Evaluation of Hindpaw Position in Rats during Chronic Constriction Injury (CCI) Produced with

Different Suture Materials

Keith C. Kajander,**t,' Carol H. Pollock,$ and Heather Berg* *Department of Oral Science, ?Department of Cell Biology and Neuroanatomy, and Program in Neuroscience,

and $Department of Psychology, University of Minnesota, Minneapolis, Minnesota 55455

Abstract Bennett and Xie (1988) described an experimental peripheral neuropathy that is produced by loosely ligating a rat's left sciatic nerve with chromic gut suture. Four ligations, which are tied tightly enough to constrict the nerve and retard epineurial blood flow, produce a chronic constriction injury (CCI). Maves et al. (1993) reported that if the ligations are tied more loosely (i.e., no retardation of blood flow) than those that produce the CCI, rats exhibit postural changes only when the ligations are of chromic gut. We decided to evaluate effects of different suture materials on the abnormalities in paw position associated with the CCI (Attal et al., 1990). Five groups of rats were included in this study. In three of the groups, the CCI was produced with chromic gut, plain gut, or polyglactin (Vicryl@) suture. Rats in the fourth group served as sham injury control animals, and rats in the fifth group served as unoperated control animals. Our results indicate that the position in which the rats held the affected hindpaw varied significantly among treatment groups. Rats whose CCI was induced with chromic gut suture spent more time with the hindpaw in an abnormal position than rats in the other treatment groups. And as compared to rats in the unoperated control group, rats whose CCI was induced with either plain gut or polyglactin suture also spent more time with the hindpaw in an abnormal position. Though these different suture materials produced similar degrees of nerve constriction, the effects on paw position were greater with chromic gut suture. These results suggest that chromic gut suture, when used to produce the CCI, may have more than just a constrictive effect on the sciatic nerve. However, since all suture materials produced changes in paw position, constriction is likely to play an important role in the development of abnormalities in paw position observed in rats with the CCI.

Key words behavior, animal, hyperalgesia, neuralgia, pain measurement, sciatic nerve, sutures

The chronic constriction injury (CCI) in the rat has been proposed as an animal model of neuropathic pain (Bennett and Xie, 1988). This injury is produced by tying four chro- mic gut ligatures loosely around the sciatic nerve. These ligations are tied so as to retard, but not stop, blood flow in the epineurial vessels. Behavioral studies have demonstrated that rats with the CCI experience heat hyperalgesia, cold allodynia, and mechanical allodynia (Bennett and Xie,

1988). In addition, Attal et al. (1990) reported that rats with the CCI hold the injured hindpaw in various abnormal positions, which, they suggested, indicated that these rats experience dysesthesia or spontaneous pain.

A report by Maves et al. (1993) suggested that the type of suture material may be of critical importance for producing the behavioral changes associated with the CCI. They used chromic gut suture to produce a sciatic nerve injury slightly different from the CCI (i.e., a less constrictive injury). These rats exhibited an alteration in posture and

@mmn.tc.umn.edu. in withdrawal responses to a thermal stimulus, indicative of

~matosnsory and Motor Research, Vol. 13, No. 2, 1996, pp. 95- 101 Accepted kbruary 28, 1996 95

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KAJANDER ET AL.

thermal hyperalgesia. Maves et al. (1993) concluded that some substance in chromic gut suture material, and not only the constrictive nature of the injury, is responsible for the behavioral signs of neuropathic pain. It has since been spec- ulated that substances in chromic gut induce a neuritis, and that this neuritis may be responsible for the behavioral changes associated with nerve injury (Maves et al., 1994).

Kupers et al. (1992) evaluated the effect of two suture materials (chromic gut and polypropylene) on changes in behavior associated with the CCI. They reported that type of suture material is not particularly important for producing behavioral changes. For example, both chromic gut (re- sorbable) and polypropylene (nonresorbable) ligations in- duced alterations in walking pattern. However, the altered walking pattern lasted longer in rats whose CCI was induced with nonresorbable sutures. Thus, Kupers et al. (1992, 1994) concluded that the constrictive effect of the ligations is very important for the development of behavioral changes associated with the CCI.

Because of differences in the results of these two stud- ies, we decided to examine this issue of suture material again. We used three different resorbable suture materials to induce the CCI, and then evaluated the effects of these different suture materials on hindpaw position. All observa- tions were made by a “blinded” observer who was com- pletely unaware of previous literature on the CCI, of treat- ment groups included in this experiment, and of expected outcomes. Some of these data have been presented in ab- stract form (Pollock et al., 1992).

MATERIALS AND METHODS Animals and Treatment Groups The same rats described in another paper (Xu et a]., 1996) were used in these experiments. Adult (n = 44; 400-425 g at the time of sacrifice) male Sprague-Dawley rats (Harlan Sprague-Dawley, Inc., Madison, WI) were randomly di- vided into five groups. Nine rats composed each group ex- cept the untreated control group, which consisted of eight rats. For rats that received a surgical intervention, the left side was the treated side; the right side remained untreated. Rats in one group (group C) were ligated with 4-0 chromic gut suture material (i.e., the standard CCI procedure; see below, and see also Bennett and Xie, 1988). Rats in two other groups had the same procedure as the rats in group C, except that the ligations were tied with 4-0 plain gut (group G) or 4-0 polyglactin (Vicryl? group P) suture mate- rials. Rats in a fourth group received a sham injury (group S); the sciatic nerve was surgically exposed but not ligated. Rats in the fifth group served as unoperated controls (group U). All surgeries were performed on the same day.

Surgical Procedures Rats were anesthetized with sodium pentobarbital (50 mg/ kg, i.p., supplemented as necessary). The left sciatic nerve

was exposed (groups C, G, P, and S) at the level of the midthigh by blunt dissection through the biceps femoris. Just proximal to trifurcation of the nerve, 6 mm of nerve was freed of adhering tissue. For rats in groups C, G, and P, four ligatures were tied loosely around the nerve, with 1-2 mm between each ligature. The nerve was barely con- stricted when viewed at ~ 4 2 . 5 with a dissecting micro- scope, but epineurial blood flow was retarded. For rats in group S, no ligations were tied. The incision was closed in layers, and animals were allowed to recover from anesthesia before being returned for housing. Four to six rats were housed together postoperatively in plastic cages with soft bedding. All procedures reported in this paper were ap- proved by the Animal Care Committee at the University of Minnesota.

Behavioral Observer

All data were collected by one trained observer, who was a college student (Berg). She was trained (by Pollock and Kajander), with the aid of a drawing (Fig. I) , to identify seven different positions in which the hindlimb is commonly held by injured rats. These positions, which have been ob- served in our laboratory, are similar to those described by Attal et al. (1990).

The observer was exposed to only very limited back- ground information about the CCI. She knew nothing about expected changes in hindpaw position, and was also un- aware that different treatment groups were included in this study. Although it was evident that most (36 of 44) of the rats had received surgery, the observer did not know what the surgical procedures entailed, or that different suture materials had been used in different animals. Moreover, the observer was unaware of the expected outcomes of this study. Finally, during the course of the experiment, the observer and other people in the laboratory were instructed not to discuss her data. This observer was thus as close to “blind to the experiment” as we can reasonably expect.

Behavioral Procedures

During a behavioral observation session, the position in which the left hindpaw was held while a rat was standing was observed. All rats in all groups were evaluated in this manner. For each rat, hindpaw position was observed once during the week before surgery and once a week for 10 weeks after surgery. Thus, hindpaw position of each rat was observed 11 times during the experiment. Behavioral procedures were conducted as follows. Each animal was first “gentled” (i.e., handled carefully while being stroked) for 30 sec and then placed on a raised glass surface. A small, clear plastic cage (13 cm wide X 23 cm long X 13 cm high) with three small holes in it was placed over the animal. The rat could move freely within the cage. The

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TYPE OF SUTURE AFFECTS HINDPAW POSITION DURING CCI

FIGURE 1. A trained, “blinded’ observer judged the hindpaw position of each rat for 180 sec during an observational session. The hindpaw was judged to be in one of the seven different hindpaw positions illustrated in this figure. Position 0, illustrated in the middle of the figure, represents the typical rat’s normal hindpaw position. Beginning in the upper left-hand comer of the figure, six abnormal hindpaw positions (1-6) are illustrated, as seen in rats after a nerve injury by observers in our laboratory. The observer measured the number of seconds each rat held its left hindpaw in each of these six abnormal positions during each observational session.

observations began immediately after the cage was placed over the rat. Each observational session was 180 sec in duration. For all animals, the amount of time (in seconds) that the left hindpaw (i.e., the hindpaw ipsilateral to the surgery in groups C, G , P, and S) was held in each of seven different positions (Fig. 1) was recorded by the observer. At the end of the 180 sec, the animal was removed from the glass surface, placed in a transport cage, and returned to housing until the next session.

Data Presentation

The percentage of time (180 sec = 100%) each rat held the left hindpaw in an abnormal position (i.e., positions 1-6) during each observational session was first determined. Mean percentages for each group during each observational session were then determined. Mean data were collapsed into three periods: (1) an early period (postoperative obser-

vational sessions 1 -3), (2) a middle period (sessions 4-7), and (3) a late period (sessions 8-10). In most figures, data from positions 1-6 have been collapsed into a single cat- egory designated as “abnormal hindpaw position.” Collaps- ing data in this manner minimized the number of repeated statistical tests and was necessary, since there is no generally satisfactory nonparametric alternative to the repeated- measures analysis of variance (ANOVA).

Statistics

The observational data were analyzed using three differ- ent nonparametric tests: (1) Kruskal-Wallis one-way AN- OVA, (2) Mann-Whitney U test, and (3) Wilcoxon signed- rank test for matched pairs. First, the collapsed data (amounts of time rats spent with the hindpaw in an abnormal position) were evaluated at each of the three collapsed obser- vational periods (early, middle, and late) for differences

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KAJANDER ET AL

among treatment groups, using a Kruskal-Wallis one-way ANOVA. Thus, three Kruskal-Wallis tests were performed on the data-one for each collapsed observational period.

Second, if the amounts of time rats spent with the hindpaw in an abnormal position in a given collapsed obser- vational period differed significantly among treatment p u p s (as determined by the Kruskal-Wallis test), Mann- Whitney tests were performed on each of the 10 possible pairwise comparisons within each collapsed observational period. (Significance levels of these 10 tests were corrected for multiple comparisons; we used p < 0.01 to claim sig- nificance in the text at p < 0.05.) The Mann-Whitney U tests were used to determine which treatments differed significantly from one another within a particular collapsed observational period. For example, during the early period, one of the 10 comparisons made was between chromic gut (group C) and plain gut (group G); nine other similar com- parisons were made for this period.

Finally, for each of the five treatment groups, three Wilcoxon tests (significance levels were corrected for multiple comparisons; we used p S 0.01 to claim signifi- cance in the text at p < 0.05) were performed to evaluate for differences among the three collapsed observational periods. For example, for treatment group C, three Wil- coxon tests were used to evaluate differences between (1) the early period and the middle period, (2) the early period and the late period, and (3) the middle period and the late period.

RESULTS

In the observational session during the week before the day of surgery, all rats spent 100% of the time with the left hindpaw in position 0 (i.e., the normal position). Illustrated in Figure 2 is the mean percentage of time rats in the chromic gut, plain gut, and polyglactin groups (groups C, G, and P) spent with the left hindpaw in the different hindpaw positions during each of the postoperative sessions. During the first 6 weeks after surgery and again in weeks 9 and 10, rats in group C (Fig. 2A) spend the majority of time with the hindpaw held in one of the abnormal positions (most commonly position 1). During the first 4 weeks after injury, rats in group G (fig. 2B) spent the majority of time with the hindpaw in one of the abnormal positions (again, most commonly position I). After that, however, rats in group G spent most of the time with the hindpaw in the normal position. On the other hand, rats in group P (Fig. 2C) spent the majority of time (3.60%) during each weeks with the hindpaw in a normal position (position 0). Rats in the sham injury group (group S, not illustrated) spent very little time with the hindpaw in an abnormal position (see Fig. 4, be- low), and rats in the normal control group (group U, also not illustrated) spent no time with the hindpaw in an abnormal

position (see Fig. 4). Although previously in our laboratory we have observed rats with the hindpaw held in positions 3 or 4, none of the rats in this experiment held the hindpaw in either of these two positions.

Figure 3 illustrates the percentage of time each rat in groups C and G held the hindpaw in an abnormal position during each postoperative observational session. Rats in group C (Fig. 3A) demonstrated much greater variability over the 10 weeks than did rats in group G. Three rats in group C appeared similar to those in group G, in that the percentage of time they held the hindpaw in an abnormal position decreased over time. Three other rats in group C demonstrated a decrease in percentage of time in an abnor- mal position from 3 to 5 weeks after injury, followed by a return toward increased time in an abnormal position. Fi- nally, three rats in group C demonstrated no change in

A

C .- E i=

C

Postoperative Test Sessions

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TYPE OF SUTURE AFFECTS HINDPAW POSITION DURING CCI

percentage of time spent with the hindpaw in an abnormal position. Because such great variability existed among these rats, no significant differences were observed among the collapsed observational periods for rats in group C (Wil- coxon, p > 0.05).

All rats in group C (Fig. 3B), returned to holding the hindpaw in a normal position at all times by the eighth session following the injury. Rats held the hindpaw in an abnormal position significantly more in the early period than in either the middle period or the late period (Wilcoxon, p < 0.05). Thus, rats in group G held the paw in an abnormal position much more of the time during the first 3 weeks following injury. There were no significant differences in paw position among collapsed periods for any of the other treatment groups (i.e., P, S, and U).

Figure 4 illustrates the percentage of time rats in each of the five treatment groups spent with the hindpaw held in an abnormal position as a function of collapsed postoperative periods. Significant differences existed among treatment groups in each of the three (early, middle, and late) periods (Kruskal-Wallis, p < 0.05). Group C exhibited the greatest number of differences. Rats in group C held the hindpaw in an abnormal position a significantly greater amount of time than rats in groups P, S, and U during the early and middle observational periods (Mann-Whitney, p < 0.05). In addition, they held the hindpaw in an abnormal position a significantly greater amount of time than rats in groups G, S, and U in the late observational period (Mann-Whitney, p < 0.05). Rats in group G held the hindpaw in an abnormal

FIGURE 2. Observational data from three of the groups (A, chromic gut [group C]; B, plain gut [group GI; and C, polyglactin [group PI) are presented in this figure. The mean percentage of time animals held the left hindpaw in each of the seven positions (0-6) is plotted as a function of the 10 postoperative observational ses- sions. Data from the preoperative session are not presented in these graphs. During the preoperative session, all animals in all groups held the hindpaw 100% of the time in position 0. Also, data from the other two groups (sham injury [group S] and unoperated [group U]) are not presented in this figure, because rats in group U held the hindpaw 100% of the time in position 0 during the entire experiment; some rats in group S occasionally, after surgery, held their hindpaw in a position other than 0, but this did not occur often. During the first 6 weeks after surgery and again in weeks 9 and 10, rats in group C (A) spent >50% of the time with the hindpaw held in one of the abnormal positions (most commonly position 1). During the first 4 weeks after injury, rats in group G (B) spent >50% of the time with the hindpaw held in one of the abnormal positions (again, most commonly position 1). After that, however, most of the time was spent with the hindpaw in the no- position. Rats in group P (C) spent the majority of time (360%) during all postoperative sessions with the hindpaw in a normal position (position 0). Hindpaw positions 3 and 4 were not observed in this experiment.

5 Gut

FIGURE 3. The percentage of time each animal in group C (A) and each animal in group G (B) held the left hindpaw in an abnormal position (positions 1-6 combined) is illustrated for each of the 10 postoperative sessions. Rats in group C (A) exhibited greater over- all variability than rats in any of the other groups; the majority of rats in group C still held the hindpaw in an abnormal position after session 5. Few animals in group G (B) held the hindpaw in an abnormal position after session 5.

position a significantly greater amount of time than rats in the P, S, and U groups during the early observation period. Other significant differences are indicated in Figure 4.

DISCUSSION

This behavioral study of the CCI included five treatment groups: (1) rats whose CCI was created with chromic gut suture; (2) rats whose CCI was created with plain gut suture; (3) rats whose CCI was created with polyglactin suture; (4) rats with a sham injury; and (5) rats in which no surgery was performed (unoperated control rats). All observations were conducted by a trained individual who was unaware of ("blinded" to) literature on the CCI, different treatment groups, and hypothesized outcomes. Our results indicate that the amount of time rats held the injured hindpaw in an abnormal position varied among groups. Rats in the chromic gut group spent significantly more time with the hindpaw in an abnormal position. However, rats in the plain gut group and rats in the polyglactin group also spent time with the hindpaw held in an abnormal position.

Maves et al. (1993) evaluated the role of the type of suture material used to produce a nerve injury. As they

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D

P S

Early Middle Late

Collapsed Observational Periods FIGURE 4. The mean percentage of time rats held the left hindpaw in an abnormal position (positions 1-6 combined) is plotted as a function of collapsed postoperative periods (early, middle, and late). Rats in group C particularly, but also rats in group G, held the hindpaw in an abnormal position much more often than did rats in any of the other three treatment groups (Mann-Whitney test, p < 0.05). Letters above a bar indicate groups that the histo- gram significantly ( p < 0.05) differs from during that period. For example, in the early period, rats in group P held the hindpaw in an abnormal position significantly more than did rats in group U. (C, chromic gut; G, plain gut; P, polyglactin; S, sham injury; U, unoperated.)

stated, they produced an injury that was different from the CCI: They tied the ligations more loosely, and consequently they did not observe retardation of blood flow in the epineu- rial vessels. Using their model of nerve injury, they ob- served alterations in hindpaw position in rats in which the injury was made with chromic gut suture, but not in rats whose ligations were tied with other suture materials (i.e., plain gut or silk). They hypothesized that the chemical con- stituents of chromic gut (e.g., pyrogallol) contribute to the development of behaviors associated with the CCI. They spec- ulated that the neuritis associated with chromic gut is greater than that associated with the other suture materials, and that this neuritis may contribute to the behavioral changes seen in some cases of nerve injury (Maves et al., 1994).

On the other hand, Kupers et al. (1992) observed changes in rats’ walking patterns following a CCI in which the ligations were tied with either chromic gut or polypropyl- ene. The only difference that emerged between these two experimental groups was that over time rats with chromic gut ligations returned toward normal walking, whereas rats

whose ligations were tied with polypropylene (a nonre- sorbable suture material) did not. From their description of surgical procedures, it appears that Kupers et al. (1992) tried to replicate the CCI model as originally described by Bennett and Xie (1988). Thus, the results of Kupers et al. (1992) support the hypothesis proposed by Bennett and Xie (1988)-namely, that constriction of the nerve is the most important factor in the CCI model for development of behav- iors thought to be indicative of neuropathic pain.

In the current experiment, we observed that rats in the chromic gut group held the injured hindpaw in an abnormal position for a much greater percentage of time than did rats in the other treatment groups. Our data suggest that Maves et al. (1993) may have a valid argument. In addition to just the effect of constriction, some chemical agent in chromic gut suture may produce an additional effect on the nerve. And it is possible that this additional effect can be attributed to a neuritis that develops as a result of tying ligations around the nerve. This possibility raises an interesting issue, however: Why did Maves et al. (1993) not observe any behavioral effects of the other suture materials?

If inflammation is the important factor in the develop- ment of behaviors associated with neuropathic pain in these models, one would expect all suture materials to produce some observable behavioral effects. All suture materials used in the studies of Maves et al. (1993), Kupers et al. (1992), and in the current study produced an inflammatory reaction (Edlich et al., 1973). Chromic gut appears to pro- duce greater inflammation than the other materials (Edlich et al., 1973; Sanz et al., 1988; Pul et al., 1991; cf. Stewart et al., 1990; Dixon et al., 1993). The degree and extent of inflammation differ with each type of material, however, and absolute differences between any of these materials do not appear to be well documented. Thus, the differences in duration of the positional effect seen in our study may be attributable to differences in the level of inflammation pro- duced by the various suture materials; to the possibility that these different suture materials exhibit differing durations in which they remain intact around the nerve (Nealon et al., 1990; Moy et al., 1991); or to some combination of both of these factors. Whichever is the primary factor, the in- flammatory response associated with each type of suture material may contribute to the group differences in duration of the abnormal paw position observed in our study. How- ever, if inflammation is the most important factor, we are not sure why Maves et al. (1993) did not see any changes in their model when they used plain gut or silk sutures- materials that also induce an inflammatory response.

Considering our results and the results of Kupers et al. (1992), we hypothesize, as they did, that the constrictive nature of the injury contributes to development of neuro- pathic pain in the CCI model. However, we cannot rule out a role for inflammation in the development of these behavioral signs.

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TYPE OF SUTURE AFFECTS HINDPAW POSITION DURING CCI

ACKNOWLEDGMENTS

We thank D. T. Hamamoto, M. A. Kleive, A. K. Roche, and J. L. Sutton for their valuable comments on an earlier version of this paper. This work was supported by Grant No. NS 29567 from the National Institutes of Health.

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