Pathobiology of pain in sickle cell disease

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Abstract

The overall goal of this program is to improve pain management and behavior deficits observed in sickle cell disease (SCD) patients. Our work aims to identify objective pain sensitivity measurements that can serve as clinical endpoints to test the efficacy of novel analgesic agents. We also aim to conduct mechanistic studies in mouse models of SCD and to conduct pre-clinical screen of potential therapeutic agents able to reduce SCD pain. Pain phenotypes in sickle cell disease (SCD) patients are highly variable. A small percentage of SCD patients experience many vaso-occlusive crises/year, 5% of patients account for over 30% of pain episodes, while 39% report few episodes of severe pain. The underlying mechanisms of such variability of pain phenotype is incompletely understood and clearly, a better understanding of the pathobiology of SCD is needed to improve its therapy. Humanized sickle cell mice recapitulate several phenotypes of SCD patients and provide models for the study of SCD pain. In a large cross-sectional study of SCD mice, we examined thermosensory response and sensory nerve fiber function using sine-wave electrical stimulation at 2000, 250, and 5 Hz to preferentially stimulate A, A, and C sensory nerve fibers respectively. We have shown in two strains of SCD mice, compared to respective controls, have decreases in 2000, 250, and 5Hz current vocalization thresholds in patterns that suggest sensitization of a broad spectrum of sensory nerve fibers during basal conditions. In addition, the pattern and degree of sensitization of sensory fibers varied according to strain, sex, age, and genotype of the mice. In a similarly variable pattern, both Townes and BERKs also had significantly altered sensitivity to noxious thermal stimuli in agreement with what has been shown by others. Therefore, the analysis of somatosensory function using sine-wave electrical stimulation in humanized sickle cell mice suggests that in SCD, both myelinated and unmyelinated, fibers are sensitized. The pattern of sensory fiber sensitization is distinct from that observed in pain models of neuropathic and inflammatory pain. Using the same paradigm of quantitative sensory testing used in sickle cell mice, we have shown that sickle cell disease patients, who display a severe pain phenotype, have sensitization of myelinated sensory nerve fibers. In 2021, we built on our previous studies of the behavioral deficits identified in the SCD mouse. We have shown that Townes and BERK SCD mice, while not having strokes, recapitulate neurocognitive deficits reported in humans. We showed that SCD mice have increased levels of reactive oxygen species, protein carbonylation, and lipid peroxidation in hippocampus and cortex, thus suggesting increased cerebral oxidative stress. Further, cerebral oxidative stress was associated with caspase-3 activity alterations and vascular endothelial abnormalities, white matter changes, and disruption of the blood brain barrier, similar to those reported after ischemic/oxidative injury. Additionally, after repeated hypoxia/reoxygenation exposure, homozygous Townes had enhanced microglia activation. Our findings indicate that oxidative stress and stress-induced tissue damage is increased in susceptible brain regions, which may, in turn, contribute to neurocognitive deficits in SCD mice. These observations suggest that altered nociception and cognitive and behavioral deficits in SCD mice mirror those described in SCD patients and that aging, anemia, and profound neuropathologic changes in hippocampus and cerebellum are possible biologic correlates of those deficits. We have also recently shown that these neurocognitive deficits in SCD mice are associated with increased oxidative stress and abnormalities of the blood brain barrier. These findings further support using SCD mice for studies of cognitive deficits in SCD and point to vulnerable brain areas with susceptibility to neuronal injury in SCD and to mechanisms that potentially underlie those neurocognitive deficits and alterations in nociception.