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Comparison of Burrowing and Stimuli-Evoked Pain Behaviors as End-Points in Rat Models of Inflammatory Pain and Peripheral Neuropathic Pain.

Muralidharan A, Kuo A, Jacob M, Lourdesamy JS, Carvalho LM, Nicholson JR, Corradini L, Smith MT - Front Behav Neurosci (2016)

Bottom Line: For FCA- and CCI-rats, but not the corresponding groups of sham-rats, evoked mechanical hypersensitivity developed in a temporal manner in the ipsilateral hindpaws.By contrast, mechanical hyperalgesia and mechanical allodynia in the ipsilateral hindpaws of FCA- and CCI-rats respectively, exhibited minimal inter-animal variability.However, large group sizes are needed to ensure studies are adequately powered due to considerable inter-animal variability.

View Article: PubMed Central - PubMed

Affiliation: Centre for Integrated Preclinical Drug Development, The University of Queensland Brisbane, QLD, Australia.

ABSTRACT
Establishment and validation of ethologically-relevant, non-evoked behavioral end-points as surrogate measures of spontaneous pain in rodent pain models has been proposed as a means to improve preclinical to clinical research translation in the pain field. Here, we compared the utility of burrowing behavior with hypersensitivity to applied mechanical stimuli for pain assessment in rat models of chronic inflammatory and peripheral neuropathic pain. Briefly, groups of male Sprague-Dawley rats were habituated to the burrowing environment and trained over a 5-day period. Rats that burrowed ≤ 450 g of gravel on any 2 days of the individual training phase were excluded from the study. The remaining rats received either a unilateral intraplantar injection of Freund's complete adjuvant (FCA) or saline, or underwent unilateral chronic constriction injury (CCI) of the sciatic nerve- or sham-surgery. Baseline burrowing behavior and evoked pain behaviors were assessed prior to model induction, and twice-weekly until study completion on day 14. For FCA- and CCI-rats, but not the corresponding groups of sham-rats, evoked mechanical hypersensitivity developed in a temporal manner in the ipsilateral hindpaws. Although burrowing behavior also decreased in a temporal manner for both FCA-and CCI- rats, there was considerable inter-animal variability. By contrast, mechanical hyperalgesia and mechanical allodynia in the ipsilateral hindpaws of FCA- and CCI-rats respectively, exhibited minimal inter-animal variability. Our data collectively show that burrowing behavior is altered in rodent models of chronic inflammatory pain and peripheral neuropathic pain. However, large group sizes are needed to ensure studies are adequately powered due to considerable inter-animal variability.

No MeSH data available.


Related in: MedlinePlus

Cumulative mean (±SEM) weight of gravel burrowed vs. time curves for (A) Cohorts 1–3 rats administered a unilateral ip.l. injection of FCA (n = 11) or saline (n = 8), and (B) Cohorts 1–4 rats that underwent CCI (n = 21) or sham (n = 16) surgery. (C,D) Correlation between the degree of burrowing performance and mechanical hyperalgesia or mechanical allodynia for individual (C) FCA- and (D) CCI-rats tested. At days 2–10 following a unilateral i.pl. injection of FCA, there was a significant (P ≤ 0.05) temporal reduction in burrowing behavior compared with insignificant changes in the burrowing behavior of sham-rats. For CCI-rats, there was a significant (P ≤ 0.05) reduction in the mean (±SEM) weight of gravel burrowed between days 2 and 14 post-CCI surgery c.f. the corresponding values for the sham-control rats. Significant correlation between burrowing performance and mechanical hyperalgesia was observed only on day 4/5 in FCA-rats, in contrast to the lack of significant correlation between burrowing behavior and the extent of mechanical allodynia in the ipsilateral hindpaws of CCI-rats. *P ≤ 0.05 (Two-way ANOVA, post-hoc: Bonferroni) relative to that observed in the corresponding groups of sham-control rats.
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Figure 5: Cumulative mean (±SEM) weight of gravel burrowed vs. time curves for (A) Cohorts 1–3 rats administered a unilateral ip.l. injection of FCA (n = 11) or saline (n = 8), and (B) Cohorts 1–4 rats that underwent CCI (n = 21) or sham (n = 16) surgery. (C,D) Correlation between the degree of burrowing performance and mechanical hyperalgesia or mechanical allodynia for individual (C) FCA- and (D) CCI-rats tested. At days 2–10 following a unilateral i.pl. injection of FCA, there was a significant (P ≤ 0.05) temporal reduction in burrowing behavior compared with insignificant changes in the burrowing behavior of sham-rats. For CCI-rats, there was a significant (P ≤ 0.05) reduction in the mean (±SEM) weight of gravel burrowed between days 2 and 14 post-CCI surgery c.f. the corresponding values for the sham-control rats. Significant correlation between burrowing performance and mechanical hyperalgesia was observed only on day 4/5 in FCA-rats, in contrast to the lack of significant correlation between burrowing behavior and the extent of mechanical allodynia in the ipsilateral hindpaws of CCI-rats. *P ≤ 0.05 (Two-way ANOVA, post-hoc: Bonferroni) relative to that observed in the corresponding groups of sham-control rats.

Mentions: For rats in Cohorts 1–3 that received a unilateral i.pl. injection of FCA, there was a significant temporal decrease in the cumulative mean (±SEM) weight of gravel burrowed [F(1, 8, 8/136) = 9.15, 6.03, 4.36; P ≤ 0.05] between days 2 and 10 in contrast to the insignificant change in the weight of gavel burrowed by sham-rats across the 14-day experimental period (Figure 5A). Likewise, between days 3 and 14 post-surgery, there was a significant [F(1, 7, 7/245) = 7.9, 10.4, 6.8; P ≤ 0.05] temporal decrease in the burrowing behavior of rats with a unilateral CCI of the sciatic nerve relative to that of sham-control rats (Figure 5B). However, there was significant between-cohort variability in the burrowing behavior of both FCA- and CCI-rats relative to that of their respective sham-controls (Supplementary Figures 3A–C, 4A–D, respectively; see the respective supplementary figure legends for individual cohort statistical analyses). Specifically, comparison of the burrowing behavior of FCA-rats between the different cohorts showed significant [F(2, 5, 10/40 = 3.2, 9.3, 2.2; P ≤ 0.05] between-cohort variability in burrowing behavior on days 2 and 4/5 post-i.pl. FCA injection (Supplementary Figure 5A). Likewise, For CCI-rats, there was significant [F(3, 4, 12/68 = 2.4, 7.3, 2.3; P ≤ 0.05] between cohort variability in burrowing behavior on day 14 post-CCI surgery (Supplementary Figure 5B). In contrast, there were no between-cohort differences in the burrowing behavior of saline-injected rats [F(2, 5, 10/25 = 2.3, 1.4, 0.6; Supplementary Figure 5C] or sham surgery animals [F(3, 4, 12/48 = 1.4, 0.8, 1.2; Supplementary Figure 5D]. Although different cohorts had different experimenters, the between-experimenter differences are mitigated as testers are not present in the room during the burrowing sessions.


Comparison of Burrowing and Stimuli-Evoked Pain Behaviors as End-Points in Rat Models of Inflammatory Pain and Peripheral Neuropathic Pain.

Muralidharan A, Kuo A, Jacob M, Lourdesamy JS, Carvalho LM, Nicholson JR, Corradini L, Smith MT - Front Behav Neurosci (2016)

Cumulative mean (±SEM) weight of gravel burrowed vs. time curves for (A) Cohorts 1–3 rats administered a unilateral ip.l. injection of FCA (n = 11) or saline (n = 8), and (B) Cohorts 1–4 rats that underwent CCI (n = 21) or sham (n = 16) surgery. (C,D) Correlation between the degree of burrowing performance and mechanical hyperalgesia or mechanical allodynia for individual (C) FCA- and (D) CCI-rats tested. At days 2–10 following a unilateral i.pl. injection of FCA, there was a significant (P ≤ 0.05) temporal reduction in burrowing behavior compared with insignificant changes in the burrowing behavior of sham-rats. For CCI-rats, there was a significant (P ≤ 0.05) reduction in the mean (±SEM) weight of gravel burrowed between days 2 and 14 post-CCI surgery c.f. the corresponding values for the sham-control rats. Significant correlation between burrowing performance and mechanical hyperalgesia was observed only on day 4/5 in FCA-rats, in contrast to the lack of significant correlation between burrowing behavior and the extent of mechanical allodynia in the ipsilateral hindpaws of CCI-rats. *P ≤ 0.05 (Two-way ANOVA, post-hoc: Bonferroni) relative to that observed in the corresponding groups of sham-control rats.
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4862327&req=5

Figure 5: Cumulative mean (±SEM) weight of gravel burrowed vs. time curves for (A) Cohorts 1–3 rats administered a unilateral ip.l. injection of FCA (n = 11) or saline (n = 8), and (B) Cohorts 1–4 rats that underwent CCI (n = 21) or sham (n = 16) surgery. (C,D) Correlation between the degree of burrowing performance and mechanical hyperalgesia or mechanical allodynia for individual (C) FCA- and (D) CCI-rats tested. At days 2–10 following a unilateral i.pl. injection of FCA, there was a significant (P ≤ 0.05) temporal reduction in burrowing behavior compared with insignificant changes in the burrowing behavior of sham-rats. For CCI-rats, there was a significant (P ≤ 0.05) reduction in the mean (±SEM) weight of gravel burrowed between days 2 and 14 post-CCI surgery c.f. the corresponding values for the sham-control rats. Significant correlation between burrowing performance and mechanical hyperalgesia was observed only on day 4/5 in FCA-rats, in contrast to the lack of significant correlation between burrowing behavior and the extent of mechanical allodynia in the ipsilateral hindpaws of CCI-rats. *P ≤ 0.05 (Two-way ANOVA, post-hoc: Bonferroni) relative to that observed in the corresponding groups of sham-control rats.
Mentions: For rats in Cohorts 1–3 that received a unilateral i.pl. injection of FCA, there was a significant temporal decrease in the cumulative mean (±SEM) weight of gravel burrowed [F(1, 8, 8/136) = 9.15, 6.03, 4.36; P ≤ 0.05] between days 2 and 10 in contrast to the insignificant change in the weight of gavel burrowed by sham-rats across the 14-day experimental period (Figure 5A). Likewise, between days 3 and 14 post-surgery, there was a significant [F(1, 7, 7/245) = 7.9, 10.4, 6.8; P ≤ 0.05] temporal decrease in the burrowing behavior of rats with a unilateral CCI of the sciatic nerve relative to that of sham-control rats (Figure 5B). However, there was significant between-cohort variability in the burrowing behavior of both FCA- and CCI-rats relative to that of their respective sham-controls (Supplementary Figures 3A–C, 4A–D, respectively; see the respective supplementary figure legends for individual cohort statistical analyses). Specifically, comparison of the burrowing behavior of FCA-rats between the different cohorts showed significant [F(2, 5, 10/40 = 3.2, 9.3, 2.2; P ≤ 0.05] between-cohort variability in burrowing behavior on days 2 and 4/5 post-i.pl. FCA injection (Supplementary Figure 5A). Likewise, For CCI-rats, there was significant [F(3, 4, 12/68 = 2.4, 7.3, 2.3; P ≤ 0.05] between cohort variability in burrowing behavior on day 14 post-CCI surgery (Supplementary Figure 5B). In contrast, there were no between-cohort differences in the burrowing behavior of saline-injected rats [F(2, 5, 10/25 = 2.3, 1.4, 0.6; Supplementary Figure 5C] or sham surgery animals [F(3, 4, 12/48 = 1.4, 0.8, 1.2; Supplementary Figure 5D]. Although different cohorts had different experimenters, the between-experimenter differences are mitigated as testers are not present in the room during the burrowing sessions.

Bottom Line: For FCA- and CCI-rats, but not the corresponding groups of sham-rats, evoked mechanical hypersensitivity developed in a temporal manner in the ipsilateral hindpaws.By contrast, mechanical hyperalgesia and mechanical allodynia in the ipsilateral hindpaws of FCA- and CCI-rats respectively, exhibited minimal inter-animal variability.However, large group sizes are needed to ensure studies are adequately powered due to considerable inter-animal variability.

View Article: PubMed Central - PubMed

Affiliation: Centre for Integrated Preclinical Drug Development, The University of Queensland Brisbane, QLD, Australia.

ABSTRACT
Establishment and validation of ethologically-relevant, non-evoked behavioral end-points as surrogate measures of spontaneous pain in rodent pain models has been proposed as a means to improve preclinical to clinical research translation in the pain field. Here, we compared the utility of burrowing behavior with hypersensitivity to applied mechanical stimuli for pain assessment in rat models of chronic inflammatory and peripheral neuropathic pain. Briefly, groups of male Sprague-Dawley rats were habituated to the burrowing environment and trained over a 5-day period. Rats that burrowed ≤ 450 g of gravel on any 2 days of the individual training phase were excluded from the study. The remaining rats received either a unilateral intraplantar injection of Freund's complete adjuvant (FCA) or saline, or underwent unilateral chronic constriction injury (CCI) of the sciatic nerve- or sham-surgery. Baseline burrowing behavior and evoked pain behaviors were assessed prior to model induction, and twice-weekly until study completion on day 14. For FCA- and CCI-rats, but not the corresponding groups of sham-rats, evoked mechanical hypersensitivity developed in a temporal manner in the ipsilateral hindpaws. Although burrowing behavior also decreased in a temporal manner for both FCA-and CCI- rats, there was considerable inter-animal variability. By contrast, mechanical hyperalgesia and mechanical allodynia in the ipsilateral hindpaws of FCA- and CCI-rats respectively, exhibited minimal inter-animal variability. Our data collectively show that burrowing behavior is altered in rodent models of chronic inflammatory pain and peripheral neuropathic pain. However, large group sizes are needed to ensure studies are adequately powered due to considerable inter-animal variability.

No MeSH data available.


Related in: MedlinePlus