Cage-lid hanging behavior as a translationally relevant measure of pain in mice

Zhang, Hantao; Lecker, Irene; Collymore, Chereen; Dokova, Anastassia; Pham, Maian Christine; Rosen, Sarah F.; Crawhall-Duk, Hayley; Zain, Maham; Valencia, Megan; Filippini, Helena Fetter; Li, Jerry; D’Souza, Abigail; Cho, Chulmin; Michailidis, Vassilia; Whissell, Paul D.; Patel, Ingita; Steenland, Hendrik W.; Lee, Wai-Jane Virginia; Moayedi, Massieh; Sterley, Toni-Lee; Bains, Jaideep S.; Stratton, Jo Anne; Matyas, John R.; Biernaskie, Jeff; Dubins, David N.; Vukobradovic, Igor; Bezginov, Alexandr; Flenniken, Ann M.; Martin, Loren J.; Mogil, Jeffrey S.; Bonin, Robert P.

doi:10.1097/j.pain.0000000000002127

Cited by 42 publications

(51 citation statements)

References 47 publications

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“…37 Motor behavior is the most commonly used method to assess the degree of pain in animal models. 42 Zhang et al 31 We used MRI to assess the characteristics of IDD in cynomolgus monkeys. The study found that with increasing age, the IVDs in cynomolgus monkeys underwent degeneration.…”

Section: Discussionmentioning

confidence: 99%

Correlation between motor behavior and age‐related intervertebral disc degeneration in cynomolgus monkeys

Wang

Zhu²,

Pan

et al. 2022

JOR Spine

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Background The motor behavior in patients with lumbar intervertebral disc degeneration (IDD) and animal models should be changed due to pain. However, there does not seem to be a strong correlation between IDD and motor behavior. Therefore, it is necessary to understand the correlation between motor behavior and age‐related IDD. Methods Twenty‐one healthy male cynomolgus monkeys (Macaca fascicularis) distributed across the age range were included in this study. The experimental animals were divided into two groups: caged group (n = 14) and free‐range group (n = 7). The data of IDD and motor behavior were obtained through magnetic resonance imaging (MRI) and PrimateScan Automatic Behavior Analysis System. More than 20 basic motor behaviors could be recorded and quantified, and then reclassified into 9 combined categories. We defined the sum of the duration of activity‐related combined categories as the total duration of activity in 3 hours. The activity zone of the cynomolgus monkeys in the cage could be divided into top and bottom zones. Analyze the correlation between motor behavior and IDD. Results Age was correlated with both Pfirrmann grades (r = .700; P < .001) and T2 values (r = −.369; P < .001). The T2 value in the caged group was 45.97 ± 8.35 ms, which was significantly lower than the 55.90 ± 8.73 ms in the free‐range group (P < .001). The mean T2 values were positively correlated with hanging duration (r = .548, P < .05), the total duration of activity (r = .496, P < .05), and top zone duration (r = .541, P < .05). Conclusions There is an interactional relationship between IDD and motor behavior. Motor behavior could be used as one of the diagnostic indicators of IDD. It could also be used to infer the presence or extent of IDD in animal models. Avoiding a sedentary lifestyle and engaging in exercise in daily life could alleviate IDD.

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Section: Discussionmentioning

confidence: 99%

Correlation between motor behavior and age‐related intervertebral disc degeneration in cynomolgus monkeys

Wang

Zhu²,

Pan

et al. 2022

JOR Spine

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“…Recent studies have characterized a variety of spontaneous mouse behaviors that may be reflective of pain state, including free-choice temperature preference assays. 10 , 11 , 13 , 16 – 19 , 38 However, most assays used to assess thermal preference rely on mouse avoidance responses to noxious temperatures rather than assessment of native preference. 11 In contrast, our assay does not necessarily expose mice to noxious temperature ranges and therefore provides a measure of response to innocuous temperature, allowing for a study of thermal allodynia or thermotaxis.…”

Section: Discussionmentioning

confidence: 99%

“…Previous work done in our lab has shown that gabapentin at 100 mg/kg produces analgesia without impacting locomotion in mice. 38 After another 30 minutes, they were recorded in the arena for 30 minutes. All capsaicin injections were conducted after placing the mice under light isoflurane anesthesia, with toe-pinch reflex present.…”

Section: Methodsmentioning

confidence: 99%

Differential modulation of thermal preference after sensitization by optogenetic or pharmacological activation of heat-sensitive nociceptors

Zain

Bonin

2021

Mol Pain

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Common approaches to studying mechanisms of chronic pain and sensory changes in pre-clinical animal models involve measurement of acute, reflexive withdrawal responses evoked by noxious stimuli. These methods typically do not capture more subtle changes in sensory processing nor report on the consequent behavioral changes. In addition, data collection and analysis protocols are often labour-intensive and require direct investigator interactions, potentially introducing bias. In this study, we develop and characterize a low-cost, easily assembled behavioral assay that yields self-reported temperature preference from mice that is responsive to peripheral sensitization. This system uses a partially automated and freely available analysis pipeline to streamline the data collection process and enable objective analysis. We found that after intraplantar administration of the TrpV1 agonist, capsaicin, mice preferred to stay in cooler temperatures than saline injected mice. We further observed that gabapentin, a non-opioid analgesic commonly prescribed to treat chronic pain, reversed this aversion to higher temperatures. In contrast, optogenetic activation of the central terminals of TrpV1+ primary afferents via in vivo spinal light delivery did not induce a similar change in thermal preference, indicating a possible role for peripheral nociceptor activity in the modulation of temperature preference. We conclude that this easily produced and robust sensory assay provides an alternative approach to investigate the contribution of central and peripheral mechanisms of sensory processing that does not rely on reflexive responses evoked by noxious stimuli.

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“…The assays performed in the preclinical portion of this study were all conducted in a testing room and examined pain behaviors in various contexts such as evoked pain, spontaneous pain, and muscle strength. We acknowledge that animal behavior in this context may not completely reflect home-cage behavior, such as voluntary wheel-running, cage-lid hanging, and general home-cage activity, which reduces stress from test that occur out of the animal's home environment (60,61). Home-cage behaviors may also be more translational to quality-of-life assessments.…”

Section: Discussion: (1496 Words)mentioning

confidence: 99%

Translating outcomes from the clinical setting to preclinical models: chronic pain and functionality in chronic musculoskeletal pain

Lenert

Gomez

Lane

et al. 2021

Preprint

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Fibromyalgia (FM) is a chronic pain disorder characterized by chronic widespread musculoskeletal pain (CWP), tenderness, and fatigue, which interferes with daily functioning and quality of life. In clinical studies, this symptomology is assessed, while preclinical models of CWP are limited to nociceptive assays. The aim of the study was to investigate the human-to-model translatability of clinical behavioral assessments for pain and muscle function in a preclinical model of CWP. We assessed correlations between pain behaviors and muscle function in a preclinical model of CWP and in women with fibromyalgia to examine whether similar relationships between outcomes existed in both settings, for usability of clinical assays in model systems. For preclinical measures, the acidic saline model of FM which induces widespread muscle pain, was used in adult female mice. Two gastrocnemius injections of acidic or physiological pH saline were given following baseline measures, five days apart. An array of adapted pain measures and functional assays were assessed for three weeks. For clinical measures, pain and functional assays were assessed in adult women with FM. For both preclinical and clinical outcomes, movement-evoked pain (MEP) was associated with mechanical pain sensitivity. Mechanical sensitivity was correlated to shifts in weight-bearing preclinically and was predictive of functionality in patients. Preclinically, it is imperative to expand how the field assesses pain behaviors when studying multi- symptom disorders like FM. Targeted pain assessments to match those performed clinically is an important aspect of improving preclinical to clinical translatability of animal models.SummaryPreclinical assessments of chronic musculoskeletal pain recapitulate several outcome measures for clinical assessment of patients with FM, particularly prolonged resting pain, and MEP.

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Cage-lid hanging behavior as a translationally relevant measure of pain in mice

Abstract: Supplemental Digital Content is Available in the Text. Cage-lid hanging behavior is impaired by sustained pain in mice and can be used as an ethologically valid and translationally relevant pain outcome measure.

Cited by 42 publications

References 47 publications

Correlation between motor behavior and age‐related intervertebral disc degeneration in cynomolgus monkeys

Correlation between motor behavior and age‐related intervertebral disc degeneration in cynomolgus monkeys

Differential modulation of thermal preference after sensitization by optogenetic or pharmacological activation of heat-sensitive nociceptors

Translating outcomes from the clinical setting to preclinical models: chronic pain and functionality in chronic musculoskeletal pain

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