Human sensory neurons: Membrane properties and sensitization by inflammatory mediators

Davidson, Steve; Copits, Bryan A.; Zhang, Jingming; Page, Guy; Ghetti, A.; Gereau, Robert W.

doi:10.1016/j.pain.2014.06.017

Cited by 161 publications

(206 citation statements)

References 56 publications

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“…However, these effects are generally seen in DRG neurons in culture for several days. As described in MATERIALS AND METH-ODS, our preliminary experiments indicated that supplements of these trophic factors were necessary to obtain viable human DRG neurons for recordings, in agreement with recently published data (Davidson et al 2014); thus both NGF and GDNF were added into the primary human DRG culture. Therefore it is possible that differences in exposure to NGF and/or GDNF could have contributed to the different firing behavior that we observed between human and rat DRG neurons.…”

Section: Discussionsupporting

confidence: 86%

“…The mean input resistance (153 Ϯ 20 M⍀) and action potential threshold (964 Ϯ 85 pA) of human DRG neurons are different from the input resistance (659 Ϯ 51 M⍀) and threshold for action potential (251 Ϯ 29 pA) for native rat DRG neurons but are comparable to those reported by Davidson et al (2014) from a different set of human donors (input resistance: 97.51 Ϯ 10.09 M⍀; threshold: 1,430 Ϯ 110 pA), confirming that these properties are intrinsic to human DRG neurons. The action potential width in human DRG neurons (6.83 Ϯ 0.78 ms) was threefold greater than that of rat DRG neurons (2.33 Ϯ 0.12 ms), and human DRG neurons manifested increased firing frequencies compared with rat DRG neurons.…”

Section: Discussionsupporting

confidence: 69%

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Human Na_v1.8: enhanced persistent and ramp currents contribute to distinct firing properties of human DRG neurons

Han

Estacion

Huang

et al. 2015

Journal of Neurophysiology

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Although species-specific differences in ion channel properties are well-documented, little has been known about the properties of the human Nav1.8 channel, an important contributor to pain signaling. Here we show, using techniques that include voltage clamp, current clamp, and dynamic clamp in dorsal root ganglion (DRG) neurons, that human Na(v)1.8 channels display slower inactivation kinetics and produce larger persistent current and ramp current than previously reported in other species. DRG neurons expressing human Na(v)1.8 channels unexpectedly produce significantly longer-lasting action potentials, including action potentials with half-widths in some cells >10 ms, and increased firing frequency compared with the narrower and usually single action potentials generated by DRG neurons expressing rat Na(v)1.8 channels. We also show that native human DRG neurons recapitulate these properties of Na(v)1.8 current and the long-lasting action potentials. Together, our results demonstrate strikingly distinct properties of human Na(v)1.8, which contribute to the firing properties of human DRG neurons.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionsupporting

confidence: 69%

Human Na_v1.8: enhanced persistent and ramp currents contribute to distinct firing properties of human DRG neurons

Han

Estacion

Huang

et al. 2015

Journal of Neurophysiology

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“…Upon the delivery, DRGs were rapidly dissected from nerve roots and minced in a calcium-free HBSS (Gibco). Human DRG cultures were prepared as previously reported with some modifications 46, 47 . DRGs were digested at 37°C in humidified O 2 incubator for 120 min with collagenase Type II (Worthington, 285 units/mg, 12 mg/ml final concentration) and dispase II (Roche, 1 unit/mg, 20 mg/ml) in PBS with 10 mM HEPES, pH adjusted to 7.4 with NaOH.…”

Section: Methodsmentioning

confidence: 99%

Inhibition of mechanical allodynia in neuropathic pain by TLR5-mediated A-fiber blockade

Kim

Bang

et al. 2015

Nat Med

284

289

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SUMMARY Mechanical allodynia, induced by normally innocuous low-threshold mechanical stimulation, represents a cardinal feature of neuropathic pain. Blockade or ablation of high-threshold small-diameter unmyelinated C-fibers has limited effects on mechanical allodynia1–4. While large myelinated A-fibers, in particular Aβ-fibers, have previously been implicated in mechanical allodynia5–7, an A-fiber-selective pharmacological blocker is still lacking. Here we report a new method for targeted silencing of A-fibers in neuropathic pain. We found that Toll-like receptor 5 (TLR5) is co-expressed with neurofilament-200 in large-diameter A-fiber neurons in the dorsal root ganglion (DRG). Activation of TLR5 with its ligand flagellin results in neuronal entry of the membrane impermeable lidocaine derivative QX-314, leading to TLR5-dependent blockade of sodium currents predominantly in A-fiber neurons of mouse DRGs. Intraplantar co-application of flagellin and QX-314 (flagellin/QX-314) dose-dependently suppressed mechanical allodynia following chemotherapy, nerve injury, and diabetic neuropathy, but this blockade is abrogated in Tlr5-deficient mice. In vivo electrophysiology demonstrated that flagellin/QX-314 co-application selectively suppressed Aβ-fiber conduction in naive and chemotherapy-treated mice. TLR5-mediated Aβ blockade but not capsaicin-mediated C-fiber blockade also reduced chemotherapy-induced ongoing pain without impairing motor function. Finally, flagellin/QX-314 co-application suppressed sodium currents in large-diameter human DRG neurons. Thus, our findings provide a new tool for targeted silencing of Aβ-fibers and neuropathic pain treatment.

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“…Such investigations are important for translation of findings made in rodents to humans (see Davidson et al 2014).…”

mentioning

confidence: 99%

Electrical maturation of spinal neurons in the human fetus: comparison of ventral and dorsal horn

Tadros

Lim

Hughes

et al. 2015

Journal of Neurophysiology

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-The spinal cord is critical for modifying and relaying sensory information to, and motor commands from, higher centers in the central nervous system to initiate and maintain contextually relevant locomotor responses. Our understanding of how spinal sensorimotor circuits are established during in utero development is based largely on studies in rodents. In contrast, there is little functional data on the development of sensory and motor systems in humans. Here, we use patch-clamp electrophysiology to examine the development of neuronal excitability in human fetal spinal cords (10 -18 wk gestation; WG). Transverse spinal cord slices (300 m thick) were prepared, and recordings were made, from visualized neurons in either the ventral (VH) or dorsal horn (DH) at 32°C. Action potentials (APs) could be elicited in VH neurons throughout the period examined, but only after 16 WG in DH neurons. At this age, VH neurons discharged multiple APs, whereas most DH neurons discharged single APs. In addition, at 16 -18 WG, VH neurons also displayed larger AP and after-hyperpolarization amplitudes than DH neurons. Between 10 and 18 WG, the intrinsic properties of VH neurons changed markedly, with input resistance decreasing and AP and after-hyperpolarization amplitudes increasing. These findings are consistent with the hypothesis that VH motor circuitry matures more rapidly than the DH circuits that are involved in processing tactile and nociceptive information. action potential; excitability; pain; motoneuron THE ABILITY TO INTERACT APPROPRIATELY with our environment arises, in part, from the capacity of the spinal cord to receive, modify, and relay sensory information and respond to this information via motor commands that produce coordinated movement.

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Human sensory neurons: Membrane properties and sensitization by inflammatory mediators

Cited by 161 publications

References 56 publications

Human Na_v1.8: enhanced persistent and ramp currents contribute to distinct firing properties of human DRG neurons

Human Na_v1.8: enhanced persistent and ramp currents contribute to distinct firing properties of human DRG neurons

Inhibition of mechanical allodynia in neuropathic pain by TLR5-mediated A-fiber blockade

Electrical maturation of spinal neurons in the human fetus: comparison of ventral and dorsal horn

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Human sensory neurons: Membrane properties and sensitization by inflammatory mediators

Cited by 161 publications

References 56 publications

Human Nav1.8: enhanced persistent and ramp currents contribute to distinct firing properties of human DRG neurons

Human Nav1.8: enhanced persistent and ramp currents contribute to distinct firing properties of human DRG neurons

Inhibition of mechanical allodynia in neuropathic pain by TLR5-mediated A-fiber blockade

Electrical maturation of spinal neurons in the human fetus: comparison of ventral and dorsal horn

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Human Na_v1.8: enhanced persistent and ramp currents contribute to distinct firing properties of human DRG neurons

Human Na_v1.8: enhanced persistent and ramp currents contribute to distinct firing properties of human DRG neurons