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.