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PAIN MECHANISMS

Experimental Neuropathy in Mice Is Associated with Delayed Behavioral Changes Related to Anxiety and Depression

Takahiro Suzuki, MD, PhD^*, Mitsuyuki Amata, BS^*, Gaku Sakaue, MD, PhD^*, Shinya Nishimura, MD, PhD, Takaya Inoue, MD, PhD^*, Masahiko Shibata, MD, PhD^*, and Takashi Mashimo, MD, PhD^*

From the *Department of Anesthesiology, Osaka University Medical School, Osaka, Japan; and Intensive Care Unit, Osaka University Hospital, Osaka, Japan.

Address correspondence and reprint requests to Takahiro Suzuki, Department of Anesthesiology, Osaka University Medical School, 2–2 Yamadaoka, Suita, Osaka 565-0871, Japan. Address e-mail to tsuzuki{at}anes.med.osaka-u.ac.jp.

Abstract

BACKGROUND: Patients with chronic pain frequently suffer affective disorders, particularly anxiety and depression. Although clinical research on the relationship between pain and depressive symptoms has been done, it is not clear whether pain causes depression or depression exaggerates pain. To investigate the relation between pain and affect, we measured anxiety and depression-related behaviors in mice after spinal nerve ligation using classical behavioral tests.

METHODS: After unilateral ligation of the left fifth lumbar nerve, we measured pain behaviors using von Frey and radiant heat tests. Activity level, anxiety-related behaviors, and depression-related behaviors were tested with open field, light-dark exploration, elevated plus-maze, and forced swim tests.

RESULTS: Sensory hypersensitivity was observed within a few days after ligation. Anxiety and depression-related behaviors were not seen 2 and 7 days after ligation. However, 15 and 30 days after ligation we found clear evidence of anxiety and depression-related behaviors, without loss of mobility.

CONCLUSIONS: Nerve injury can trigger affective disturbances in mice that appear much later than sensory hypersensitivity.

Affective disorders such as depression and anxiety are common in patients suffering from chronic pain (1–7). Numerous studies have shown a reciprocal relationship between chronic pain and affective disturbance. Each disorder makes patients more vulnerable to the other, although the exact nature of interaction is unclear. Personality factors may influence pain processing (1,3). For example, patients with greater anxiety state and depression at the initial assessment are more likely to develop chronic pain from herpes zoster (3). Depressive symptoms significantly predict the development of chronic pain (4). Conversely, patients suffering from chronic pain are at an increased risk for depression (2).

Although various investigations of neuropathic pain in rodent models have been used to explore mechanisms of chronic pain, only a few animal studies have investigated the relationship between pain and affect. In a rat model of spinal nerve ligation, Kontinen et al. (8) reported that rats showed allodynia but no apparent modifications in affective behaviors 14 days after nerve ligation.

We have reinvestigated this subject by examining behaviors indicative of altered emotional state in mice. We used the fifth lumbar nerve ligation, a procedure known to cause pain behaviors that last for several months or longer (9,10). We report the effects of spinal nerve ligation on sensitivity to mechanical and thermal stimuli and on behaviors associated with anxiety and depression. We assessed anxiety-related behaviors using open field (11), light/dark exploration (12), and elevated plus-maze (13) tests. We assessed depression-related behaviors with the forced swim test (14). These behavioral studies have been widely used in screening anxiolytics and antidepressants.

METHODS

Animals
After approved by the Animal Research Committee of Osaka University Medical School, we studied male C57BL/6 mice (Japan SLC. Hamamatsu, Shizuoka, Japan), weighing 24–28 g (8-wk old) at the time of surgery. Mice were housed in groups of 5–10 and maintained under standard laboratory conditions with chow and water available ad libitum. Lighting was on a regular light/dark cycle, with lights on from 6:00 to 20:00.

Surgical Procedures
The left fifth lumbar nerves of mice were tightly ligated with 6-0 silk under sevoflurane anesthesia as previously described (10). Control animals were sham-operated by exposing, but not ligating the left fifth lumbar nerve.

Assessment of Allodynia and Hyperalgesia
To assess allodynia and hyperalgesia, each group of eight mice was subjected to spinal nerve ligation or sham operation, respectively.

Tactile Allodynia
To measure mechanical sensitivity of the hindpaw, mice were placed in individual plastic boxes on a mesh floor and allowed to acclimate for 30 min. A series of calibrated von Frey filaments (Stoelting, Wood Dale, IL) was applied perpendicularly to the plantar surface of the hindpaw with sufficient force to bend the filaments for 6 s. Brisk withdrawal or paw flinching were considered positive responses. In the absence of a response, the filament of next greater force was applied. In the presence of a response, the filament of next lower force was applied. The tactile stimulus producing a 50% likelihood of withdrawal was determined using the "up–down" method.

Thermal Hyperalgesia
Thermal sensitivity was assessed by the method of Hargreaves et al. (15) by focusing a thermal beam (Paw Stimulator Analgesia Meter Model 390, IITC) on the left hindlimb footpads of mice placed on a glass surface. The withdrawal response latency (s) was measured with a 20-s cut-off time.

Behavioral Tests
Activity during the open field, light/dark exploration, elevated plus-maze, and forced swim test was recorded and videotaped via an overhead camera. Open field data were automatically analyzed by a computer-operated tracking system (NIH Image and Image OF, O’hara & CO, Tokyo, Japan). Activity during the other tests was scored by investigators watching the videotapes.

Open Field Test
Mice were placed in the 60 x 60 cm² field surrounded by 50 cm high wall under dim light (15 lux). Activity was measured for 10 min to assess total distance traveled and the time spent in the central zone (area >12 cm from walls). Total distance traveled was indicative of general level of activity, while the percent time spent in the center was used as an index of the anxiety state of mice (11), defined as % time spent in center = [time spent in center (s)]/[600 (s)] x 100.

Light/Dark Exploration Test
The apparatus consisted of a dark compartment (13 x 22 x 26 cm³) connected by a 5 x 5 cm² window to a bright compartment (illuminated, 600 lux, 23 x 22 x 26 cm³). Mice were placed in the dark compartment and activity was measured for 5 min. The percent time spent in the bright compartment and number of entries into the bright compartment were used as an index of the anxiety state of mice (12). The percent time spent in the bright side was defined as % time spent in bright side = [time spent in bright side (s)]/[300 (s)] x 100.

Elevated Plus-Maze Test
Mice were placed in the middle of a plus-shaped cross, elevated to a height of 40 cm with two open and closed arms (passages). Open arms (25 x 5 cm²) and closed arms (25 x 5 cm² with transparent walls 15 cm high) were connected by a central platform (5 x 5 cm²) and arranged so that the arms of the same type were opposite to each other. Activity was measured for 5 min to assess total entries to arms, the time spent by mice on open arms and entries to open arms. Total arm entries were used to indicate the general level of activity, while the percent time spent on and percent entries onto open arms were used as an index of the anxiety state of mice (13,16–18) and defined as % time spent in open arms = [time spent in open arms (s)]/[time spent in open arms (s) + time spent in closed arms (s)] x 100, and % entries to open arms = [number of entry to open arms]/[number of entry to open arms + number of entry to closed arms] x 100.

Forced Swim Test
Mice were placed in a clear glass cylinder containing water (diameter 22 cm, depth 14 cm, 25°C) for 6 min. The duration of immobility was recorded during the last 5 min of the 6 min trial. A mouse was considered to be immobile when floating motionless or making only those movements necessary to keep its head above the water. Immobility time was used as an index of a "depressive" behavior (14,19).

In all cases, the experimenter was blind to the type of operation (sham or ligated). All mice were tested sequentially over 2 days. All tests were performed in the mornings. Day 1 started with general activity testing in the open field followed by the light/dark paradigm. On Day 2, mice were tested in the elevated plus-maze, and then in the forced swim paradigm. Mice were tested only once in each behavioral procedure to prevent habituation.

First, two groups of 15 mice with either sham operation or nerve ligation were compared 8 wk after the lesion in the affective behavior experiments. Next, to study the onset of affective behavioral changes, two groups of eight mice sham-operated or nerve-ligated were compared 2, 7, 15, 30 days after the lesion. The four behavioral tests were performed during two consecutive days.

Rotorod Test
Motor performance was evaluated on a rotorod (Model 7650, Ugo Basile, Varese, Italy). Mice were placed on the rotorod cylinder, and the time the mice remained on the rotorod was measured. The initial speed of the rotorod was 4 rpm, which was increased 2 rpm every 1 min. If the mice remained on the rod for 6 min, then the test was completed. If mice fell in <10 s, they were given a second trial. The mice were trained for 3 days before sham-operation or nerve ligation, and the rotorod test was performed 2, 7, 15, and 30 days after the lesion. Each group consisted of six mice.

Evaluation of Diurnal Activity and Circadian Rhythms
The diurnal activity of mice was continuously measured and compared between ligated and sham groups using a set of activity monitors (Mini Motionlogger Actigraph, Ambulatory Monitoring, Ardsley, NY). Ten mice were group-housed in a cage with an activity monitor and the total vibration of cage was measured for 24 h during 2 wk through the sixth and seventh weeks after ligation to assess diurnal activity and circadian rhythms. The mean activity score, % minutes scored as sleep, the number of blocks of contiguous sleep epochs, the mean duration of sleep epochs and the long sleep episodes were used as the indices for the Actigraph.

Passive Avoidance Test
The apparatus for the passive-avoidance task was used as a measure of the ability to learn and remember an association between an aversive experience and environmental cues (20). The apparatus consisted of two identical chambers, one illuminated and one dark (O’hara & CO). Twenty-four hours after sham operation or nerve ligation, mice were initially placed in the light chamber, and the latency to enter the dark chamber was recorded. When the four paws of the mouse were inside the dark chamber, an electric shock of 0.2 mA (duration, 1 s) was delivered (the training test). 24 h, 7 days, or 30 days after the training test, the mouse was returned to the light chamber, and the latency to enter the dark chamber was recorded. Each group consisted of six mice.

Statistics
All data are expressed as mean ± sem. Data were analyzed using nonparametric Mann–Whitney U-test with significance levels set at P < 0.05.

RESULTS

Hypersensitivity to mechanical and thermal stimuli was observed within 2 days of nerve ligation and remained present for at least 3 mo (Fig. 1).

View larger version (12K): [in this window] [in a new window]   Figure 1. Development of hypersensitivity in nerve-ligated mice. (a) Decreased withdrawal threshold to mechanical stimuli (in g) (b) Decreased withdrawal latency to heat stimuli (in s) in nerve-ligated mice. Ligated mice (closed circles); sham-operated (open circles). Values are mean ± sem. n = 8; *P < 0.001 compared with sham-operated mice on the same postoperative day (Mann–Whitney U-test).

There was no difference between the two groups in locomotor activity in open field and elevated plus-maze 8 wk after surgery (Figs. 2a and e). However, at this time ligated mice spent less time in the central area in open field (Fig. 2b), spent less time in and had fewer entries into the bright side in the light/dark assay (Figs. 2c and d), and spent less time and had fewer entries into the open arms in elevated plus-maze test (Figs. 2f and g). Ligated mice also exhibited increased immobility time in the forced swim test (Fig. 2h). The correlation between pain behavior and affective behaviors is shown in Figure 2i. Although all ligated mice showed hypersensitivity in the von Frey test, not all mice showed stronger affective behaviors. Some mice showed strong correlation in all behavioral indices, but the others did not.

View larger version (21K): [in this window] [in a new window]   Figure 2. Behavioral evaluation of sham- operated and nerve-ligated mice performed 8 wk after the operation. Open field test (a: distance traveled b: % time spent in center), light/dark exploration test (c: % time spent in bright side d: entries to bright side), elevated plus-maze test (e: total entries f: % time spent in open arms g: % entries to open arms) and forced swim test (h: immobility). Correlation (i) between pain behavior and affective behaviors of each mouse. Values are mean ± sem. n = 15; *P < 0.05 compared with sham-operated mice (Mann–Whitney U-test).

Having discovered differences in behavior 8 wk after the lesion, our next study compared affective behaviors between sham and ligated mice at different postoperative times. Although no significant increase or decrease was observed in locomotor activity in the open field and elevated plus-maze test in ligated mice at any postoperative time compared to sham mice (Figs. 3a and c), ligated mice showed changes of affective behaviors 15 and 30 days after the lesion. Thirty days after operation, ligated mice spent less time in the central area than did sham mice in the open field test (Fig. 3b), and spent less time in the bright side and made fewer entries to the bright side in the light/dark test (data not shown) when compared to sham mice. In elevated plus-maze test, 30 days after operation ligated mice spent less time on (Fig. 3d) and made fewer entries onto the open arms (data not shown) compared to sham mice. In the forced swim test, 15 and 30 days after operation, ligated mice had greater immobility time than sham mice had (Fig. 3e).

View larger version (12K): [in this window] [in a new window]   Figure 3. Onset of affective behavior changes. Two groups of eight mice sham-operated and nerve-ligated compared 2, 7, 15, 30 days after the lesion. Onset of affective behavior changes in open field (a: distance traveled b: % time spent in center), elevated plus-maze test (c: total entries d: % time spent in open arms) and forced swim test (e: immobility). Values are mean ± sem. *P < 0.05 compared with sham-operated mice (Mann–Whitney U-test).

No mouse of either group fell from the rotorod cylinder at 2, 7, 15, and 30 days after the lesion (Table 1).

The diurnal activity of both groups was constantly measured using an activity monitor all through the sixth and seventh weeks after operation. The activity patterns and circadian rhythms of both groups were similar. Sleep disturbances or atypical hyperactivity were not found (Fig. 4). Table 2 shows the indices of the Actigraph (the mean activity score, % minutes scored as sleep, the number of blocks of contiguous sleep epochs, the mean duration of sleep epochs and the long sleep episodes). There were no significant differences between sham and ligated mice. No loss of the ability to learn and remember an association between an aversive experience and environmental cues in ligated mice was observed in the passive avoidance test. Neither group of mice entered a dark compartment of an electrical shock again, at 24 h, a week, and a month after the training test.

View larger version (41K): [in this window] [in a new window]   Figure 4. Continuous activity recordings of sham (a) and nerve-ligated mice (b) at seventh week after the lesion. x-axis corresponds to time (24 h) of the sequential 7 days, and y-axis corresponds to the magnitude of activity. If the activity of mice increases, the activity monitor recording shows high magnitude. The magnitude and the pattern of terms and intervals were similar between sham and ligated mice.

There was no significant difference in body weight between ligated and sham mice during this period. The body weight at the time of surgery and 8 wk postoperation was 26.4 ± 0.5 g and 30.5 ± 0.8 g, respectively, in the sham mice, and 25.9 ± 0.8 g and 31.0 ± 0.9 g, respectively, in the ligated mice.

DISCUSSION

With maximal hypersensitivity to mechanical and thermal stimuli, anxiety and depression-related behaviors were not detected 2 and 7 days after nerve ligation. Apparent changes in affective behaviors were detectable at 15 days and more clearly present at 30 days after ligation.

These findings cannot be explained by motor dysfunction in the ligated mice, as there was no loss of motor coordination in the rotorod test nor reduction in distance traveled in the open field and total entries in the elevated plus-maze test. Thus, nerve injury induced sensory hypersensitivity and modified the affective behaviors without apparent loss of mobility due to motor dysfunction.

There were no apparent differences in activity patterns and circadian rhythms between sham and ligated mice during the sixth and seventh week after ligation. During this period, it may be assumed that ligated mice show affective behaviors, because significant differences in behavior indicative of emotional change were observed both 30 days and 8 wk after operation. This result suggests that the affective behaviors indicative of anxiety and depression were modified without disturbance of spontaneous activity and circadian rhythms. Also the result in passive avoidance testing suggests that nerve ligation might not induce the apparent deficit of memory associated with an aversive experience and environmental cues, and that the behavioral changes might not originate from the loss of ability to learn and remember. These findings demonstrate that anxiety and depression-related behaviors, rather than stemming directly from motor dysfunction or disability due to painful stimuli, are likely to originate in emotional changes.

In contrast to the present study, another study measuring behavior after spinal nerve ligation in rats (8) found no difference in anxiety and depression-related behaviors compared to sham-operated rats when measured 14 days after nerve ligation. This is not really at variance with the present results in mice where behavioral changes were absent at 7 days and only started to become apparent at 15 days and were not fully developed until 30 days. Since Kontinen et al. (8) did not pursue their study beyond 14 days, it is impossible to know whether behavioral changes developed in rats at a later time. The reason for the difference between the studies at 14/15 days (presence and absence respectively of a difference in anxiety and depression-related behaviors) is not clear. Although no loss of motor coordination in rotorod test and no reduction of locomotion was observed in the open field and elevated plus-maze test in this study, Kontinen et al. reported that rats with spinal nerve ligation showed a significant decrease in locomotor activity. Motor dysfunction might have reduced the sensitivity of the tests, which are based on movement. And Kontinen et al. also observed that the spinal nerve-ligated rats could not swim properly.

In the present study, however, no apparent difficulty in swimming was observed in any groups in the forced swim test. Moreover, as we measured the motionless time, but not distance of swimming, longer immobility time did not directly associate with loss of ability to swim properly. Our data showed no increase of immobility time at 2 and 7 days after nerve ligation compared to sham-operated mice, but a significant increase was found at 15 and 30 days after nerve ligation. Differences in the model used and the test procedure by Kontinen et al., where they used rats subjected to fifth and sixth lumbar nerve ligation and the rats were tested twice, before and after operation, may also be relevant.

Kim and Chung suggested the single fifth lumber nerve ligation induced less motor impairment compared with the fifth and sixth lumber nerve ligation model in rats (9). Behavioral tests were not repeated in the present study, since the first testing session may have significant effects on the results of the second testing session. Repeated exposure to the test situation decreases exploratory activity in rodents (21). Habituation might thus have a crucial effect on anxiety and depression-related behaviors, possibly masking small behavioral effects. In our preliminary study, we investigated the behavioral tests twice, both before the lesion and 15 days, 30 days, or 8 wk after the lesion. In the second testing session, activity was much less than in the first testing session and there was no difference in affective behaviors between ligated and sham mice in the second testing session. Thus, the present results are consistent with those found in rats by Kontinen et al.

Neuropathy per se might act as a chronic stress on emotion. Although many stress models in rodents have been used to examine the effect of stress on emotion, the mice model spinal nerve ligation mice model seems different from chronic mild stress in previous reports (22). These models of chronic mild stress, which have been established as animal models of depression, are repeated acute stresses. By contrast, the stimulus of neuropathy induced by spinal nerve ligation appears weaker but is a continuous form of chronic stress.

Bomholt et al. examined hypothalamo-pituitary-adrenal axis function in a rat chronic constriction injury model. Twenty-one days after a chronic constriction injury there was no differences in serum corticosterone and adrenocorticotropic hormone concentration compared with sham rats. The response of these hormone levels after the restraint stress was also similar between chronic constriction injury and sham rats (23).

In the present study sensory hypersensitivity, which develops rapidly, may initiate the slow progressive development of affective behaviors. It is also possible that sensory hypersensitivity and affective behaviors develop independently from the same cause (nerve injury). Although observable behavioral changes must be evidence of an underlying cortical change, the mechanism for these changes is not known. Further studies need to examine the neural mechanism of affective changes, especially in hypothalamo-pitutary-adrenal axis, hippocampus and amygdala, several weeks after spinal nerve injury (24–29).

Footnotes

Accepted for publication February 13, 2007.

This study was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Science and Culture of Japan.

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