Journal of neurophysiology
-
Sphingosine-1-phosphate (S1P) is released by immune cells and is thought to play a key role in chemotaxis and the onset of the inflammatory response. The question remains whether this lipid mediator also contributes to the enhanced sensitivity of nociceptive neurons that is associated with inflammation. Therefore we examined whether S1P alters the excitability of small diameter, capsaicin-sensitive sensory neurons by measuring action potential (AP) firing and two of the membrane currents critical in regulating the properties of the AP. ⋯ In contrast, internal perfusion with GDP-beta-S and S1P increased the number of APs evoked by the current ramp. These results and our finding that the mRNAs for S1PRs are expressed in both the intact dorsal root ganglion and cultures of adult sensory neurons supports the notion that S1P acts on S1PRs linked to G proteins. Together these findings demonstrate that S1P can regulate the excitability of small diameter sensory neurons by acting as an external paracrine-type ligand through activation of G-protein-coupled receptors and thus may contribute to the hypersensitivity during inflammation.
-
The subthalamic nucleus (STN) is the most common target for the treatment of Parkinson's disease (PD) with deep brain stimulation (DBS). DBS of the globus pallidus internus (GPi) is also effective in the treatment of PD. The output fibers of the GPi that form the lenticular fasciculus pass in close proximity to STN DBS electrodes. ⋯ Model predictions regarding the degree of GPi fiber activation matched well with experimental recordings in both monkeys. Only axonal activation of the STN neurons showed a statistically significant increase in both monkeys when comparing clinically effective and ineffective stimulation. Nonetheless, both neural targets may play important roles in the therapeutic mechanisms of STN DBS.
-
Peripheral nerve injury increases spontaneous action potential discharge in spinal dorsal horn neurons and augments their response to peripheral stimulation. This "central hypersensitivity, " which relates to the onset and persistence of neuropathic pain, reflects spontaneous activity in primary afferent fibers as well as long-term changes in the intrinsic properties of the dorsal horn (centralization). To isolate and investigate cellular mechanisms underlying "centralization," sciatic nerves of 20-day-old rats were subjected to 13-25 days of chronic constriction injury (CCI; Mosconi-Kruger polyethylene cuff model). ⋯ By contrast, in tonic cells, CCI reduced the amplitude and frequency of spontaneous and miniature EPSCs. Such changes may relate to the putative role of tonic cells as inhibitory GABAergic interneurons, whereas increased synaptic drive to delay cells may relate to their putative role as the excitatory output neurons of the substantia gelatinosa. Complementary changes in synaptic excitation of inhibitory and excitatory neurons may thus contribute to pain centralization.
-
Cathodal galvanic currents activate primary vestibular afferents, whereas anodal currents inhibit them. Pulsed galvanic vestibular stimulation (GVS) was used to determine the latency and initiation of the human vestibuloocular reflex. Three-dimensional galvanic vestibuloocular reflex (g-VOR) was recorded with binocular dual-search coils in response to a bilateral bipolar 100-ms rectangular pulse of current at 0.9 (near-threshold), 2.5, 5.0, 7.5, and 10.0 mA in 11 normal subjects. ⋯ At 10-mA stimulation, the g-VOR [x, y, z] on the cathodal side was [0.77 +/- 0.10, -0.05 +/- 0.05, -0.18 +/- 0.06 degrees ] (mean +/- 95% confidence intervals) and on the anodal side was [0.79 +/- 0.10, 0.16 +/- 0.05, -0.19 +/- 0.06 degrees ], with a vertical divergence of 0.20 degrees. Although the horizontal g-VOR could have arisen from activation of the horizontal semicircular canal afferents, the vertical-torsional g-VOR resembled the vestibuloocular reflex in response to roll-plane head rotation about an Earth-horizontal axis and might be a result of both vertical semicircular canal and otolith afferent activations. Pulsed GVS is a promising technique to investigate latency and initiation of the human vestibuloocular reflex because it does not require a large mechanical apparatus nor does it pose problems of head inertia or slippage.
-
Comparative Study
Inflammation-susceptible Lewis rats show less sensitivity than resistant Fischer rats in the formalin inflammatory pain test and with repeated thermal testing.
Comparisons between Lewis and Fischer inbred strains of rats are used frequently to study the effect of inherent differences in function of the hypothalamic-pituitary-adrenal axis on pain-relevant traits, including differential susceptibility to chronic inflammatory disease and differential responsiveness to analgesic drugs. Increasing use of genetic models including transgenic knockout mice and inbred strains of rodents has raised our awareness of, and the importance of, thorough characterization (or phenotyping) of the strains of rodents being compared. Furthermore, genetic variability in analgesic sensitivity is correlated with, and may be caused by, genetically determined baseline sensitivity. ⋯ Unexpectedly, the more inflammation-susceptible Lewis rats were less sensitive in the formalin inflammatory nociception test, and showed a significant decrease in sensitivity with repeated thermal nociceptive testing, whereas Fischer rats did not. These results affect the interpretation of previously observed results. Further study of the underlying mechanisms and the relevance to differential susceptibility to chronic inflammation is warranted.