title: Transient receptor potential vanilloid 1 mediates pain in mice with severe sickle cell disease.
abstract: 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.
authors.affiliation: Department of Pediatrics and Children's Research Institute, Division of Hematology/Oncology, Medical College of Wisconsin, Milwaukee, WI, USA. cheryl.hillery@bcw.edu
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Hillery
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Kerstein
authors.forename: Daniel
authors.initials: D
authors.lastname: Vilceanu
authors.forename: Marie E
authors.initials: ME
authors.lastname: Barabas
authors.forename: Dawn
authors.initials: D
authors.lastname: Retherford
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Brandow
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Wandersee
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Stucky
mesh_terms: D000200:Action Potentials; D000755:Anemia, Sickle Cell / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002211:Capsaicin / Q000009:adverse effects / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D000860:Hypoxia; D007546:Isoquinolines / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008839:Microelectrodes; D009619:Nociceptors / Q000187:drug effects / Q000378:metabolism*; D010146:Pain / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D010147:Pain Measurement / Q000379:methods; D018408:Patch-Clamp Techniques; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: C503120:1-isoquinolin-5-yl-3-(4-trifluoromethyl-benzyl)-urea; D007546:Isoquinolines; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D014508:Urea; D002211:Capsaicin