Mouse models for studying pain in sickle disease: effects of strain, age, and acuteness

Abstract

Clinical management of severe pain associated with sickle cell disease (SCD) remains challenging. Development of optimal therapy would be facilitated by use of murine model(s) with varying degrees of sickling and pain tests that are most sensitive to vasoocclusion. We found that young (≤3 month old) NY1DD and S+SAntilles mice (having modest and moderate sickle phenotype, respectively) exhibit evidence of deep tissue/musculoskeletal pain. Deep tissue pain and cold sensitivity in S+SAntilles mice increased significantly with both age and incitement of hypoxia/reoxygenation (H/R). C57/BL6 mice (genetic background strain of NY1DD and S+SAntilles) were hypersensitive to mechanical and heat stimuli, even without the sickle transgene. H/R treatment of HbSS-BERK mice with severe sickle phenotype resulted in significantly decreased withdrawal thresholds and enhanced mechanical, thermal and deep tissue hyperalgesia. Deep hyperalgesia incited by H/R in HbSS-BERK was ameliorated by CP 55940, a cannabinoid receptor agonist. Thus, assessment of deep tissue pain appears to be the most sensitive measure for studying pain mechanisms across mouse models of SCD, and HbSS-BERK mice may best model vaso-occlusive and chronic pain of SCD.

Cannabinoid receptor-specific mechanisms to alleviate pain in sickle cell anemia via inhibition of mast cell activation and neurogenic inflammation

“…3 We also found that cannabinoids mitigate chronic and hypoxia/reoxygenation (H/R)-evoked acute hyperalgesia in sickle mice. 4,5 Cannabinoids have anti-inflammatory effects and provide protection from ischemia/reperfusion injury. [6][7][8][9][10] Since pain is a manifestation of complex sickle pathobiology including inflammation, vascular dysfunction and ischemia/reperfusion injury, we investigated cannabinoid receptor-specific modulation of vascular function, inflammation and hyperalgesia.…”

“…19 Since vascular dysfunction, ischemia/reperfu-sion injury and inflammation are hallmark features of SCA, we hypothesized that targeting specific cannaboid receptors may have beneficial effects on sickle pathobiology and pain. We used transgenic HbSS-BERK mice, hereafter referred to as sickle mice, which show features of pain and inflammation similar to patients with SCA, 4,5,20 and sickle mice with deletion of CB2R, to examine the contribution of each cannaboid receptor in mast cell activation, neurogenic inflammation, and pain.…”

Updated Mechanisms of Sickle Cell Disease-Associated Chronic pain

“…Control SCD mice (HBAA) are also available, in which only human α-and normal human β-globin alleles are expressed. [40,42] The phenotypes in SCD mice are highly similar to those observed in SCD patients. Both Berkley (HBSS-BERK) and Townes (HBSS) SCD mice display many of the pathophysiological changes observed in SCD patients including anemia, organ damage, hypoxia-induced cell sickling, and pain sensitivity.…”

“…[40] Two common mouse models of SCD are the Berkeley [41] and Townes [42] models. In both of these models, the mouse α-and β-globin alleles have been knocked down, and human α-and human sickle β-globin alleles have been inserted.…”

“…[42,43,45,46] Exposure to a hypoxic environment induces cell sickling in SCD mice, and can be used in the laboratory to induce a vaso-occlusive episode. [40] A major limitation of both SCD models is the severity of the disease. In SCD patients, the severity of the disease depends on a multitude of factors including γ-globin expression, β-globin expression (both normal and sickle), α-globin expression, and environment.…”