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Analgesic dorsal root ganglionic field stimulation blocks conduction of afferent impulse trains selectively in nociceptive sensory afferents.

ABSTRACT: Increased excitability of primary sensory neurons after peripheral nerve injury may cause hyperalgesia and allodynia. Dorsal root ganglion field stimulation (GFS) is effective in relieving clinical pain associated with nerve injury and neuropathic pain in animal models. However, its mechanism has not been determined. We examined effects of GFS on transmission of action potentials (APs) from the peripheral to central processes by in vivo single-unit recording from lumbar dorsal roots in sham injured rats and rats with tibial nerve injury (TNI) in fiber types defined by conduction velocity. Transmission of APs directly generated by GFS (20 Hz) in C-type units progressively abated over 20 seconds, whereas GFS-induced Aβ activity persisted unabated, while Aδ showed an intermediate pattern. Activity generated peripherally by electrical stimulation of the sciatic nerve and punctate mechanical stimulation of the receptive field (glabrous skin) was likewise fully blocked by GFS within 20 seconds in C-type units, whereas Aβ units were minimally affected and a subpopulation of Aδ units was blocked. After TNI, the threshold to induce AP firing by punctate mechanical stimulation (von Frey) was reduced, which was reversed to normal during GFS. These results also suggest that C-type fibers, not Aβ, mainly contribute to mechanical and thermal hypersensitivity (von Frey, brush, acetone) after injury. Ganglion field stimulation produces use-dependent blocking of afferent AP trains, consistent with enhanced filtering of APs at the sensory neuron T-junction, particularly in nociceptive units.

SUBMITTER: Chao D

PROVIDER: S-EPMC7669706 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Lamina 5 sensorimotor cortex pyramidal neurons project to the spinal cord, participating in the modulation of several modalities of information transmission. A well-studied mechanism by which the corticospinal projection modulates sensory information is primary afferent depolarization, which has been characterized in fast muscular and cutaneous, but not in slow-conducting nociceptive skin afferents. Here we investigated whether the inhibition of nociceptive sensory information, produced by activation of the sensorimotor cortex, involves a direct presynaptic modulation of C primary afferents. In anaesthetized male Wistar rats, we analyzed the effects of sensorimotor cortex activation on post tetanic potentiation (PTP) and the paired pulse ratio (PPR) of dorsal horn field potentials evoked by C-fiber stimulation in the sural (SU) and sciatic (SC) nerves. We also explored the time course of the excitability changes in nociceptive afferents produced by cortical stimulation. We observed that the development of PTP was completely blocked when C-fiber tetanic stimulation was paired with cortex stimulation. In addition, sensorimotor cortex activation by topical administration of bicuculline (BIC) produced a reduction in the amplitude of C-fiber responses, as well as an increase in the PPR. Furthermore, increases in the intraspinal excitability of slow-conducting fiber terminals, produced by sensorimotor cortex stimulation, were indicative of primary afferent depolarization. Topical administration of BIC in the spinal cord blocked the inhibition of C-fiber neuronal responses produced by cortical stimulation. Dorsal horn neurons responding to sensorimotor cortex stimulation also exhibited a peripheral receptive field and responded to stimulation of fast cutaneous myelinated fibers. Our results suggest that corticospinal inhibition of nociceptive responses is due in part to a modulation of the excitability of primary C-fibers by means of GABAergic inhibitory interneurons.

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Project description:Matching energy supply and demand is critical in the bioenergetic homeostasis of all cells. This is a special problem in neurons where high levels of energy expenditure may occur at sites remote from the cell body, given the remarkable length of axons and enormous variability of impulse activity over time. Positioning mitochondria at areas with high energy requirements is an essential solution to this problem, but it is not known how this is related to impulse conduction in vivo. Therefore, to study mitochondrial trafficking along resting and electrically active adult axons in vivo, confocal imaging of saphenous nerves in anaesthetised mice was combined with electrical and pharmacological stimulation of myelinated and unmyelinated axons, respectively. We show that low frequency activity induced by electrical stimulation significantly increases anterograde and retrograde mitochondrial traffic in comparison with silent axons. Higher frequency conduction within a physiological range (50 Hz) dramatically further increased anterograde, but not retrograde, mitochondrial traffic, by rapidly increasing the number of mobile mitochondria and gradually increasing their velocity. Similarly, topical application of capsaicin to skin innervated by the saphenous nerve increased mitochondrial traffic in both myelinated and unmyelinated axons. In addition, stationary mitochondria in axons conducting at higher frequency become shorter, thus supplying additional mitochondria to the trafficking population, presumably through enhanced fission. Mitochondria recruited to the mobile population do not accumulate near Nodes of Ranvier, but continue to travel anterogradely. This pattern of mitochondrial redistribution suggests that the peripheral terminals of sensory axons represent sites of particularly high metabolic demand during physiological high frequency conduction. As the majority of mitochondrial biogenesis occurs at the cell body, increased anterograde mitochondrial traffic may represent a mechanism that ensures a uniform increase in mitochondrial density along the length of axons during high impulse load, supporting the increased metabolic demand imposed by sustained conduction.

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Analgesic dorsal root ganglionic field stimulation blocks conduction of afferent impulse trains selectively in nociceptive sensory afferents.

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