Criticality and degeneracy in injury-induced changes in primary afferent excitability and the implications for neuropathic pain

Ratté, Stéphanie; Zhu, Yi; Lee, Kwan Yeop

doi:10.7554/elife.02370

Cited by 60 publications

(74 citation statements)

References 70 publications

(93 reference statements)

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“…146 This makes it very difficult to predict, for example, how effective benzodiazepines will be against a certain type of pain (for detailed discussions, see Refs. 14,33,111,147).…”

Section: Implications For Therapeutic Interventionsmentioning

confidence: 99%

Synaptic Inhibition and Disinhibition in the Spinal Dorsal Horn

Prescott

2015

Progress in Molecular Biology and Translational Science

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“…146 This makes it very difficult to predict, for example, how effective benzodiazepines will be against a certain type of pain (for detailed discussions, see Refs. 14,33,111,147).…”

Section: Implications For Therapeutic Interventionsmentioning

confidence: 99%

Synaptic Inhibition and Disinhibition in the Spinal Dorsal Horn

Prescott

2015

Progress in Molecular Biology and Translational Science

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“…5, these kinds of features can be tuned while keeping other features fixed if maximal conductances are covaried along approximately linear paths in parameter space. This provides a link to recent experimental observations (45)(46)(47) and theoretical models of activity-dependent ion channel regulation (48,49) in which linear correlations between conductance densities are seen.…”

Section: Ion Channels Have Paradoxical Effects On Excitability In Difmentioning

confidence: 99%

Ion channel degeneracy enables robust and tunable neuronal firing rates

Drion

O’Leary

Marder

2015

Proc. Natl. Acad. Sci. U.S.A.

129

165

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Firing rate is an important means of encoding information in the nervous system. To reliably encode a wide range of signals, neurons need to achieve a broad range of firing frequencies and to move smoothly between low and high firing rates. This can be achieved with specific ionic currents, such as A-type potassium currents, which can linearize the frequency-input current curve. By applying recently developed mathematical tools to a number of biophysical neuron models, we show how currents that are classically thought to permit low firing rates can paradoxically cause a jump to a high minimum firing rate when expressed at higher levels. Consequently, achieving and maintaining a low firing rate is surprisingly difficult and fragile in a biological context. This difficulty can be overcome via interactions between multiple currents, implying a need for ion channel degeneracy in the tuning of neuronal properties.FI curve | bifurcation | Type I excitability | Type II excitability | reduced neuron model F iring rates encode the intensities of many signals in the nervous system, whether these are inputs from sensory organs, internal representations of percepts, or muscle contraction commands in motor nerves. For a neuron to represent continuously varying signals in its firing rate, it must be able to fire at low, high, and all intermediate frequencies. Experimentally, this means the frequency-input current (or FI) curve has a specific shape, called Type I, such that firing frequency smoothly approaches zero at current threshold (1-6). By contrast, so-called Type II neurons have a lower bound in their firing frequency and move abruptly from quiescence to fast spiking, with this transition visible as a sharp jump in the FI curve at threshold (1,3,5).Type I behavior is physiologically unlikely with a minimal set of membrane currents such as the voltage-gated sodium and delayed-rectifier potassium currents in the standard squid giant axon Hodgkin-Huxley model, which is Type II. Classic experimental (1, 7) and theoretical studies (3-5, 8, 9) revealed that a Type II membrane (such as a squid giant axon) can be turned into a Type I membrane by adding an inactivating (A-type) potassium conductance, I A . As the density of I A channels increases from zero, the membrane is able to support progressively lower firing frequencies at spiking threshold. The resulting linearization of the FI curve from Type II to Type I has clear consequences for encoding information in firing rate as well as other computational properties such as thresholding and gain scaling, all of which are subjects of intense research (10-17).We now show that this picture is incomplete. Using rigorous but intuitive methods (18) and building on previous technical results (19-21), we show that introducing I A to a Type II neuron progressively linearizes but then delinearizes the FI curve as I A density increases further. Consequently, I A density must be tuned in a strict range to achieve Type I behavior. However, we show that other, unrelated currents including v...

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“…These are all neural processes that are not only changed by nerve injury (Lekan et al, 1997, Costigan et al, 2002, Yaksh, 2006, Wilson et al, 2012, Ratte et al, 2014) but appear to contribute to the signs and symptoms of peripheral neuropathy (Siau and Bennett, 2006). For example, in models of traumatic nerve injury, which is often associated with paresthesias, dysesthesias, and ongoing pain, there are changes in the regulation of [Ca 2+ ] i in both putative nociceptive and non-nociceptive neurons in a pattern that appears to depend on whether or not the neurons were injured or were adjacent to those that were injured.…”

mentioning

confidence: 99%

Sensory neuron subpopulation-specific dysregulation of intracellular calcium in a rat model of chemotherapy-induced peripheral neuropathy

Yılmaz

Gold

2015

Neuroscience

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The purpose of the present study was to test the prediction that the unique manifestation of chemotherapeutic-induced peripheral neuropathy (CIPN) would be reflected in a specific pattern of changes in the regulation of the intracellular Ca2+ concentration ([Ca2+]i) in subpopulations of cutaneous neurons. To test this prediction, we characterized the pattern of changes in mechanical nociceptive threshold associated with paclitaxel administration (2 mg/kg, iv, every other day for four days), as well as the impact of target of innervation and paclitaxel treatment on the regulation of [Ca2+]i in subpopulations of putative nociceptive and non-nociceptive neurons. Neurons innervating the glabrous and hairy skin of the hindpaw as well as the thigh were identified with retrograde tracers, and fura-2 was used to assess changes in [Ca2+]i. Paclitaxel was associated with a persistent decrease in mechanical nociceptive threshold in response to stimuli applied to the glabrous skin of the hindpaw, but not the hairy skin of the hindpaw or the thigh. However, in both putative nociceptive and non-nociceptive neurons, resting [Ca2+]i was significantly lower in neurons innervating the thigh after treatment. The magnitude of the depolarization-evoked Ca2+ transient was also lower in putative non-nociceptive thigh neurons. More interestingly, while paclitaxel had no detectable influence on either resting or depolarization-evoked Ca2+ transients in putative non-nociceptive neurons, in putative nociceptive neurons there was a subpopulation- specific decrease in the duration of the evoked Ca2+ transient that was largely restricted to neurons innervating the glabrous skin. These results suggest that peripheral nerve length alone, does not account for the selective distribution of CIPN symptoms. Rather, they suggest the symptoms of CIPN reflect an interaction between the toxic actions of the therapeutic and unique properties of the neurons deleteriously impacted.

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Criticality and degeneracy in injury-induced changes in primary afferent excitability and the implications for neuropathic pain

Cited by 60 publications

References 70 publications

Synaptic Inhibition and Disinhibition in the Spinal Dorsal Horn

Synaptic Inhibition and Disinhibition in the Spinal Dorsal Horn

Ion channel degeneracy enables robust and tunable neuronal firing rates

Sensory neuron subpopulation-specific dysregulation of intracellular calcium in a rat model of chemotherapy-induced peripheral neuropathy

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