Cold hypersensitivity increases with age in mice with sickle cell disease. Pain 2014 Dec;155(12):2476-2485
Date
06/24/2014Pubmed ID
24953902Pubmed Central ID
PMC4250326DOI
10.1016/j.pain.2014.05.030Scopus ID
2-s2.0-84922744582 (requires institutional sign-in at Scopus site) 50 CitationsAbstract
Sickle cell disease (SCD) is associated with acute vaso-occlusive crises that trigger painful episodes and frequently involves ongoing, chronic pain. In addition, both humans and mice with SCD experience heightened cold sensitivity. However, studies have not addressed the mechanism(s) underlying the cold sensitization or 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. Furthermore, 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 transient receptor potential ankyrin 1 (Trpa1) channels, as well as the 2-pore domain potassium channels, TREK-1 (Kcnk2), TREK-2 (Kcnk10), and TRAAK (Kcnk4). 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.
Author List
Zappia KJ, Garrison SR, Hillery CA, Stucky CLAuthor
Cheryl L. Stucky PhD Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Age FactorsAging
Anemia, Sickle Cell
Animals
Cold Temperature
Cryopyrin-Associated Periodic Syndromes
Endothelin-1
Ganglia, Spinal
Gene Expression Regulation
Hemoglobin A
In Vitro Techniques
Mice
Mice, Inbred C57BL
Mice, Transgenic
Nerve Fibers, Unmyelinated
Pain Threshold
Potassium Channels, Tandem Pore Domain
Sensory Receptor Cells
Skin
TRPC Cation Channels
TRPM Cation Channels