Cold hypersensitivity increases with age in mice with sickle cell disease

Abstract

Sickle cell disease (SCD) is associated with acute vaso-occlusive crises that trigger painful episodes and frequently involves ongoing, chronic pain. Additionally, both humans and mice with SCD experience heighted cold sensitivity. However, studies have not addressed the mechanism(s) underlying the cold sensitization, nor its progression with age. Here we measured thermotaxis behavior in young and aged mice with severe SCD. Sickle mice had a marked increase in cold sensitivity measured by a cold preference test. Further, cold hypersensitivity worsened with advanced age. We assessed whether enhanced peripheral input contributes to the chronic cold pain behavior by recording from C fibers, many of which are cold-sensitive, in skin-nerve preparations. We observed that C fibers from sickle mice displayed a shift to warmer (more sensitive) cold-detection thresholds. To address mechanisms underlying the cold sensitization in primary afferent neurons, we quantified mRNA expression levels for ion channels thought to be involved in cold detection. These included the Transient Receptor Potential Melastatin 8 (Trpm8) and TRP Ankyrin 1 (Trpa1) channels, as well as the two-pore domain potassium channels, TREK-1 (Kcnk2), TREK-2 (Kcnk4), and TRAAK (Kcnk10). Surprisingly, transcript expression levels of all of these channels were comparable between sickle and control mice. We further examined transcript expression of 83 additional pain-related genes and found increased mRNA levels for endothelin 1 and tachykinin receptor 1. These factors may contribute to hypersensitivity in sickle mice at both the afferent and behavioral levels. Sensory neurons from sickle cell disease mice are sensitized to cold, mirroring behavioral observations, and have increased expression of endothelin 1 and tachykinin receptor 1.

Central sensitization associated with low fetal hemoglobin levels in adults with sickle cell anemia

“…These results are in contrast with the heat pain hyperalgesia and light touch allodynia reported in SCD mice and heat pain hyperalgesia in children with SCD [12, 18, 21, 30, 31]. However, our results are similar to another QST study of adults with SCD, which likewise did not show increased heat pain thresholds [13].…”

“…QST in SCD shows increased sensitivity to painful stimuli [12, 18–21, 26–30] which is heightened by age [18, 30, 31]. [27].…”

Updated Mechanisms of Sickle Cell Disease-Associated Chronic pain

“…[49] Research thus far shows no differences in pain behavior between HBSS-BERK and Townes mice. Pain hypersensitivity also increases with age in SCD mice, [50] which correlates with the phenomena observed in SCD patients. [19] …”

“…In an ex-vivo saphenous nerve preparation from HBSS-BERK and control mice, Zappia et al found that HBSS-BERK C-fibers responded at warmer temperatures when compared to control fibers during a decreasing temperature ramp from 32°C to 2°C (19.2 ± 1.2 °C vs. 14.6 ± °C). [50] This could represent sensitization of peripheral afferent terminals to cold stimuli as the control fibers can withstand colder temperatures without firing, thereby explaining cold hypersensitivity behavior observed in SCD mice. In a separate study of HBSS-BERK mice, mechanical allodynia was found to result from enhanced activation of mechanoreceptors.…”

“…[58] PCR analysis of the DRG from HBSS-BERK and HBAA mice revealed an upregulation of Tachykinin receptor 1 and endothelin 1(ET-1). [50] Substance P, the primary ligand of Tachykinin receptor 1, is known to play a role in pain sensation and is linked to spinal cord injury and cutaneous neurogenic inflammation. [59] The upregulation of its receptor in HBSS mice may represent an increase in SP activity.…”