Cross-centre replication of suppressed burrowing behaviour as an ethologically relevant pain outcome measure in the rat: a prospective multicentre study

Wodarski, Rachel; Delaney, Ada; Ultenius, Camilla; Morland, Rosie; Andrews, Nick; Baastrup, Catherine; Bryden, Luke A.; Caspani, Ombretta; Christoph, Thomas; Gardiner, Natalie J.; Huang, Wenlong; Kennedy, Jeffrey D.; Koyama, Suguru; Li, Dominic; Ligocki, Marcin; Lindstén, Annika; Ian, Machin; Pekcec, Anton; Robens, A.; Rotariu, Sanziana M.; Voß, Sabrina; Segerdahl, Märta; Stenfors, Carina; Svensson, Camilla I.; Treede, Rolf‐Detlef; Uto, Katsuhiro; Yamamoto, Kazumi; Rutten, Kris; Rice, Andrew S.C.

doi:10.1097/j.pain.0000000000000657

Cited by 78 publications

(94 citation statements)

References 71 publications

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“…These data should be interpreted in the context of previous studies demonstrating that both nest building and burrowing behavior can be analyzed as indicators of distress and pain associated with experimental procedures in laboratory rodents. [26][27][28][29] As a short-and long-term consequence of prolonged seizure activity, fecal corticosterone metabolite levels proved to be increased in different phases of the study. However, the alterations of this biochemical stress marker were not very robust, as effects were often observed only in one of the animal groups prepared for tethered or telemetric recordings and were not always reflected by alterations in serum or hair corticosterone.…”

Section: Discussionmentioning

confidence: 94%

“…Whereas nest complexity levels normalized in subsequent phases, burrowing behavior proved to be reduced throughout all post‐SE phases including the latency phase. These data should be interpreted in the context of previous studies demonstrating that both nest building and burrowing behavior can be analyzed as indicators of distress and pain associated with experimental procedures in laboratory rodents …”

Section: Discussionmentioning

confidence: 97%

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Toward evidence‐based severity assessment in rat models with repeated seizures: III. Electrical post‐status epilepticus model

et al. 2019

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Objective Ethical approval of experiments in chronic epilepsy models requires a careful balancing of the expected gain‐in‐knowledge with the level of distress. Thus recommendations for evidence‐based severity assessment and classification are urgently needed for preclinical epilepsy research. Methods Therefore, we have completed a comprehensive analysis of alterations in behavioral, biochemical, and physiological parameters in a rat electrical post‐status epilepticus model. Selected parameters were repeatedly analyzed during different experimental phases to obtain information about the level of distress throughout the course of the model. Results Behavioral patterns comprised an increase in activity along with a reduction in risk assessment behavior, active social interaction, saccharin preference as well as nonessential, but evolutionary‐determined behavior such as nest building and burrowing. Among the biochemical parameters, fecal corticosterone metabolites proved to be increased in different phases of the experiment. In the early post‐insult phase, this increase was reflected by elevated serum corticosterone concentrations. Telemetric recordings demonstrated increases in home cage activity and heart rate in selected experimental phases but argued against relevant changes in heart rate variability. Comparison between animals with tethered or telemetric recordings including a principal component analysis revealed differences between both groups. Significance The present findings further confirm that burrowing behavior and saccharin preference might serve as valid parameters for severity assessment in chronic epilepsy models. Considering the course of alterations providing evidence for a more pronounced level of distress in the early phase following status epilepticus (SE), we suggest a classification of the electrical post‐SE model as severe. This suggestion may serve as a guidance for laboratory‐specific evaluations. Comparison between data from animals with tethered and telemetric recordings indicated an impact of the mode of recordings. However, further research is necessary to analyze the validity of telemetry as a putative refinement measure.

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 97%

Toward evidence‐based severity assessment in rat models with repeated seizures: III. Electrical post‐status epilepticus model

et al. 2019

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“…SBB is a part of rodents' behavioral repertoire and has been used as a proxy of well-being. 34 Pain has also been shown to reduce burrowing in several experimental models 35,[75][76][77] -see also 13,78,79 -although some interanimal 76 and interlaboratory 77 variability has been reported. Another evidence from segregation between sensory and affective impacts of neuropathies comes from a work using the cuff model reporting that upon cuff removal thresholds to mechanical stimulus evolved to near baseline values, while anxiety-like behavior maintained elevated.…”

Section: Discussionmentioning

confidence: 99%

Evidence for lack of direct causality between pain and affective disturbances in a rat peripheral neuropathy model

Guimarães

Soares

Cunha

et al. 2018

Genes Brain and Behavior

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Chronic pain is frequently accompanied by the manifestation of emotional disturbances and cognitive deficits. While a causality relation between pain and emotional/cognitive disturbances is generally assumed, several observations suggest a temporal dissociation and independent mechanisms. We therefore studied Sprague‐Dawley rats that presented a natural resistance to pain manifestation in a neuropathy model (spared nerve injury [SNI]) and compared their performance in a battery of behavioral paradigms—anxiety, depression and fear memory—with animals that presented a pain phenotype. Afterward, we performed an extensive volumetric analysis across prefrontal, orbitofrontal and insular cortical areas. The majority of SNI animals manifested mechanical allodynia (low threshold [LT]), but 13% were similar to Sham controls (high threshold [HT]). Readouts of spontaneous hypersensivity (paw flinches) were also significantly reduced in HT and correlated with allodynia. To increase the specificity of our findings, we segregated the SNI animals in those with left (SNI‐L) and right (SNI‐R) lesions and the lack of association between pain and behavior still remains. Left‐lesioned animals, independent of the LT or HT phenotype, presented increased anxiety‐like behaviors and decreased well‐being. In contrast, we found that the insular cortex (agranular division) was significantly smaller in HT than in LT. To conclude, pain and emotional disturbances observed following nerve injury are to some extent segregated phenomena. Also, HT and LT SNI presented differences in insular volumes, an area vastly implicated in pain perception, suggesting a supraspinal involvement in the manifestation of these phenotypes.

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“…When considering burrowing behavior as a parameter, the effort for analysis needs to be taken into account. Although burrowing behavior in general can be easily assessed with a simple experimental setup, it requires a short training phase and baseline measurements, and for rats the common procedure is based on analysis in a separate cage and not the home cage …”

Section: Discussionmentioning

confidence: 99%

Toward evidence‐based severity assessment in rat models with repeated seizures: II. Chemical post–status epilepticus model

et al. 2019

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Objective Considering the complexity of neuronal circuits and their epilepsy‐associated alterations, epilepsy models cannot be completely replaced by in vitro experimental approaches. Decisions about ethical approval of in vivo studies require a thorough weighing of the animal's burden and the benefit regarding the expected gain in knowledge. Methods Based on combined behavioral, biochemical, and physiological analyses, we assessed the impact on animal well‐being and condition in different phases of the pilocarpine post–status epilepticus (SE) model in rats. Results As a consequence of SE, increased levels of impairment were evident in the early postinsult phase and late chronic phase, whereas only mild impairment was observed in the interim phase. Parameters that stood out as sensitive indicators of animal distress include burrowing, which proved to be affected throughout all experimental phases, saccharin preference, fecal corticosterone metabolites, heart rate, and heart rate variability. Significance The cumulative burden with temporary but not long‐lasting phases of more pronounced impairment suggests a classification of severe as a basis for laboratory‐specific prospective and retrospective evaluation. Among the parameters analyzed, burrowing behavior and saccharin preference stand out as candidate parameters that seem to be well suited to obtain information about animal distress in epileptogenesis models.

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Cross-centre replication of suppressed burrowing behaviour as an ethologically relevant pain outcome measure in the rat: a prospective multicentre study

Abstract: Supplemental Digital Content is Available in the Text.This unique multicenter approach provides high-quality evidence validating burrowing as a robust and reproducible outcome measure to infer the global effect of pain on rodents.

Cited by 78 publications

References 71 publications

Toward evidence‐based severity assessment in rat models with repeated seizures: III. Electrical post‐status epilepticus model

Toward evidence‐based severity assessment in rat models with repeated seizures: III. Electrical post‐status epilepticus model

Evidence for lack of direct causality between pain and affective disturbances in a rat peripheral neuropathy model

Toward evidence‐based severity assessment in rat models with repeated seizures: II. Chemical post–status epilepticus model

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