Program: Oral and Poster Abstracts
Type: Oral
Session: 113. Hemoglobinopathies, Excluding Thalassemia Basic and Translational Science: Innovative Therapeutic Approaches in Sickle Cell Disease
Methods: Townes transgenic humanized mice expressing sickle hemoglobin (HbSS / HbAS) and normal human hemoglobin (HbAA) controls (4-12 weeks of age, 20-25g) were used in this study. Mice were characterized for hyperalgesia by quantifying cutaneous mechanical sensitivity of the hind paw and forelimb grip force. Mechanical sensitivity of the hind paw was evaluated by determining the frequency of withdrawal responses and paw withdrawal threshold. The frequency of paw withdrawal evoked by a standard von Frey monofilament with a bending force of 9.3 mN applied to the plantar surface of the hind paws was determined from 10 trials on each paw. Withdrawal threshold was determined using an electronic von Frey anesthesiometer pressed against the plantar surface with increasing force until withdrawal occurred. To assess deep tissue hyperalgesia, the tensile force of peak forelimb exertion was measured using a computerized grip force meter. To evaluate the analgesic effects of MCC22, paw withdrawal frequency was determined before and at various times after administration of 8.0 µmol/kg i.p.
Results: Pain Characterization: HbSS sickle mice exhibited robust mechanical hyperalgesia as shown by a significant increase in paw withdrawal frequency compared to HbAS and HbAA controls (Figure1A, p<0.001). Paw withdrawal frequency in HbAS mice was also greater than those for HbAA mice (p<0.001), but less than HbSS mice. HbSS mice had lower mechanical withdrawal thresholds compared to both HbAS and HbAA mice (Figure 1B, p<0.001), while HbAS did not differ from HbAA mice. HbSS and HbAS mice also displayed lower forelimb grip force compared to HbAA mice (Figure 1C, p<0.001), although grip force in HbSS was lower than HbAS mice (p<0.001). Administration of MCC22 (8.0 µmol/kg i.p.) reduced hyperalgesia within 30 minutes as evidenced by a decrease in paw withdrawal frequency in both HbSS and HbAS mice (Figure 1D, p<0.001).
Figure 1A – D
Conclusions: Hyperalgesia was demonstrated in both HbAS and HbSS mice. MCC22 potently attenuated mechanical hyperalgesia in these SCD mice. The use of bivalent ligands that target heteromers involved in signaling pain may offer novel and effective treatments for pain in patients with SCD. We speculate that an analgesic with potential anti-inflammatory and mu-agonist activity may provide a novel approach to sickle pain.
Disclosures: Belcher: CSL Behring: Research Funding ; Seattle Genetics: Research Funding ; Biogen Idec: Research Funding . Vercellotti: Biogen Idec: Research Funding ; CSL Behring: Research Funding ; Cydan: Research Funding ; Seattle Genetics: Research Funding .
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