Sensitization of nociceptive spinal neurons contributes to pain in a transgenic model of sickle cell disease

Abstract

Chronic pain is a major characteristic feature of sickle cell disease (SCD). The refractory nature of pain and the development of chronic pain syndromes in many patients with SCD suggest that central neural mechanisms contribute to pain in this disease. We used HbSS-BERK sickle mice, which show chronic features of pain similar to those observed in SCD, and determined whether sensitization of nociceptive neurons in the spinal cord contributes to pain and hyperalgesia in SCD. Electrophysiological recordings of action potential activity were obtained from single, identified dorsal horn neurons of the spinal cord in anesthetized mice. Compared to control HbAA-BERK mice, nociceptive dorsal horn neurons in sickle mice exhibited enhanced excitability as evidenced by enlarged receptive fields, increased rate of spontaneous activity, lower mechanical thresholds, enhanced responses to mechanical stimuli, and prolonged after-discharges following mechanical stimulation. These changes were accompanied by increased phosphorylation of mitogen activated protein kinases (MAPKs) in the spinal cord that are known to contribute to neuronal hyperexcitability, including c-Jun N-terminal kinase (JNK), p44/p42 extracellular signaling-regulated kinase (ERK), and p38. These findings demonstrate that central sensitization contributes to pain in SCD.

Mechanisms of Pain in Sickle Cell Disease

“…Indeed, second-order neurons in the dorsal horn of the spinal cord show constitutive nociceptor sensitization in electrophysiological recordings in the "ERK sickle mice [42]. Nociceptive neurons in the dorsal horn of sickle mice show increased excitability and an increased rate of spontaneous activity [42]. These electrophysiological responses are accompanied by higher response to mechanical stimuli and prolonged after-discharges following the mechanical stimulus, suggestive of central sensitization [42].…”

“…Nociceptive neurons in the dorsal horn of sickle mice show increased excitability and an increased rate of spontaneous activity [42]. These electrophysiological responses are accompanied by higher response to mechanical stimuli and prolonged after-discharges following the mechanical stimulus, suggestive of central sensitization [42]. This sustained and continuous activation of spinal neurons may lead to increased release of neuropeptides and nociceptive mediators, which may be released into the periphery antidromically, in turn activating the peripheral nerve terminals without noxious insult.…”

“…This peripheral nociceptor activation leads to the activation of glial cells and neuronal activating transcription factor 3 "TF3 in the dorsal root ganglion DRG [10], which may lead to the transmission of increased action potentials to the second-order neurons of the spinal cord. Indeed, second-order neurons in the dorsal horn of the spinal cord show constitutive nociceptor sensitization in electrophysiological recordings in the "ERK sickle mice [42]. Nociceptive neurons in the dorsal horn of sickle mice show increased excitability and an increased rate of spontaneous activity [42].…”

Spinal glial activation and oxidative stress are alleviated by treatment with curcumin or coenzyme Q in sickle mice

“…4 We recently observed that spinal nociceptive neurons are sensitized in sickle mice, suggestive of central sensitization. 5 Bidirectional signaling occurs between neurons and immunocompetent cells present in the CNS, including microglia, astrocytes and oligodendrocytes. 4 Activated microglia release reactive oxidative species (ROS), inflammatory cytokines, neurotrophic factors, and prostaglandins that excite nociceptive neurons and contribute to the persistence of chronic pain.…”

Updated Mechanisms of Sickle Cell Disease-Associated Chronic pain

“…Cataldo et al recently found an increase in spontaneous firing, receptor field size, and electrophysiological responses to low-threshold stimuli and mechanical stimuli in spinal dorsal horn neurons of HBSS-BERK SCD mice when compared to HBAA-BERK control mice. [53] The increases in several known signaling pathway components were observed including phosphorylated ERK, p38, TLR4, and IL-6. ERK phosphorylation has been shown to lead to decreased potassium currents associated with the Kv4.2 potassium channels translating into hyperexcitability of dorsal horn neurons.…”