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Since 1967, spinal cord stimulation (SCS) has been used to manage chronic intractable pain of the trunk and limbs. Compared to traditional high-intensity, low-frequency (<100 Hz) SCS that is thought to produce paresthesia and pain relief by stimulating large myelinated fibers in the dorsal column (DC), low-intensity, high-frequency (10 kHz) SCS has demonstrated long-term pain relief without generation of paresthesia. To understand this paresthesia-free analgesic mechanism of 10 kHz SCS, we examined whether 10 kHz SCS at intensities below sensory thresholds would modulate spinal dorsal horn (DH) neuronal function in a neuron type-dependent manner. By using in vivo and ex vivo electrophysiological approaches, we found that low-intensity (sub-sensory threshold) 10 kHz SCS, but not 1 kHz or 5 kHz SCS, selectively activates inhibitory interneurons in the spinal DH. This study suggests that low-intensity 10 kHz SCS may inhibit pain sensory processing in the spinal DH by activating inhibitory interneurons without activating DC fibers, resulting in paresthesia-free pain relief., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Isolectin B4-binding (IB4+) dorsal root ganglion (DRG) neurons are distinct from peptidergic DRG neurons in their terminal location in the spinal cord and respective contributions to various classes and modalities of nociception. In DRG neurons innervating the mouse colon (c-DRG neurons), the reported proportion of IB4+ population is inconsistent across studies, and little is known regarding their role in colorectal mechanonociception. To address these issues, in C57BL/6J mice, we quantified IB4+ binding after labeling c-DRG neurons with Fast Blue and examined functional consequences of ablating these neurons by IB4-conjugated saporin. Sixty-one percent of Fast Blue-labeled neurons in the L6 DRG were IB4+, and 95% of these IB4+ c-DRG neurons were peptidergic. Intrathecal administration of IB4-conjugated saporin reduced the proportion of IB4+ c-DRG neurons to 37%, which was due to the loss of c-DRG neurons showing strong to medium IB4+ intensity; c-DRG neurons with weak IB4+ intensity were spared. However, this loss altered neither nociceptive behaviors to colorectal distension nor the relative proportions of stretch-sensitive colorectal afferent classes characterized by single-fiber recordings. These findings demonstrate that more than 1 half of viscerosensory L6 c-DRG neurons in C57BL/6J mouse are IB4+ and suggest, in contrast to the reported roles of IB4+/nonpeptidergic neurons in cutaneous mechanonociception, c-DRG neurons with strong-to-medium IB4+ intensity do not play a significant role in colorectal mechanonociception.

Previous studies in rat and mouse documented that a subpopulation of dorsal root ganglion (DRG) neurons innervating non-visceral tissues express tyrosine hydroxylase (TH). Here we studied whether or not mouse DRG neurons retrogradely traced with Fast Blue (FB) from colorectum or urinary bladder also express immunohistochemically detectable TH. The lumbar sympathetic chain (LSC) and major pelvic ganglion (MPG) were included in the analysis. Previously characterized antibodies against TH, norepinephrine transporter type 1 (NET-1) and calcitonin gene-related peptide (CGRP) were used. On average, ∼14% of colorectal and ∼17% of urinary bladder DRG neurons expressed TH and spanned virtually all neuronal sizes, although more often in the medium-sized to small ranges. Also, they were more abundant in lumbosacral than thoracolumbar DRGs, and often coexpressed CGRP. We also detected several TH-immunoreactive (IR) colorectal and urinary bladder neurons in the LSC and the MPG, more frequently in the former. No NET-1-IR neurons were detected in DRGs, whereas the majority of FB-labeled, TH-IR neurons in the LSC and MPG coexpressed this marker (as did most other TH-IR neurons not labeled from the target organs). TH-IR nerve fibers were detected in all layers of the colorectum and the urinary bladder, with some also reaching the basal mucosal cells. Most TH-IR fibers in these organs lacked CGRP. Taken together, we show: (1) that a previously undescribed population of colorectal and urinary bladder DRG neurons expresses TH, often CGRP but not NET-1, suggesting the absence of a noradrenergic phenotype; and (2) that TH-IR axons/terminals in the colon or urinary bladder, naturally expected to derive from autonomic sources, could also originate from sensory neurons., (Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.)

Dorsal root ganglion (DRG) neurons express mRNAs for numerous two-pore domain K(+) (K(2P)) channels and G-protein coupled receptors (GPCR). Recent studies have shown that TRESK is a major background K(+) channel in DRG neurons. Here, we demonstrate the pharmacological properties of TRESK, including GPCR agonist-induced effects on DRG neurons. TRESK mRNA was highly expressed in DRG compared to brain and spinal cord. Similar to cloned TRESK, native TRESK was inhibited by acid and arachidonic acid (AA), but not zinc. Native TRESK was also activated by GPCR agonists such as acetylcholine, glutamate, and histamine. The glutamate-activated TRESK was blocked by lamotrigine in DRG neurons. In COS-7 cells transfected with mouse TRESK, 30 microM lamotrigine inhibited TRESK by approximately 50%. Since TRESK is target of modulation by acid, AA, GPCR agonists, and lamotrigine, it is likely to play an active role in the regulation of excitability in DRG neurons.

Recent studies have suggested that acid-sensitive background K+ channels such as TASK-1 and TASK-3, members of two-pore domain K+ (K2P) channel family, express and contribute to extracellular acidification-induced responses in dorsal root ganglia (DRG) neurons. However, it has remained to address whether other acid-sensitive background K+ channels are functionally expressed in DRG neurons. Here we characterized biophysical and pharmacological properties of a novel acid-sensitive background K+ channel in DRG neurons isolated from neonatal rats. We recorded an 80-pS K+ channel with a weak inward rectification current-voltage relationship in cell-attached patches in 150mM KCl bath solution. The 80-pS K+ channel was inhibited by extracellular low pH (pHo 6.3). Interestingly, the channel was similar to TASK-2 cloned from mouse and rat in biophysical and pharmacological properties. However, extracellular alkaline condition which activates TASK-2 channel, failed to activate the 80-pS K+ channel. Lidocaine and quinine more inhibited the channel activity of 80-pS K+ channel than that of TASK-2 channel. Our results suggest that the acid-sensitive 80-pS K+ channels may regulate resting membrane potential and may play a critical role in various processes such as cell metabolism, pH, and pain sensation in DRG neurons.