Cellular/Molecular
TNFα Reduces Spiking of GABAergic Neurons in Pain Pathway
Haijun Zhang, Hui Nei, and Patrick M. Dougherty
(see pages 12844–12855)
Potentially harmful thermal, chemical, or mechanical stimuli activate peripheral nociceptive neurons, which synapse in the superficial layers of the spinal dorsal horn, primarily in the substantia gelatinosa (SG). When tissue is damaged, inflammatory mediators, such as tumor necrosis factor-α (TNFα), are released, and they sensitize nociceptors, causing hyperalgesia. Inflammatory molecules also increase the frequency of EPSCs in spinal neurons, which may further contribute to hyperalgesia. Zhang et al. report that TNFα also decreased the frequency of spontaneous IPSCs in mouse spinal cord slices, and decreased spontaneous spiking of GABAergic neurons in the SG. Furthermore, TNFα reduced the hyperpolarization-activated cation current (Ih)—which often underlies spontaneous spiking—in these neurons. These effects were mediated by TNFα receptor 1 and activation of the p38 mitogen-activated protein kinase (MAPK). Blocking inhibitory transmission occluded the effect of TNFα on EPSC frequency, indicating that TNFα increases EPSC frequency via disinhibition of excitatory neurons.
Development/Plasticity/Repair
Neuronal Activity Can Modulate Spike-Timing Variability
Robert H. Cudmore, Laure Fronzaroli-Molinieres, Pierre Giraud, and Dominique Debanne
(see pages 12885–12895)
The shape, timing, and frequency of a neuron's action potentials are determined by the types, conductance properties, and distribution of ion channels it expresses. Alterations in channel expression can underlie experience-dependent plasticity. The D-type current (ID) is a fast-activating, slow-inactivating voltage-sensitive potassium current that is activated below spike threshold and delays the spiking of hippocampal pyramidal cells following depolarization. Cudmore et al. show that ID also affects the precision of spike timing in rat CA3 pyramidal neurons in slices. CA3 neurons showed a slow ramping depolarization and long spike delay. The ID-specific blocker dendrotoxin eliminated the ramp and decreased the delay and variability in timing of the first spike. Blocking all excitatory synaptic activity had similar effects, and it occluded the effects of dendrotoxin, suggesting that activity levels regulate ID. Modeling experiments suggested that such regulation of ID could serve to maximize temporal precision while avoiding excessive synchronous bursting.
ID delays spiking and increases spike-time variability in CA3 pyramidal neurons (top). Blocking ID decreases the delay and the variability (bottom). See the article by Cudmore et al. for details.
Behavioral/Systems/Cognitive
Different Forms of Disgust Produce Unique Physiological Responses
Neil A. Harrison, Marcus A. Gray, Peter J. Gianaros, and Hugo D. Critchley
(see pages 12878–12884)
Emotions are associated with physiological effects produced by the autonomic nervous system. In fact, some researchers have hypothesized that emotions are simply the experience of autonomic responses. Others argue, however, that autonomic responses are not sufficiently distinct to account for the range of emotions we experience. Moreover, spinal cord injury does not eliminate emotional experience despite elimination of most interoceptive inputs. Still, autonomic responses might be more distinct and able to shape emotions than previously appreciated. Harrison et al. used functional magnetic resonance imaging together with peripheral physiological recordings to investigate differences between disgust elicited by viewing people eating foul food or being operated on. Although both scenes produced strong disgust, these feelings were associated with distinct gastric and cardiac effects as well as differential activation in the insula and other brain regions. Therefore, interoception could contribute to the perception of emotion. Whether differences in brain activity resulted from different afferent input or different efferent output is not clear, however.
Neurobiology of Disease
Decreasing GRK2 Levels Prolongs PGE2-Induced Hyperalgesia
Niels Eijkelkamp, Huijing Wang, Anibal Garza-Carbajal, Hanneke L. D. M. Willemen, Fried J. Zwartkruis, et al.
(see pages 12806–12815)
Prostaglandin E2 (PGE2) is an inflammatory mediator that activates G-protein-coupled receptors (GPCRs) on nociceptors, leading to increased cAMP production and activation of protein kinase A (PKA). This ultimately sensitizes nociceptors, causing acute hyperalgesia. Inflammation can also prime nociceptors so subsequent inflammation produces longer-lasting hyperalgesia. In primed nociceptors, PGE2 activates an alternative signaling pathway involving protein kinase Cε (PKCε). Eijkelkamp et al. suggest that GPCR kinase 2 (GRK2) is involved in this switch from acute to persistent pain. Injection of a priming inflammatory agent decreased GRK2 expression in mouse nociceptors, and PGE2-induced hyperalgesia was prolonged in transgenic mice that had similarly reduced GRK2 levels. Although PGE2 acted via the same receptors in GRK2-deficient mice, PKA was not required. Instead, a guanine-nucleotide exchange protein directly activated by cAMP (Epac)—a protein that activates PKCε—was involved. Activation of Epac caused it to associate with GRK2 in wild-type mice, and its activation of downstream effectors was potentiated in GRK2-deficient mice.
In this issue
