency in models of chronic painhave been shown to exert differing analgesic profilesin nerve-injured rats (17). Finally, different receptorstrigger thermal hyperalgesia and mechanically evokedpain behavior after nerve injury (18). It is possible,therefore, that the analgesic properties of oil can in-fluence some, but not all, neuropathic pain symptomsin rats.

Fatty acids, specifically PUFAs, are crucial compo-nents of neuronal (and other) cell membranes and aresubstrates of bioactive molecules such as prostaglan-dins, thromboxanes, and leukotrienes (12,13). PUFAplay a significant role in cytokine production andfunction (13) and act directly upon nuclear receptors(19). Consequently, some fatty acids or their metabo-lites could act like hormones to control the activityof specific transcription factors (19). While the �-6PUFAs have been traditionally regarded as mainlyproinflammatory, the �-3 PUFA have been consideredbeneficial because of their antiinflammatory proper-ties. For example, replacement of �-6 PUFA with �-3PUFA in cell membranes resulted in a decreased cel-lular response to inflammatory stimuli in rodents (20).In humans, �-3 PUFA have been shown to attenuateinflammation in patients with chronic inflammatorydiseases (21). The results of the present study, impli-cating �-3 PUFA as possible pro-nociceptive com-pounds, seem to contradict this evidence. It is possible

Figure 1. The isolated effect of oil on the development of tactileallodynia (A) and heat hyperalgesia (B) in partial sciatic nerveligation injury (PSL)-injured rats (n � 10–11 rats/group). A differ-ence score/group was computed by subtracting the average preop-erative from the average post-PSL value (� sem). A. Compared withbaseline all six groups developed significant tactile allodynia (de-creased threshold to touch) after PSL (P � 0.001). Levels of allodyniawere not significantly different among groups (P � 0.41; analysis ofvariance). B. But for the corn oil group, all other rats developed asignificant heat hyperalgesia (response duration to heat; P � 0.05)that was significantly different among groups (P � 0.005; analysis ofvariance). *P � 0.05 versus canola and hemp oils.

Figure 2. The correlation between daily �-3 polyunsaturated fattyacids (PUFA) consumption (mg) and levels of heat hyperalgesia ofthe 6 experimental groups (n � 10–11 rats/group). A differencescore/group of the response duration to heat was computed bysubtracting the average preoperative value from the average post-partial sciatic nerve ligation (PSL) value (� sem). A significantcorrelation was found between �-3 consumption and levels of heathyperalgesia (P � 0.006).

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that �-3 PUFA could exert their pro-nociceptive effectvia noninflammatory mechanisms, for example bychanging the properties of neuronal cell membrane orby direct effect on the neural cell nucleus, inducingpro-nociceptive neurophysiological changes. Indeed,it has been shown that �-3 PUFA enhanced conduc-tion through slow tetrodotoxin-resistant sodium chan-nels in rat dorsal root ganglion neurons (22), resultingin hyperpolarization that could augment pain. Alter-natively, it has been shown that some partial nerveinjuries, like the PSL, create a pain model that ismainly neuropathic and not inflammatory. Indeed,activated macrophages play only a limited role in theonset of mechanical allodynia in the spinal nerve liga-tion model (23). Similarly, rats undergoing the partialsciatic nerve transaction model, a modification of thePSL model, have been compared with rats undergoingthe CCI model, whose nociceptive abnormalities arepartially related to inflammation (24). The number ofmacrophages in the epineurium of the injured nervewas strikingly increased after CCI compared with thetransaction model (25). We suggest, therefore, that theantiinflammatory properties of �-3 PUFA might notbe relevant in the PSL injury. It is possible that dietaryfat modifies chronic neuropathic pain not by alteringthe synthesis of proinflammatory prostaglandins andcytokine compounds but by acting on other systemsrelated to the generation and perpetuation of suchchronic sensory abnormalities.

In summary, this research shows that commerciallyavailable dietary oils could play a role in the develop-ment of chronic neuropathic pain after PSL in rats. Theeffect of oil on pain behavior may be associated withlevels of �-3, but not �-6, PUFA in the tested oils. Thisstudy might open the way for experiments that willfurther examine the role of PUFAs in nociception inanimal models and possibly in humans with neuro-pathic pain.

The advice of Drs. Gary J. Bennett from the Anesthesia ResearchUnit and Centre for Research on Pain, and Errol Marliss from theNutrition and Food Science Centre, McGill University, Montreal, isgreatly appreciated. The authors thank Lina Naso for her outstand-ing technical assistance.

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