Pain is a major comorbidity of sickle cell disease (SCD). Opioids are the mainstay for pain treatment but remain suboptimal. We discuss mechanism-based treatable targets devoid of opioids to prevent and/or treat SCD pain.
Understanding the pathogenesis of pain is critical to develop targeted therapies. Nevertheless, acute and chronic pain can have independent and/or overlapping mechanisms. The origin of pain involves neurovascular and neuroimmune interactions from the periphery and/or central nervous system. Immunomodulatory components of acute and/or chronic sickle pain for targeting/preventing pain genesis include mast cell and microglial activation, neurogenic inflammation, and leukocyte-derived elastase. Vascular modulators include hypoxia/reperfusion injury, oxidative stress, hemolysis, and adhesion molecules. However, existent pain requires analgesics devoid of an inadvertent effect on sickle pathobiology. Recent analgesic targets include cannabinoid and nociceptin receptors and serotonergic spinothalamic pathway. Complementary approaches (e.g., acupuncture, hypnosis, perception-based therapies) have shown analgesic potential. Owing to heterogeneity in pain development, it remains challenging to combat SCD pain with any one therapy.
SCD pain involves neuroimmune and neurovascular interactions. Such interactions have pronociceptive impacts and impart therapy resistance. Elucidating molecular and cellular entities affecting neuronal interactions in sickle microenvironment may prevent SCD pain and/or provide improved analgesic approaches.
aIntel Corporation, Hillsboro, Oregon, USA
bDepartment of Medicine, Division of Hematology, Oncology and Transplantation, Vascular Biology Center, University of Minnesota, Minneapolis, Minnesota, USA
Correspondence to Kalpna Gupta, PhD, Vascular Biology Center, Medicine, Hematology, Oncology and Transplantation, University of Minnesota, Mayo Mail Code 480, 420 Delaware Street SE, Minneapolis, MN 55455, USA. Tel: +1 612 625 7648; fax: +1 612 625 6919; e-mail: firstname.lastname@example.org