Bradykinin receptor expression and bradykinin-mediated sensitization of human sensory neurons

Abstract

Bradykinin is a peptide implicated in inflammatory pain in both humans and rodents. In rodent sensory neurons, activation of B1 and B2 bradykinin receptors induces neuronal hyperexcitability. Recent evidence suggests that human and rodent dorsal root ganglia (DRG), which contain the cell bodies of sensory neurons, differ in the expression and function of key GPCRs and ion channels; whether bradykinin receptor expression and function are conserved across species has not been studied in depth. In this study, we used human DRG tissue from organ donors to provide a detailed characterization of bradykinin receptor expression and bradykinin-induced changes in the excitability of human sensory neurons. We found that B2 and, to a lesser extent, B1 receptors are expressed by human DRG neurons and satellite glial cells. B2 receptors were enriched in the nociceptor subpopulation. Using patch-clamp electrophysiology, we found that acute bradykinin increases the excitability of human sensory neurons, whereas prolonged exposure to bradykinin decreases neuronal excitability in a subpopulation of human DRG neurons. Finally, our analyses suggest that donor's history of chronic pain and age may be predictors of higher B1 receptor expression in human DRG neurons. Together, these results indicate that acute bradykinin-induced hyperexcitability, first identified in rodents, is conserved in humans and provide further evidence supporting bradykinin signaling as a potential therapeutic target for treating pain in humans.

Electrophysiological analyses of human dorsal root ganglia and human induced pluripotent stem cell-derived sensory neurons from male and female donors

“…Additionally, the current study has only used hiPSC-SNs from people with no history of pain. Differences in neuronal excitability and mRNA expression have been reported in hDRG-N from patients with pain history versus patients with no pain history[5,13,15,20–22,43]. Future work will need to be done to determine if the differences in hDRG-N are reproducible in hiPSC-SNs from pain patients.…”

“…Several groups have made use of hDRG-N[1,8,12,20–23,27,35,36,39,43] and hiPSC-SNs [4,28,30,32] in studies of neuronal excitability using patch-clamp electrophysiology. This is the first analysis of electrophysiological recordings obtained from the same lab of both cell types.…”

“…hDRG-N have been used in several studies to look at effects of various compounds in potentiating and attenuating neuronal excitability[2]. Because hDRG-N contain a variety of neuronal subtypes such as nociceptors and mechanoreceptors, data analysis requires a large dataset as well as separating neurons by subtype based on firing patterns such as multi versus single firing neurons, rheobase, and AP waveform properties[6,16,43]. hDRG-N cultures also contain other cell types such as satellite glia, therefore some effects of the compound being tested may be due to interactions with the other cell types.…”

“…This makes hDRG-N advantageous for studies looking at the properties of the DRG holistically rather than as a single cell type. However, it also makes hDRG-N data analysis difficult, requiring researchers to separate cells by firing properties without knowing the neuronal cell type[43] or the need for more advanced techniques such as patch-seq[29], which has yet to be published in human sensory neurons.…”

Intestinal barrier function in the naked mole-rat: an emergent model for gastrointestinal insights

“…However, differences in the functionality of these receptors and the downstream effector signalling in NMRs remain to be elucidated. Future studies will also explore the different cells expressing this marker (epithelial cells ( 77 ) and nerve fibres ( 78 )) in NMRs, and how these modulate visceral pain and mucosal ion secretion. The role of 5-HT in the NMR gastrointestinal tract has not been previously characterised.…”