Emerging neurotechnology for antinoceptive mechanisms and therapeutics discovery

Abstract

The tolerance, abuse, and potential exacerbation associated with classical chronic pain medications such as opioids creates a need for alternative therapeutics. Phenotypic screening provides a complementary approach to traditional target-based drug discovery. Profiling cellular phenotypes enables quantification of physiologically relevant traits central to a disease pathology without prior identification of a specific drug target. For complex disorders such as chronic pain, which likely involves many molecular targets, this approach may identify novel treatments. Sensory neurons, termed nociceptors, are derived from dorsal root ganglia (DRG) and can undergo changes in membrane excitability during chronic pain. In this review, we describe phenotypic screening paradigms that make use of nociceptor electrophysiology. The purpose of this paper is to review the bioelectrical behavior of DRG neurons, signaling complexity in sensory neurons, various sensory neuron models, assays for bioelectrical behavior, and emerging efforts to leverage microfabrication and microfluidics for assay development. We discuss limitations and advantages of these various approaches and offer perspectives on opportunities for future development.

Sensory neurons sprouting is dependent on osteoclast-derived extracellular vesicles involving the activation of epidermal growth factor receptors

“…MEAs enable non-invasive, thus repeatable, recordings of extracellular action potentials. Although recordings of random DRG cultures have been previously demonstrated (Black et al, 2019), these are not adapted to the study of peripheral innervation. Here, we employed microElectrode-microFluidic (μEF) devices (Figure 7A), which allowed us to monitor axonal activity with great fidelity (Figure 7B) (Heiney et al, 2019; Lopes et al, 2018).…”

Neuronal cultures show bidirectional axonal conduction with antidromic action potentials depolarizing the soma

“…Moreover, in the few studies where neurons were seeded only in one compartment, the propagating event detection methods presumed orthodromic propagation from the somal to the axonal compartment (forward propagation) (Habibey et al, 2017; Lewandowska et al, 2016). It is important to note that no study has previously attempted to characterize the signal conduction of DRG cultures (Black et al, 2019). Still, preliminary in vitro experiments using DRGs had suggested that most APs propagate orthodromically (Heiney et al, 2019).…”

“…Unlike mature hippocampal neurons, DRG neurons did not fire in bursts but rather exhibited sporadic spontaneous activity. In physiological conditions, this relatively low level of activity also occurs in vivo (Black et al, 2019). As DRG explants were placed outside the MEA active area, activity was only recorded in the microchannels ( Fig.…”

“…It is The copyright holder for this preprint this version posted March 8, 2021. ; https://doi.org/10.1101/2021.03.07.434278 doi: bioRxiv preprint seeded only in one compartment, the propagating event detection methods presumed orthodromic propagation from the somal to the axonal compartment (forward propagation) (Habibey et al, 2017;Lewandowska et al, 2016). It is important to note that no study has previously attempted to characterize the signal conduction of DRG cultures (Black et al, 2019).…”

“…Still, the majority of in vitro studies have focused on molecular processes (e.g. antero/retrograde axonal transport), with no electrophysiological characterizations of axon physiology (Black et al, 2019; Nascimento et al, 2018). Thus, it remains to be shown if cultured DRGs recapitulate the ability to generate APs at their distal terminals in both physiological and pathological contexts (e.g., EAPs after axotomy).…”