Targeting pain at its source in sickle cell disease

Abstract

Sickle cell disease (SCD) is a genetic disorder associated with hemolytic anemia, end-organ damage, reduced survival, and pain. One of the unique features of SCD is recurrent and unpredictable episodes of acute pain due to vasoocclusive crisis requiring hospitalization. Additionally, patients with SCD often develop chronic persistent pain. Currently, sickle cell pain is treated with opioids, an approach limited by adverse effects. Because pain can start at infancy and continue throughout life, preventing the genesis of pain may be relatively better than treating the pain once it has been evoked. Therefore, we provide insights into the cellular and molecular mechanisms of sickle cell pain that contribute to the activation of the somatosensory system in the peripheral and central nervous systems. These mechanisms include mast cell activation and neurogenic inflammation, peripheral nociceptor sensitization, maladaptation of spinal signals, central sensitization, and modulation of neural circuits in the brain. In this review, we describe potential preventive/therapeutic targets and their targeting with novel pharmacologic and/or integrative approaches to ameliorate sickle cell pain.

Keywords: analgesia; mast cell; neurogenic inflammation; opioid; pain; sickle cell disease; substance P; vasoocclusive crises.

Fig. 1.

Pain pathways from the periphery to the brain and from the brain and central nervous system to the periphery. We propose that sickle pathobiology replete with vasoocclusion, ischemia-reperfusion injury, inflammation, and oxidative stress activates mast cells, which in turn leads to peripheral nociceptor sensitization. Signals from the periphery are transmitted to the dorsal horn of the spinal cord via primary afferents, which are modulated and further transmitted to the brain. However, sickle cell disease pathobiology may influence each of these components of pain independently. Moreover, sustained hyperexcitability of second-order neurons in the spinal cord may lead to an antidromic release of action potentials and neurotransmitters from the central nervous system to the periphery, leading to a feedback loop of peripheral and central sensitization. In addition to receiving signals from the spinal cord, the brain may modulate pain by releasing neurotransmitters through the descending inhibitory pathway into the dorsal horn, which may have an inhibitory or facilitatory effect on pain. DRG, dorsal root ganglion.