Figure 1.
Figure 1. Sickle cell disease from a point mutation to a systemic dysfunction and pain. Circulation of sickle RBCs leads to multiple pathophysiologic problems, including, but not limited to, hemolysis, hypoxia/reperfusion, ischemia, excessive inflammation and free heme, vascular dysfunction, organ damage, and vaso-occlusion (left panel). Each of these can contribute to a noxious microenvironment evoking nociceptive mechanisms of pain. Emerging data have identified several cellular and molecular targets that contribute to nociceptive activity in sickle cell disease (middle panel). These targets may be located in the periphery and/or the CNS, suggesting that the sickle microenvironment can activate the transmission of pain from the periphery as well as influence the CNS directly. Mechanisms of nociception are complex, involving the peripheral neural activity and CNS (right panel) involving several different processes. (1) Transduction involves the generation of action potentials (electrical activity) from the noxious environment in the periphery; (2) transmission is the process of transmitting the action potentials to the dorsal horn of the spinal cord through the primary afferents and first-order neurons in the DRG; (3) modulation is the complex processing of signals in the dorsal horn of the spinal cord after activation of second-order neurons and neuromodulation (amplification or inhibition) from interneurons and/or descending projections from the brainstem with inhibitory or facilitatory pathways involving neurotransmitters; this processing of neural activity results in the inhibition or facilitation of nociceptive activity, which is relayed to the higher brain centers; and (4) perception is the transcription of nociceptive signals to the subjective emotional experience of pain in the higher centers of brain. There are exceptions, including “top down” mechanisms of pain and perception-based modulation as described in the text. In addition, peripheral and/or central sensitization may occur in response to ongoing noxious stimuli, resulting in reduced firing threshold potential leading to the generation of pain with innocuous stimuli. Nerve impulses travel orthodromically from the periphery to the spinal cord, but under sustained activation they can travel antidromically (dashed brown arrow), releasing neurotransmitters such as SP in the periphery. In addition, release of neuropeptides can also occur in the periphery from activated axonal nerve endings by axonal reflex. Due to the genetic nature of SCD, an ongoing noxious microenvironment replete with algogenic factors may induce the nociceptive mechanisms during infancy and sustain the activation through adulthood if the disease remains uncontrolled, leading to peripheral and central sensitization resulting in chronic pain recalcitrant to therapy. ER stress, endoplasmic reticulum stress; Glu, glutamic acid; Pro, proline; sRBC, sickle red blood cell; TLR4, Toll-like receptor 4; Val, valine.

Sickle cell disease from a point mutation to a systemic dysfunction and pain. Circulation of sickle RBCs leads to multiple pathophysiologic problems, including, but not limited to, hemolysis, hypoxia/reperfusion, ischemia, excessive inflammation and free heme, vascular dysfunction, organ damage, and vaso-occlusion (left panel). Each of these can contribute to a noxious microenvironment evoking nociceptive mechanisms of pain. Emerging data have identified several cellular and molecular targets that contribute to nociceptive activity in sickle cell disease (middle panel). These targets may be located in the periphery and/or the CNS, suggesting that the sickle microenvironment can activate the transmission of pain from the periphery as well as influence the CNS directly. Mechanisms of nociception are complex, involving the peripheral neural activity and CNS (right panel) involving several different processes. (1) Transduction involves the generation of action potentials (electrical activity) from the noxious environment in the periphery; (2) transmission is the process of transmitting the action potentials to the dorsal horn of the spinal cord through the primary afferents and first-order neurons in the DRG; (3) modulation is the complex processing of signals in the dorsal horn of the spinal cord after activation of second-order neurons and neuromodulation (amplification or inhibition) from interneurons and/or descending projections from the brainstem with inhibitory or facilitatory pathways involving neurotransmitters; this processing of neural activity results in the inhibition or facilitation of nociceptive activity, which is relayed to the higher brain centers; and (4) perception is the transcription of nociceptive signals to the subjective emotional experience of pain in the higher centers of brain. There are exceptions, including “top down” mechanisms of pain and perception-based modulation as described in the text. In addition, peripheral and/or central sensitization may occur in response to ongoing noxious stimuli, resulting in reduced firing threshold potential leading to the generation of pain with innocuous stimuli. Nerve impulses travel orthodromically from the periphery to the spinal cord, but under sustained activation they can travel antidromically (dashed brown arrow), releasing neurotransmitters such as SP in the periphery. In addition, release of neuropeptides can also occur in the periphery from activated axonal nerve endings by axonal reflex. Due to the genetic nature of SCD, an ongoing noxious microenvironment replete with algogenic factors may induce the nociceptive mechanisms during infancy and sustain the activation through adulthood if the disease remains uncontrolled, leading to peripheral and central sensitization resulting in chronic pain recalcitrant to therapy. ER stress, endoplasmic reticulum stress; Glu, glutamic acid; Pro, proline; sRBC, sickle red blood cell; TLR4, Toll-like receptor 4; Val, valine.

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