Transient receptor potential vanilloid 1 mediates pain in mice with severe sickle cell disease. Blood 2011 Sep 22;118(12):3376-83
Date
06/29/2011Pubmed ID
21708890Pubmed Central ID
PMC3179403DOI
10.1182/blood-2010-12-327429Scopus ID
2-s2.0-80053217106 (requires institutional sign-in at Scopus site) 118 CitationsAbstract
Pain is the leading cause of emergency department visits, hospitalizations, and daily suffering in individuals with sickle cell disease (SCD). The pathologic mechanisms leading to the perception of pain during acute RBC sickling episodes and development of chronic pain remain poorly understood and ineffectively treated. We provide the first study that explores nociceptor sensitization mechanisms that contribute to pain behavior in mice with severe SCD. Sickle mice exhibit robust behavioral hypersensitivity to mechanical, cold, and heat stimuli. Mechanical hypersensitivity is further exacerbated when hypoxia is used to induce acute sickling. Behavioral mechanical hypersensitivity is mediated in part by enhanced excitability to mechanical stimuli at both primary afferent peripheral terminal and sensory membrane levels. In the present study, inhibition of the capsaicin receptor transient receptor potential vanilloid 1 (TRPV1) with the selective antagonist A-425619 reversed the mechanical sensitization at both primary afferent terminals and isolated somata, and markedly attenuated mechanical behavioral hypersensitivity. In contrast, inhibition of TRPA1 with HC-030031 had no effect on mechanical sensitivity. These results suggest that the TRPV1 receptor contributes to primary afferent mechanical sensitization and a substantial portion of behavioral mechanical hypersensitivity in SCD mice. Therefore, TRPV1-targeted compounds that lack thermoregulatory side effects may provide relief from pain in patients with SCD.
Author List
Hillery CA, Kerstein PC, Vilceanu D, Barabas ME, Retherford D, Brandow AM, Wandersee NJ, Stucky CLAuthors
Amanda Brandow DO Professor in the Pediatrics department at Medical College of WisconsinCheryl L. Stucky PhD Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
Action PotentialsAnemia, Sickle Cell
Animals
Capsaicin
Disease Models, Animal
Female
Humans
Hyperalgesia
Hypoxia
Isoquinolines
Male
Mice
Mice, Inbred Strains
Microelectrodes
Nociceptors
Pain
Pain Measurement
Patch-Clamp Techniques
TRPV Cation Channels
Urea
