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Comparative Study
. 2017 Jan;124(1):346-355.
doi: 10.1213/ANE.0000000000001662.

Chronic Sciatic Neuropathy in Rat Reduces Voluntary Wheel-Running Activity With Concurrent Chronic Mechanical Allodynia

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Free PMC article
Comparative Study

Chronic Sciatic Neuropathy in Rat Reduces Voluntary Wheel-Running Activity With Concurrent Chronic Mechanical Allodynia

Ryan A Whitehead et al. Anesth Analg. .
Free PMC article

Abstract

Background: Animal models of peripheral neuropathy produced by a number of manipulations are assessed for the presence of pathologic pain states such as allodynia. Although stimulus-induced behavioral assays are frequently used and important to examine allodynia (ie, sensitivity to light mechanical touch; von Frey fiber test), other measures of behavior that reflect overall function are not only complementary to stimulus-induced responsive measures, but are also critical to gain a complete understanding of the effects of the pain model on quality of life, a clinically relevant aspect of pain on general function. Voluntary wheel-running activity in rodent models of inflammatory and muscle pain is emerging as a reliable index of general function that extends beyond stimulus-induced behavioral assays. Clinically, reports of increased pain intensity occur at night, a period typically characterized with reduced activity during the diurnal cycle. We therefore examined in rats whether alterations in wheel-running activity were more robust during the inactive phase compared with the active phase of their diurnal cycle in a widely used rodent model of chronic peripheral neuropathic pain, the sciatic nerve chronic constriction injury (CCI) model.

Methods: In adult male Sprague Dawley rats, baseline (BL) hindpaw threshold responses to light mechanical touch were assessed using the von Frey test before measuring BL activity levels using freely accessible running wheels (1 hour/day for 7 sequential days) to quantify the distance traveled. Running wheel activity BL values are expressed as total distance traveled (m). The overall experimental design was after BL measures, rats underwent either sham or CCI surgery followed by repeated behavioral reassessment of hindpaw thresholds and wheel-running activity levels for up to 18 days after surgery. Specifically, separate groups of rats were assessed for wheel-running activity levels (1 hour total/trial) during the onset (within first 2 hours) of either the (1) inactive (n = 8/group) or (2) active (n = 8/group) phase of the diurnal cycle. An additional group of CCI-treated rats (n = 8/group) was exposed to a locked running wheel to control for the potential effects of wheel-running exercise on allodynia. The 1-hour running wheel trial period was further examined at discrete 20-minute intervals to identify possible pattern differences in activity during the first, middle, and last portions of the 1-hour trial. The effect of neuropathy on activity levels was assessed by measuring the change from their respective BLs to distance traveled in the running wheels.

Results: Although wheel-running distances between groups were not different at BL from rats examined during either the inactive phase of the diurnal cycle or active phase of the diurnal cycle, sciatic nerve CCI reduced running wheel activity levels compared with sham-operated controls during the inactive phase. In addition, compared with sham controls, bilateral low-threshold mechanical allodynia was observed at all time points after surgical induction of neuropathy in rats with free-wheel and locked-wheel access. Allodynia in CCI compared with shams was replicated in rats whose running wheel activity was examined during the active phase of the diurnal cycle. Conversely, no significant reduction in wheel-running activity was observed in CCI-treated rats compared with sham controls at any time point when activity levels were examined during the active diurnal phase. Finally, running wheel activity patterns within the 1-hour trial period during the inactive phase of the diurnal cycle were relatively consistent throughout each 20-minute phase.

Conclusions: Compared with nonneuropathic sham controls, a profound and stable reduction of running wheel activity was observed in CCI rats during the inactive phase of the diurnal cycle. A concurrent robust allodynia persisted in all rats regardless of when wheel-running activity was examined or whether they ran on wheels, suggesting that acute wheel-running activity does not alter chronic low-intensity mechanical allodynia as measured using the von Frey fiber test. Overall, these data support that acute wheel-running exercise with limited repeated exposures does not itself alter allodynia and offers a behavioral assay complementary to stimulus-induced measures of neuropathic pain.

Conflict of interest statement

None of the authors have any conflicts of interest.

Figures

Figure 1
Figure 1. The effects of sciatic neuropathy (CCI) on voluntary wheel running activity during the inactive phase of the diurnal cycle
(A) Total distance traveled (m) steadily increased over a 7-day sequential habituation period of a fixed interval 1-hr/day free-access period to running wheels, while no differences were observed between groups (N = 8/gp) at any timepoint. Tukey’s test for timepoint comparisons and Šidák’ test for group comparisons at each time point. Statistical significance was set with alpha at p <0.05. (B) One hour wheel running activity after either sham surgery or unilateral sciatic nerve chronic constriction injury (CCI) revealed reduced activity in CCI rats relative to their baseline (BL) activity levels (BL indicated by a dashed horizontal line at ‘0’). Significant difference between sham- and CCI-treated rats using Tukey’s test for post-hoc contrasts. ** P < 0.01, # P < 0.02. (C, D and E) Within the one-hour activity assessment, three 20-min phases were analyzed with each phase revealing decreases in distance traveled after CCI at 1 or 2 of the 4 timepoints examined. Rats with CCI traveled the least on Day 18 during the first 20-min (phase I) of the 1-hr testing period. However, during the following 40 min (phase II and III), CCI rats consistently traveled less than sham controls on Day 10 and 14 after surgical manipulation. Significant differences between sham- and CCI-treated rats using Tukey’s test for post-hoc contrasts. ** P < 0.01, # P < 0.02, * P < 0.05.
Figure 2
Figure 2. The effects of sciatic neuropathy (CCI) on voluntary wheel running activity during the active phase of the diurnal cycle
(A) Total distance traveled (m) increased over a 7-day sequential habituation period of a fixed interval 1-hr/day free-access period to running wheels, while no differences were observed between groups (N = 6/gp) at any timepoint. Tukey’s test for timepoint comparisons and Šidák’ test for group comparisons at each time point. Statistical significance was set with alpha at p <0.05. (B) One hour wheel running activity during the active diurnal cycle relative to BL levels was similar between sham or unilateral CCI. Šidák’ test for group comparisons at each timepoint revealed no group differences. Statistical significance at p <0.05. (C, D and E) Comparison of distance traveled within three 20-min phases of the 1 hr wheel-running testing period during the active diurnal cycle revealed that CCI rats traveled similar distances to that observed with sham rats. Thus, CCI did not significantly alter wheel running on the indicated nights tested post-surgery as revealed by Šidák’ test for group comparisons at each timepoint with statistical significance set at p <0.05.
Figure 3
Figure 3. Hindpaw threshold sensitivity throughout the 18-day timecourse remains stable
(A, B) Compared to hindpaw threshold responses relative to BL levels in sham-treated rats, CCI leads to robust bilateral and persistent allodynia that is unaltered by wheel running activity occurring during the inactive portion of the diurnal cycle. No hindpaw threshold differences between CCI – locked wheel and CCI – unlocked wheel throughout the timecourse were observed. Tukey’s test for post-hoc contrasts between each group at each time were performed, and Šidák’ post-hoc comparisons were performed between each CCI group at each time. ** P < 0.001. (C, D) This separate group of rats replicated our prior results of bilateral hindpaw sensitivity following CCI compared to sham controls, which verifies (1) stable ongoing allodynia was present in rats that were also examined for wheel running activity during the active phase of the diurnal cycle, and (2) this paradigm of acute exposure to active-cycle voluntary wheel running activity does not alter the pattern of ongoing allodynia. Šidák’ post-hoc comparisons were performed between CCI and sham groups at each time. # P < 0.01.

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