ORCID
https://orcid.org/0000-0002-5869-8566
Date of Award
9-7-2023
Degree Name
Doctor of Philosophy (PhD)
Degree Type
Dissertation
Abstract
Despite the widespread prevalence of chronic pain and extensive drug development efforts, non-opioid pharmacotherapeutic options for severe and chronic pain are limited. Nociceptors in the dorsal root ganglia (DRG) are peripheral sensors of noxious stimuli that play an integral role in pain transmission. Neuroplasticity in the periphery, such as hyperexcitability and spontaneous activity of sensory neurons following inflammation or injury, plays a central role in the pathogenesis of both acute and chronic pain. As such, a detailed understanding of the mechanisms associated with peripheral sensitization may reveal novel therapeutic targets of pain. An increasing number of studies have shown that human and rodent sensory neurons are distinct from one another in transcriptional and functional profiles of ion channels and G-protein coupled receptors (GPCRs) that modulate neuronal excitability. This cross-species difference in nociceptor neurobiology highlights the need to validate that the mechanisms of peripheral sensitization and pain-associated hyperexcitability are conserved in human sensory neurons. In the first study of the thesis, we provide a detailed characterization of the electrophysiological heterogeneity in the human DRG and compare the intrinsic excitability of human sensory neurons obtained from postmortem organ donors with and without pain history. We identify two main clusters of neurons: single- and repetitive-spiking. Using patch-seq, we show that the majority of the small-to-medium diameter neurons belong to nociceptor subpopulations. Additionally, we found that human DRG neurons collected from donors with history of pain show significant cluster-dependent differences in intrinsic excitability and spike kinetic properties compared to neurons from donors without documented pain history. Finally, our in situ hybridization experiments suggest that the hyperexcitability in neurons from donors with pain history may be driven, in part, by higher levels of NaV1.8 expression in nociceptors. These results support the notion that pain-associated hyperexcitability in sensory neurons contributes to chronic pain in humans and identify NaV1.8 as a potential analgesic target. In the study presented in Chapter 3, we assess bradykinin-mediated sensitization of human sensory neurons. Bradykinin is a potent pro-inflammatory peptide that plays a key role in inflammatory hyperalgesia. Though its sensitizing effects are well-studied in rodent DRG neurons, the relative distribution of bradykinin receptors and functional effects of acute and prolonged exposure to bradykinin on human sensory neurons are not well understood. We found expression of B1 and B2 bradykinin receptors in nociceptors and satellite glial cells of the human DRG. Using electrophysiology, we found that acute bradykinin leads to increased excitability in both single- and repetitive-firing neurons, while prolonged bradykinin exposure led to reduced excitability. We hypothesize that this may be indicative of a homeostatic mechanism. Additionally, analysis of donor’s prior medical history suggests that donor’s pain history and age may be positively correlated with B1 receptor expression. Together, the work presented in this thesis shows that human sensory neurons exhibit multiple forms of dynamic plasticity associated with pain, which span from short-term, bradykinin-mediated sensitization to persistent hyperexcitability and homeostatic plasticity, and that nociceptors of the human DRG display physiological heterogeneity that contributes to pain-associated plasticity.
Language
English (en)
Chair and Committee
Robert Gereau
Recommended Citation
Yi, Jiwon, "Physiological Heterogeneity and Pain-Associated Plasticity in Human Sensory Neurons" (2023). Arts & Sciences Electronic Theses and Dissertations. 3134.
https://openscholarship.wustl.edu/art_sci_etds/3134