Dorsal root ganglia control nociceptive input to the central nervous system.

Accumulating observations suggest that peripheral somatosensory ganglia may regulate nociceptive transmission, yet direct evidence is sparse. Here, in experiments on rats and mice, we show that the peripheral afferent nociceptive information undergoes dynamic filtering within the dorsal root ganglion (DRG) and suggest that this filtering occurs at the axonal bifurcations (t-junctions). Using synchronous in vivo electrophysiological recordings from the peripheral and central processes of sensory neurons (in the spinal nerve and dorsal root), ganglionic transplantation of GABAergic progenitor cells, and optogenetics, we demonstrate existence of tonic and dynamic filtering of action potentials traveling through the DRG. Filtering induced by focal application of GABA or optogenetic GABA release from the DRG-transplanted GABAergic progenitor cells was specific to nociceptive fibers. Light-sheet imaging and computer modeling demonstrated that, compared to other somatosensory fiber types, nociceptors have shorter stem axons, making somatic control over t-junctional filtering more efficient. Optogenetically induced GABA release within DRG from the transplanted GABAergic cells enhanced filtering and alleviated hypersensitivity to noxious stimulation produced by chronic inflammation and neuropathic injury in vivo. These findings support "gating" of pain information by DRGs and suggest new therapeutic approaches for pain relief.

Physiologic regulation of heart rate and blood pressure involves connexin 36-containing gap junctions.

Chronically elevated sympathetic nervous activity underlies many cardiovascular diseases. Elucidating the mechanisms contributing to sympathetic nervous system output may reveal new avenues of treatment. The contribution of the gap junctional protein connexin 36 (Cx36) to the regulation of sympathetic activity and thus blood pressure and heart rate was determined using a mouse with specific genetic deletion of Cx36. Ablation of the Cx36 protein was confirmed in sympathetic preganglionic neurons of Cx36-knockout (KO) mice. Telemetric analysis from conscious Cx36 KO mice revealed higher variance in heart rate and blood pressure during rest and activity compared to wild-type (WT) mice, and smaller responses to chemoreceptor activation when anesthetized. In the working heart-brain stem preparation of the Cx36-KO mouse, respiratory-coupled sympathetic nerve discharge was attenuated and responses to chemoreceptor stimulation and noxious stimulation were blunted compared to WT mice. Using whole cell patch recordings, sympathetic preganglionic neurons in spinal cord slices of Cx36-KO mice displayed lower levels of spikelet activity compared to WT mice, indicating reduced gap junction coupling between neurons. Cx36 deletion therefore disrupts normal regulation of sympathetic outflow with effects on cardiovascular parameters.-Lall, V. K., Bruce, G., Voytenko, L., Drinkhill, M., Wellershaus, K., Willecke, K., Deuchars, J., Deuchars, S. A. Physiologic regulation of heart rate and blood pressure involves connexin 36-containing gap junctions.

Mechanisms underpinning sympathetic nervous activity and its modulation using transcutaneous vagus nerve stimulation.

NEW FINDINGS: What is the topic of this review? This review briefly considers what modulates sympathetic nerve activity and how it may change as we age or in pathological conditions. It then focuses on transcutaneous vagus nerve stimulation, a method of neuromodulation in autonomic cardiovascular control. What advances does it highlight? The review considers the pathways involved in eliciting the changes in autonomic balance seen with transcutaneous vagus nerve stimulation in relationship to other neuromodulatory techniques. The autonomic nervous system, consisting of the sympathetic and parasympathetic branches, is a major contributor to the maintenance of cardiovascular variables within homeostatic limits. As we age or in certain pathological conditions, the balance between the two branches changes such that sympathetic activity is more dominant, and this change in dominance is negatively correlated with prognosis in conditions such as heart failure. We have shown that non-invasive stimulation of the tragus of the ear increases parasympathetic activity and reduces sympathetic activity and that the extent of this effect is correlated with the baseline cardiovascular parameters of different subjects. The effects could be attributable to activation of the afferent branch of the vagus and, potentially, other sensory nerves in that region. This indicates that tragus stimulation may be a viable treatment in disorders where autonomic activity to the heart is compromised.

The anti-malarial drug Mefloquine disrupts central autonomic and respiratory control in the working heart brainstem preparation of the rat.

BACKGROUND: Mefloquine is an anti-malarial drug that can have neurological side effects. This study examines how mefloquine (MF) influences central nervous control of autonomic and respiratory systems using the arterially perfused working heart brainstem preparation (WHBP) of the rat. Recordings of nerve activity were made from the thoracic sympathetic chain and phrenic nerve, while heart rate (HR) and perfusion pressure were also monitored in the arterially perfused, decerebrate, rat WHBP. MF was added to the perfusate at 1 µM to examine its effects on baseline parameters as well as baroreceptor and chemoreceptor reflexes. RESULTS: MF caused a significant, atropine resistant, bradycardia and increased phrenic nerve discharge frequency. Chemoreceptor mediated sympathoexcitation (elicited by addition of 0.1 ml of 0.03% sodium cyanide to the aortic cannula) was significantly attenuated by the application of MF to the perfusate. Furthermore MF significantly decreased rate of return to resting HR following chemoreceptor induced bradycardia. An increase in respiratory frequency and attenuated respiratory-related sympathetic nerve discharge during chemoreceptor stimulation was also elicited with MF compared to control. However, MF did not significantly alter baroreceptor reflex sensitivity. CONCLUSIONS: These studies indicate that in the WHBP, MF causes profound alterations in autonomic and respiratory control. The possibility that these effects may be mediated through actions on connexin 36 containing gap junctions in central neurones controlling sympathetic nervous outflow is discussed.

Sympathetic preganglionic neurons: properties and inputs.

The sympathetic nervous system comprises one half of the autonomic nervous system and participates in maintaining homeostasis and enabling organisms to respond in an appropriate manner to perturbations in their environment, either internal or external. The sympathetic preganglionic neurons (SPNs) lie within the spinal cord and their axons traverse the ventral horn to exit in ventral roots where they form synapses onto postganglionic neurons. Thus, these neurons are the last point at which the central nervous system can exert an effect to enable changes in sympathetic outflow. This review considers the degree of complexity of sympathetic control occurring at the level of the spinal cord. The morphology and targets of SPNs illustrate the diversity within this group, as do their diverse intrinsic properties which reveal some functional significance of these properties. SPNs show high degrees of coupled activity, mediated through gap junctions, that enables rapid and coordinated responses; these gap junctions contribute to the rhythmic activity so critical to sympathetic outflow. The main inputs onto SPNs are considered; these comprise afferent, descending, and interneuronal influences that themselves enable functionally appropriate changes in SPN activity. The complexity of inputs is further demonstrated by the plethora of receptors that mediate the different responses in SPNs; their origins and effects are plentiful and diverse. Together these different inputs and the intrinsic and coupled activity of SPNs result in the rhythmic nature of sympathetic outflow from the spinal cord, which has a variety of frequencies that can be altered in different conditions.