A spicy solution for sickle cell disease

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Science Translational Medicine  04 Nov 2020:
Vol. 12, Issue 568, eabf2644
DOI: 10.1126/scitranslmed.abf2644


In mice with sickle cell disease, signaling through the capsaicin receptor appears to mitigate vaso-occlusive episodes and organ damage.

In patients with sickle cell disease (SCD), red blood cells sickle, or deform in a crescent shape, under deoxygenated conditions. This leads to inflammation and acute vaso-occlusive episodes (VOEs), as well as chronic organ damage. Severe pain is a principal manifestation of SCD, and pain control is central in disease management. However, new data suggest that triggering of nociception may serve a protective role in SCD.

In SCD, pain is primarily sensed by the capsaicin receptor, transient receptor potential vanilloid 1 (TRPV1), located on nociceptive neurons. In their recent study, Xu and colleagues investigated the role of pain in SCD by depleting TRPV1-expressing nociceptors in an SCD mouse model. Intriguingly, when these mice were treated with tumor necrosis factor α (TNFα) to induce VOEs, they developed more severe vaso-occlusion and died more quickly than SCD mice with intact nociception. This was accompanied by an exaggerated inflammatory response and rise in circulating aged neutrophils, critical to VOEs in SCD. Xu et al. determined that the protective effect of nociception was mediated by a neuropeptide called calcitonin gene–related peptide (CGRP), a powerful vasodilator with anti-inflammatory properties that is released upon sensory nerve activation. In SCD mice, administration of CGRP inhibited leukocyte activation and prolonged survival after VOE. The benefit of CGRP was unaltered by genetic elimination of its receptor in all but hematopoietic cells, identifying hematopoietic cells as the pivotal target of CGRP signaling. Finally, Xu et al. investigated whether dietary capsaicin might confer the same benefit. Capsaicin ingestion for 6 weeks prior to TNFα challenge mitigated acute vaso-occlusion and enhanced survival time in SCD mice. Furthermore, long-term maintenance on a spicy diet attenuated chronic organ damage in SCD mice, although the precise mechanism was not determined.

One important unanswered question is how capsaicin or CGRP administration would function when combined with chronic opioid therapy, often necessary for patients with SCD. There is evidence of extensive cross-talk between these pain regulatory pathways. TRPV1 itself regulates μ-opioid receptors, the main target of opioid analgesia, and may prevent opioid tolerance. Thus, the possibility of synergy, or inadvertent negative consequences, merits further investigation.

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