Mouse Models of Pain in Sickle Cell Disease

Sagi, Varun; Song-Naba, Waogwende Leonce; Benson, Barbara A.; Joshi, Sonal S.; Gupta, Kalpna

doi:10.1002/cpns.54

Cited by 18 publications

(19 citation statements)

References 82 publications

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“…We used a total of 24 mice consisting of control (HbAA-BERK) and sickle (HbSS-BERK), hereafter referred to as control and sickle mice, respectively. All mice were bred and raised in-house with ad libitum access to food and water on a 12-h light/dark cycle in conventional housing and used at ∼3.5 months of age (7). Control and sickle mice are homozygous for knockout of both murine α and β globins.…”

Section: Animalsmentioning

confidence: 99%

“…Humanized HbSS-BERK sickle mice exhibit enhanced mechanical, thermal and deep tissue hyperalgesia compared to control mice (23,24). All mice were validated by phenotyping for sickle and normal human hemoglobin by isoelectric focusing as previously described (7).…”

Section: Animalsmentioning

confidence: 99%

“…Mice were acclimatized to each test protocol in a quiet room at constant temperature, and tested for mechanical (von Frey) and spontaneous musculoskeletal/deep (grip force) as previously described (7,23). Behavioral tests were performed consecutively at a 5-min interval between tests, in a double-blind manner.…”

Section: Assessment Of Hyperalgesiamentioning

confidence: 99%

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Spatiotemporal Alterations in Gait in Humanized Transgenic Sickle Mice

et al. 2020

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Sickle cell disease (SCD) is a hemoglobinopathy affecting multiple organs and featuring acute and chronic pain. Purkinje cell damage and hyperalgesia have been demonstrated in transgenic sickle mice. Purkinje cells are associated with movement and neural function which may influence pain. We hypothesized that Purkinje cell damage and/or chronic pain burden provoke compensatory gait changes in sickle mice. We found that Purkinje cells undergoe increased apoptosis as shown by caspase-3 activation. Using an automated gait measurement system, MouseWalker, we characterized spatiotemporal gait characteristics of humanized transgenic BERK sickle mice in comparison to control mice. Sickle mice showed alteration in stance instability and dynamic gait parameters (walking speed, stance duration, swing duration and specific swing indices). Differences in stance instability may reflect motor dysfunction due to damaged Purkinje cells. Alterations in diagonal and all stance indices indicative of hesitation during walking may originate from motor dysfunction and/or arise from fear and/or anticipation of movement-evoked pain. We also demonstrate that stance duration, diagonal swing indices and all stance indices correlate with both mechanical and deep tissue hyperalgesia, while stance instability correlates with only deep tissue hyperalgesia. Therefore, objective analysis of gait in SCD may provide insights into neurological impairment and pain states.

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Section: Animalsmentioning

confidence: 99%

Section: Animalsmentioning

confidence: 99%

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Spatiotemporal Alterations in Gait in Humanized Transgenic Sickle Mice

et al. 2020

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“…Transgenic murine models of SCD, such as the Berkley model, 12 have been used to study pain mechanisms in SCD. 13,14 HbSS-BERK mice are homozygous for knockout of both murine a and b globins and carry a single copy of the linked transgenes for human a and b S globins. These mice express human a and b S globin chains (thus, human hemoglobin S), but no murine a or b globins, and share many features of SCD patients, including persistent inflammation 4,15 and hyperalgesia.…”

Section: Introductionmentioning

confidence: 99%

Sensitization of nociceptors by prostaglandin E2–glycerol contributes to hyperalgesia in mice with sickle cell disease

Khasabova¹,

Uhelski²,

Khasabov³

et al. 2019

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Pain is a characteristic feature of sickle cell disease (SCD), 1 of the most common inherited diseases. Patients may experience acute painful crises as well as chronic pain. In the Berkley transgenic murine model of SCD, HbSS-BERK mice express only human hemoglobin S. These mice share many features of SCD patients, including persistent inflammation and hyperalgesia. Cyclooxygenase-2 (COX-2) is elevated in skin, dorsal root ganglia (DRG), and spinal cord in HbSS-BERK mice. In addition to arachidonic acid, COX-2 oxidizes the endocannabinoid 2-arachidonoylglycerol (2-AG) to produce prostaglandin E2 (PGE2)–glycerol (PGE2-G); PGE2-G is known to produce hyperalgesia. We tested the hypotheses that PGE2-G is increased in DRGs of HbSS-BERK mice and sensitizes nociceptors (sensory neurons that respond to noxious stimuli), and that blocking its synthesis would decrease hyperalgesia in HbSS-BERK mice. Systemic administration of R-flurbiprofen preferentially reduced production of PGE2-G over that of PGE2 in DRGs, decreased mechanical and thermal hyperalgesia, and decreased sensitization of nociceptors in HbSS-BERK mice. The same dose of R-flurbiprofen had no behavioral effect in HbAA-BERK mice (the transgenic control), but local injection of PGE2-G into the hind paw of HbAA-BERK mice produced sensitization of nociceptors and hyperalgesia. Coadministration of a P2Y6 receptor antagonist blocked the effect of PGE2-G, indicating that this receptor is a mediator of pain in SCD. The ability of R-flurbiprofen to block the synthesis of PGE2-G and to normalize levels of 2-AG suggests that R-flurbiprofen may be beneficial to treat pain in SCD, thereby reducing the use of opioids to relieve pain.

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“…HbSS-BERK mice offspring (henceforth called pups) expressing >99% human sickle hemoglobin were used. 5 Because homozygous BERK female mice often do not breed/survive pregnancy, 6 we used heterozygous BERK female (HbAS-BERK) and male HbSS-BERK as breeding pairs (Figure 1). Breeders and pups were randomly assigned to either a sickle diet (SD) or regular diet (RD) ( Table 1) to differentiate groups by pup diet, parental diet, and gender ( Figure 1).…”

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confidence: 99%