Models that contain the Model Concept : Nociception

(The physiology associated with transmission of pain information to the brain. The pathway in humans involves NaV1.7 channels and P2 receptors on "A delta" and "C" peripheral nerve fibers.)
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    Models   Description
1.  Computational model of bladder small DRG neuron soma (Mandge & Manchanda 2018)
Bladder small DRG neurons, which are putative nociceptors pivotal to urinary bladder function, express more than a dozen different ionic membrane mechanisms: ion channels, pumps and exchangers. Small-conductance Ca2+-activated K+ (SKCa) channels which were earlier thought to be gated solely by intracellular Ca2+ concentration ([Ca]i ) have recently been shown to exhibit inward rectification with respect to membrane potential. The effect of SKCa inward rectification on the excitability of these neurons is unknown. Furthermore, studies on the role of KCa channels in repetitive firing and their contributions to different types of afterhyperpolarization (AHP) in these neurons are lacking. In order to study these phenomena, we first constructed and validated a biophysically detailed single compartment model of bladder small DRG soma constrained by physiological data. The model includes twenty-two major known membrane mechanisms along with intracellular Ca2+ dynamics comprising Ca2+ diffusion, cytoplasmic buffering, and endoplasmic reticulum (ER) and mitochondrial mechanisms. Using modelling studies, we show that inward rectification of SKCa is an important parameter regulating neuronal repetitive firing and that its absence reduces action potential (AP) firing frequency. We also show that SKCa is more potent in reducing AP spiking than the large-conductance KCa channel (BKCa) in these neurons. Moreover, BKCa was found to contribute to the fast AHP (fAHP) and SKCa to the medium-duration (mAHP) and slow AHP (sAHP). We also report that the slow inactivating A-type K+ channel (slow KA) current in these neurons is composed of 2 components: an initial fast inactivating (time constant ~ 25-100 ms) and a slow inactivating (time constant ~ 200-800 ms) current. We discuss the implications of our findings, and how our detailed model can help further our understanding of the role of C-fibre afferents in the physiology of urinary bladder as well as in certain disorders.
2.  Dorsal root ganglion (primary somatosensory) neurons (Rho & Prescott 2012)
In this paper, we demonstrate how dorsal root ganglion (DRG) neuron excitability can become pathologically altered, as occurs in neuropathic pain. Specifically, we reproduce pathological changes in spiking pattern (from transient to repetitive spiking) and the development of membrane potential oscillations and bursting.
3.  Experimental and modeling studies of desensitization of P2X3 receptors (Sokolova et al. 2006)
"The function of ATP-activated P2X3 receptors involved in pain sensation is modulated by desensitization, a phenomenon poorly understood. The present study used patch-clamp recording from cultured rat or mouse sensory neurons and kinetic modeling to clarify the properties of P2X3 receptor desensitization. ... Desensitization properties were well accounted for by a cyclic model in which receptors could be desensitized from either open or closed states. Recovery was assumed to be a multistate process with distinct kinetics dependent on the agonist-dependent dissociation rate from desensitized receptors. ... By using subthreshold concentrations of an HAD (high-affinity desensitization)-potent agonist, it might be possible to generate sustained inhibition of P2X3 receptors for controlling chronic pain."
4.  Explaining pathological changes in axonal excitability by dynamical analysis (Coggan et al. 2011)
"... To help decipher the biophysical basis for ‘paroxysmal’ spiking, we replicated afterdischarge (i.e. continued spiking after a brief stimulus) in a minimal conductance-based axon model. ... A perturbation could abruptly switch the system between two (quasi-)stable attractor states: rest and repetitive spiking. ... Initiation of afterdischarge was explained by activation of the persistent inward current forcing the system to cross a saddle point that separates the basins of attraction associated with each attractor. Termination of afterdischarge was explained by the attractor associated with repetitive spiking being destroyed. ... The model also explains other features of paroxysmal symptoms, including temporal summation and refractoriness."
5.  HMM of Nav1.7 WT and F1449V (Gurkiewicz et al. 2011)
Neuron mod files for the WT and F1449V Na+ currents from the paper: Kinetic Modeling of Nav1.7 Provides Insight Into Erythromelalgia-associated F1449V Mutation M. Gurkiewicz, A. Korngreen, S. Waxman, and A. Lampert. J.Neurophysiol. (2011). The parameters for the K65, K53 and K63 transitions were derived from microscopic reversibility relationships in the model.
6.  Kinetics of the P2X7 receptor as expressed in Xenopus oocytes (Riedel et al. 2007a,b)
"Human P2X7 receptors were expressed in Xenopus laevis oocytes and single channels were recorded using the patch-clamp technique in the outside-out configuration. ATP4- evoked two types of P2X7 receptor-mediated single channel currents characterized by short-lived and long-lived openings. ... The kinetics of the short channel openings at negative membrane potentials fitted well to a linear C-C-C-O model with two ATP4- binding steps at equal binding sites ...." and "Using the patch-clamp method, we studied the influence of external alkali and organic monovalent cations on the single-channel properties of the adenosine triphosphate (ATP)-activated recombinant human P2X(7) receptor." See the references for more.
7.  Models of Na channels from a paper on the PKC control of I Na,P (Baker 2005)
"The tetrodotoxin-resistant (TTX-r) persistent Na(+) current, attributed to Na(V)1.9, was recorded in small (< 25 mum apparent diameter) dorsal root ganglion (DRG) neurones cultured from P21 rats and from adult wild-type and Na(V)1.8 null mice. ... Numerical simulation of the up-regulation qualitatively reproduced changes in sensory neurone firing properties. ..." Note: models of NaV1.8 and NaV1.9 and also persistent and transient Na channels that collectively model Nav 1.1, 1.6, and 1.7 are present in this model.
8.  Tonic neuron in spinal lamina I: prolongation of subthreshold depol. (Prescott and De Koninck 2005)
Model demonstrates mechanism whereby two kinetically distinct inward currents act synergistically to prolong subthreshold depolarization. The important currents are a persistent Na current (with fast kinetics) and a persistent Ca current (with slower kinetics). Model also includes a slow K current and transient Ca current, in addition to standard HH currents. Model parameters are set to values used in Fig. 8A. Simulation shows prolonged depolarizations in response to two brief stimuli.
9.  TTX-R Na+ current effect on cell response (Herzog et al 2001)
"Small dorsal root ganglion (DRG) neurons, which include nociceptors, express multiple voltage-gated sodium currents. In addition to a classical fast inactivating tetrodotoxin-sensitive (TTX-S) sodium current, many of these cells express a TTX-resistant (TTX-R) sodium current that activates near -70 mV and is persistent at negative potentials. To investigate the possible contributions of this TTX-R persistent (TTX-RP) current to neuronal excitability, we carried out computer simulations using the Neuron program with TTX-S and -RP currents, fit by the Hodgkin-Huxley model, that closely matched the currents recorded from small DRG neurons. ..." See paper for more and details.
10.  TTX-R Na+ current effect on cell response (Herzog et al 2001) (MATLAB)
"Small dorsal root ganglion (DRG) neurons, which include nociceptors, express multiple voltage-gated sodium currents. In addition to a classical fast inactivating tetrodotoxin-sensitive (TTX-S) sodium current, many of these cells express a TTX-resistant (TTX-R) sodium current that activates near -70 mV and is persistent at negative potentials. To investigate the possible contributions of this TTX-R persistent (TTX-RP) current to neuronal excitability, we carried out computer simulations using the Neuron program with TTX-S and -RP currents, fit by the Hodgkin-Huxley model, that closely matched the currents recorded from small DRG neurons. ..." See paper for more and details.

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