Sensitization of nociceptors and dorsal horn neurons contributes to pain in sickle cell disease

Uhelski, Megan L.; Simone, Donald A.

doi:10.1016/j.neulet.2019.04.013

Cited by 13 publications

(11 citation statements)

References 109 publications

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“…The most prevalent and critical skin receptors relate to pressure, temperature, and pain [1] -the Pacinian corpuscle, [3] thermoreceptor, [4] and nociceptor, [5,6] respectively. All these receptors detect stimuli, measure levels of stimuli, and transmit signals to the brain triggering reactions.…”

Section: Introductionmentioning

confidence: 99%

Artificial Somatosensors: Feedback Receptors for Electronic Skins

Rahman

Walia

Naznee

et al. 2020

Advanced Intelligent Systems

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The human skin is the largest sensory organ, made up of complex sensors that detect noxious stimuli to rapidly send warning signals to the central nervous system to initiate a motor response. It is complex to mimic key skin features using existing tactile sensors, and there exists no somatosensor that responds to real stimuli of pressure, temperature, and touch. Herein, three critical skin receptors created by realizing integrated electronic systems that mimic the feedback response of somatosensors are experimentally demonstrated. Fully functional Pacinian corpuscles, thermoreceptors, and nociceptors are realized using a combination of stretchable pressure sensors, phase‐change oxide thin films, and threshold‐based resistive switching (memristor) memory elements. The ability to detect and respond to pressure, temperature, and pain stimuli above a threshold with real‐life performance characteristics is demonstrated with explanation of underlying mechanisms. The ability to design and realize artificial skin receptors enables replacement of affected human skin regions, augment skin sensitivity for agile applications in defense and sports, and drive advancements in intelligent robotics.

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Section: Introductionmentioning

confidence: 99%

Artificial Somatosensors: Feedback Receptors for Electronic Skins

Rahman

Walia

Naznee

et al. 2020

Advanced Intelligent Systems

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“…They also reported that these phenomenon were accompanied by increased phosphorylation of mitogen-activated protein kinases, including c-Jun N-terminal kinase, p38 and p44/p42 extracellular signalling-regulated kinase (ERK) in the spinal cords of BERK mice. 65,66 ERK activation increases action potential amplitude of spinal cord dorsal horn neurons leading to hyperexcitability. 67 Valverde et al 68 found elevated level of SP, elevated reactive oxygen species and activated microglial and astrocytic cells with increased glial fibrillary acidic protein in the dorsal horn of the spinal cord of BERK mice.…”

Section: Chronic Painmentioning

confidence: 99%

Mechanisms of pain in sickle cell disease

Takaoka

Cyril

Jinesh

et al. 2020

British Journal of Pain

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Objectives: The hallmark of sickle cell disease (SCD) is acute and chronic pain, and the pain dominates the clinical characteristics of SCD patients. Although pharmacological treatments of SCD targeting the disease mechanisms have been improved, many SCD patients suffer from pain. To overcome the pain of the disease, there have been renewed requirements to understand the novel molecular mechanisms of the pain in SCD. Methods: We concisely summarized the molecular mechanisms of SCD-related acute and chronic pain, focusing on potential drug targets to treat pain. Results: Acute pain of SCD is caused by vaso-occulusive crisis (VOC), impaired oxygen supply or infarction-reperfusion tissue injuries. In VOC, inflammatory cytokines include tryptase activate nociceptors and transient receptor potential vanilloid type 1. In tissue injury, the secondary inflammatory response is triggered and causes further tissue injuries. Tissue injury generates cytokines and pain mediators including bradykinin, and they activate nociceptive afferent nerves and trigger pain. The main causes of chronic pain are from extended hyperalgesia after a VOC and central sensitization. Neuropathic pain could be due to central or peripheral nerve injury, and protein kinase C might be associated with the pain. In central sensitization, neuroplasticity in the brain and the activation of glial cells may be related with the pain. Discussion: In this review, we summarized the molecular mechanisms of SCD-related acute and chronic pain. The novel treatments targeting the disease mechanisms would interrupt complications of SCD and reduce the pain of the SCD patients.

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“… 18 , 19 The reduction in pain has been attributed to suppression of inflammation as well as direct effects on nociceptors and targets within the central nervous system. 20 In some pathological conditions, inhibitors of monoacylglyerol lipase, the enzyme that hydrolyzes 2-AG to arachidonic acid and glycerol, increased the level of 2-AG and reduced hyperalgesia through mechanisms dependent on the cannaboid CB1 and CB2 receptors. 21-25 Although increasing endogenous 2-AG may seem attractive as a strategy for managing pathological pain, 2-AG is also an intermediate in the production of pro-nociceptive lipids.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of DAGLβ as a therapeutic target for pain in sickle cell disease

et al. 2022

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Sickle cell disease (SCD) is the most common inherited disease. Pain is a key morbidity of SCD and opioids are the main treatment but their side effects emphasize the need for new analgesic approaches. Humanized transgenic mouse models have been instructive in understanding the pathobiology of SCD and mechanisms of pain. Homozygous (HbSS) Berkley mice express >99% human sickle hemoglobin and several features of clinical SCD including hyperalgesia. Previously, we reported that the endocannabinoid 2-arachidonoylglycerol (2-AG) is a precursor of the pro-nociceptive mediator prostaglandin E2-glyceryl ester (PGE2-G) which contributes to hyperalgesia in SCD. We now demonstrate the causal role of 2-AG in hyperalgesia in sickle mice. Hyperalgesia in HbSS mice correlated with elevated levels of 2-AG in plasma, its synthesizing enzyme diacylglycerol lipase β (DAGLβ) in blood cells, and with elevated levels of PGE2 and PGE2-G, pro-nociceptive derivatives of 2-AG. A single intravenous injection of 2-AG produced hyperalgesia in non-hyperalgesic HbSS mice, but not in control (HbAA) mice expressing normal human HbA. JZL184, an inhibitor of 2-AG hydrolysis also produced hyperalgesia in non-hyperalgesic HbSS or hemizygous (HbAS) mice, but did not influence hyperalgesia in hyperalgesic HbSS mice. Systemic and intraplantar administration of KT109, an inhibitor of DAGLβ, decreased mechanical and heat hyperalgesia in HbSS mice. The decrease in hyperalgesia was accompanied by reductions in 2-AG, PGE2 and PGE2-G in the blood. These results indicate that maintaining the physiological level of 2-AG in the blood by targeting DAGLβ may be a novel and effective approach to treat pain in SCD.

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Sensitization of nociceptors and dorsal horn neurons contributes to pain in sickle cell disease

Cited by 13 publications

References 109 publications

Artificial Somatosensors: Feedback Receptors for Electronic Skins

Artificial Somatosensors: Feedback Receptors for Electronic Skins

Mechanisms of pain in sickle cell disease

Inhibition of DAGLβ as a therapeutic target for pain in sickle cell disease

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