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Handbook of Experimental Pharmacology 2018The functional diversity of primary afferent neurons of the dorsal root ganglia (DRG) generates a variety of qualitatively and quantitatively distinct somatosensory... (Review)
Review
The functional diversity of primary afferent neurons of the dorsal root ganglia (DRG) generates a variety of qualitatively and quantitatively distinct somatosensory experiences, from shooting pain to pleasant touch. In recent years, the identification of dozens of genetic markers specifically expressed by subpopulations of DRG neurons has dramatically improved our understanding of this diversity and provided the tools to manipulate their activity and uncover their molecular identity and function. Opioid receptors have long been known to be expressed by discrete populations of DRG neurons, in which they regulate cell excitability and neurotransmitter release. We review recent insights into the identity of the DRG neurons that express the delta opioid receptor (DOR) and the ion channel mechanisms that DOR engages in these cells to regulate sensory input. We highlight recent findings derived from DORGFP reporter mice and from in situ hybridization and RNA sequencing studies in wild-type mice that revealed DOR presence in cutaneous mechanosensory afferents eliciting touch and implicated in tactile allodynia. Mechanistically, we describe how DOR modulates opening of voltage-gated calcium channels (VGCCs) to control glutamatergic neurotransmission between somatosensory neurons and postsynaptic neurons in the spinal cord dorsal horn. We additionally discuss other potential signaling mechanisms, including those involving potassium channels, which DOR may engage to fine tune somatosensation. We conclude by discussing how this knowledge may explain the analgesic properties of DOR agonists against mechanical pain and uncovers an unanticipated specialized function for DOR in cutaneous mechanosensation.
Topics: Animals; Ganglia, Spinal; Humans; Neurons, Afferent; Pain; Receptors, Opioid, delta; Sensory Receptor Cells
PubMed: 28993838
DOI: 10.1007/164_2017_58 -
The Journal of Physiology Jul 2019While the presence of GABA receptors on primary afferents has been well described, most functional analyses have focused on the regulation of transmitter release from...
KEY POINTS
While the presence of GABA receptors on primary afferents has been well described, most functional analyses have focused on the regulation of transmitter release from central terminals and/or signalling in the sensory neuron cell body. Evidence that GABA receptors are transported to peripheral terminals and that there are several sources of GABA in the colon raise the possibility that GABA signalling in the periphery may influence colonic afferent excitability. GABA and GABA are present and functional in the colon, where exogenous agonists decrease the excitability of colonic afferents and suppress visceral nociception. Endogenous GABA release within the colon is sufficient to establish the resting excitability of colonic afferents as well as the behavioural response to noxious stimulation of the colon, primarily via GABA receptors. Peripheral GABA receptors may serve as a viable target for the treatment of visceral pain.
ABSTRACT
It is well established that GABA receptors at the central terminals of primary afferent fibres regulate afferent input to the superficial dorsal horn. However, the extent to which peripheral GABA signalling may also regulate afferent input remains to be determined. The colon was used to explore this issue because of the numerous endogenous sources of GABA that have been described in this tissue. The influence of GABA signalling on colonic afferent excitability was assessed in an ex vivo mouse colorectum pelvic nerve preparation where test compounds were applied to the receptive field. The visceromotor response (VMR) evoked by noxious colorectal distension was used to assess the impact of GABA signalling on visceral nociception, where test compounds were applied directly to the colon. Application of either GABA or GABA receptor agonists attenuated the colonic afferent response to colon stretch. Conversely, GABA and GABA receptor antagonists increased the stretch response. However, while the noxious distension-induced VMR was attenuated in the presence of GABA and GABA receptor agonists, the VMR was only consistently increased by GABA receptor antagonists. These results suggest that GABA receptors are present and functional in the peripheral terminals of colonic afferents and activation of these receptors via endogenous GABA release contributes to the establishment of colonic afferent excitability and visceral nociception. These results suggest that increasing peripheral GABA receptor signalling could be used to treat visceral pain.
Topics: Animals; Colon; Female; GABA-B Receptor Agonists; GABA-B Receptor Antagonists; Male; Mice; Mice, Inbred C57BL; Neurons, Afferent; Nociception; Receptors, GABA-A; Receptors, GABA-B; Visceral Pain
PubMed: 31077379
DOI: 10.1113/JP278025 -
ELife Jun 2022Animals can evolve dramatic sensory functions in response to environmental constraints, but little is known about the neural mechanisms underlying these changes. The...
Animals can evolve dramatic sensory functions in response to environmental constraints, but little is known about the neural mechanisms underlying these changes. The Mexican tetra, , is a leading model to study genetic, behavioral, and physiological evolution by comparing eyed surface populations and blind cave populations. We compared neurophysiological responses of posterior lateral line afferent neurons and motor neurons across populations to reveal how shifts in sensory function may shape behavioral diversity. These studies indicate differences in intrinsic afferent signaling and gain control across populations. Elevated endogenous afferent activity identified a lower response threshold in the lateral line of blind cavefish relative to surface fish leading to increased evoked potentials during hair cell deflection in cavefish. We next measured the effect of inhibitory corollary discharges from hindbrain efferent neurons onto afferents during locomotion. We discovered that three independently derived cavefish populations have evolved persistent afferent activity during locomotion, suggesting for the first time that partial loss of function in the efferent system can be an evolutionary mechanism for neural adaptation of a vertebrate sensory system.
Topics: Animals; Biological Evolution; Caves; Characidae; Lateral Line System; Locomotion
PubMed: 35708234
DOI: 10.7554/eLife.77387 -
Journal of Neurophysiology Feb 2021Somatosensory input strength can be modulated by primary afferent depolarization (PAD) generated predominantly via presynaptic GABA receptors on afferent terminals. We...
Somatosensory input strength can be modulated by primary afferent depolarization (PAD) generated predominantly via presynaptic GABA receptors on afferent terminals. We investigated whether ionotropic nicotinic acetylcholine receptors (nAChRs) also provide modulatory actions, focusing on myelinated afferent excitability in in vitro murine spinal cord nerve-attached models. Primary afferent stimulation-evoked synaptic transmission was recorded in the deep dorsal horn as extracellular field potentials (EFPs), whereas concurrently recorded dorsal root potentials (DRPs) were used as an indirect measure of PAD. Changes in afferent membrane excitability were simultaneously measured as direct current (DC)-shifts in membrane polarization recorded in dorsal roots or peripheral nerves. The broad nAChR antagonist d-tubocurarine (d-TC) selectively and strongly depressed Aδ-evoked synaptic EFPs (36% of control) coincident with similarly depressed A-fiber DRP (43% of control), whereas afferent electrical excitability remained unchanged. In comparison, acetylcholine (ACh) and the nAChR agonists, epibatidine and nicotine, reduced afferent excitability by generating coincident depolarizing DC-shifts in peripheral axons and intraspinally. Progressive depolarization corresponded temporally with the emergence of spontaneous axonal spiking and reductions in the DRP and all afferent-evoked synaptic actions (31%-37% of control). Loss of evoked response was long-lasting, independent of DC repolarization, and likely due to mechanisms initiated by spontaneous C-fiber activity. DC-shifts were blocked with d-TC but not GABA receptor blockers and retained after tetrodotoxin block of voltage-gated Na channels. Notably, actions tested were comparable between three mouse strains, in rat, and when performed in different labs. Thus, nAChRs can regulate afferent excitability via two distinct mechanisms: by central Aδ-afferent actions, and by transient extrasynaptic axonal activation of high-threshold primary afferents. Primary afferents express many nicotinic ACh receptor (nAChR) subtypes but whether activation is linked to presynaptic inhibition, facilitation, or more complex and selective activity modulation is unknown. Recordings of afferent-evoked responses in the lumbar spinal cord identified two nAChR-mediated modulatory actions: ) selective control of Aδ afferent transmission and ) robust changes in axonal excitability initiated via extrasynaptic shifts in DC polarization. This work broadens the diversity of presynaptic modulation of primary afferents by nAChRs.
Topics: Animals; Ganglia, Spinal; Mice; Mice, Inbred BALB C; Neurons, Afferent; Nicotinic Agonists; Nicotinic Antagonists; Rats; Rats, Sprague-Dawley; Receptors, Nicotinic; Synaptic Potentials
PubMed: 33326305
DOI: 10.1152/jn.00228.2020 -
Journal of Applied Physiology... Nov 2016Many airway sensory units respond to both lung inflation and deflation. Whether those responses to opposite stimuli come from one sensor (one-sensor theory) or more than... (Review)
Review
Many airway sensory units respond to both lung inflation and deflation. Whether those responses to opposite stimuli come from one sensor (one-sensor theory) or more than one sensor (multiple-sensor theory) is debatable. One-sensor theory is commonly presumed in the literature. This article proposes a multiple-sensor theory in which a sensory unit contains different sensors for sensing different forces. Two major types of mechanical sensors operate in the lung: inflation- and deflation-activated receptors (DARs). Inflation-activated sensors can be further divided into slowly adapting receptors (SARs) and rapidly adapting receptors (RARs). Many SAR and RAR units also respond to lung deflation because they contain DARs. Pure DARs, which respond to lung deflation only, are rare in large animals but are easily identified in small animals. Lung deflation-induced reflex effects previously attributed to RARs should be assigned to DARs (including pure DARs and DARs associated with SARs and RARs) if the multiple-sensor theory is accepted. Thus, based on the information, it is proposed that activation of DARs can attenuate lung deflation, shorten expiratory time, increase respiratory rate, evoke inspiration, and cause airway secretion and dyspnea.
Topics: Animals; Humans; Lung; Neurons, Afferent; Pulmonary Stretch Receptors; Reflex; Respiration; Sensory Receptor Cells; Vagus Nerve
PubMed: 27586839
DOI: 10.1152/japplphysiol.00903.2015 -
European Journal of Sport Science Feb 2018Neuromuscular fatigue compromises exercise performance and is determined by central and peripheral mechanisms. Interactions between the two components of fatigue can... (Review)
Review
Neuromuscular fatigue compromises exercise performance and is determined by central and peripheral mechanisms. Interactions between the two components of fatigue can occur via neural pathways, including feedback and feedforward processes. This brief review discusses the influence of feedback and feedforward mechanisms on exercise limitation. In terms of feedback mechanisms, particular attention is given to group III/IV sensory neurons which link limb muscle with the central nervous system. Central corollary discharge, a copy of the neural drive from the brain to the working muscles, provides a signal from the motor system to sensory systems and is considered a feedforward mechanism that might influence fatigue and consequently exercise performance. We highlight findings from studies supporting the existence of a 'critical threshold of peripheral fatigue', a previously proposed hypothesis based on the idea that a negative feedback loop operates to protect the exercising limb muscle from severe threats to homeostasis during whole-body exercise. While the threshold theory remains to be disproven within a given task, it is not generalisable across different exercise modalities. The 'sensory tolerance limit', a more theoretical concept, may address this issue and explain exercise tolerance in more global terms and across exercise modalities. The 'sensory tolerance limit' can be viewed as a negative feedback loop which accounts for the sum of all feedback (locomotor muscles, respiratory muscles, organs, and muscles not directly involved in exercise) and feedforward signals processed within the central nervous system with the purpose of regulating the intensity of exercise to ensure that voluntary activity remains tolerable.
Topics: Exercise; Fatigue; Feedback, Physiological; Humans; Neurons, Afferent; Physical Endurance
PubMed: 27821022
DOI: 10.1080/17461391.2016.1252428 -
Swiss Medical Weekly May 2019Our senses are the main information channels through which we perceive and interact with the world. Consequently, the physical and social functioning of patients... (Review)
Review
Our senses are the main information channels through which we perceive and interact with the world. Consequently, the physical and social functioning of patients suffering from severe sensory disabilities is limited on several levels. This has motivated the development of a novel therapeutic alternative: “artificial senses”, more commonly known as sensory neuroprostheses. In order to restore lost function, sensory neuroprostheses attempt to take advantage of the information transfer pathway common to all senses: (i) transduction of the physical stimulus by sensory receptors, (ii) transmission of relevant information to primary sensory areas in the brain by sensory afferents, and (iii) analysis and integration of the information at multiple levels in the central nervous system. Neurosensory deficits might occur upon damage to any of the structures involved in this process. However, damage to the peripheral sensory receptor is often the cause of neurosensory loss. Most sensory neuroprostheses attempt to “replace” the malfunctioning or missing peripheral sensory organ by directly delivering basic sensory information to the brain using electrical currents. If the prosthesis is able to deliver enough consistent information, the brain will be able to correctly interpret it and useful rehabilitation can be achieved. This review presents the main challenges related to the development, implementation and translation to clinical practice of these devices: (i) sensory information needs to be efficiently delivered to specific neural targets (e.g., peripheral afferents or specific central nuclei); (ii) then the expected physiological response must be evoked and quantified; (iii) the restoration of basic sensory abilities can lead to useful rehabilitation in meaningful everyday activities; (iv) optimal prospects require specific rehabilitation therapy and lifelong medico-technical follow-up. To conclude, the current state and future of sensory neuroprostheses will be discussed. This will include current clinical and technical challenges, future prospects, and the potential of these devices to improve our fundamental knowledge of sensory physiology and neurosensory deficits.
Topics: Humans; Neurons, Afferent; Prosthesis Design; Prosthesis Implantation; Sensation; Sensation Disorders
PubMed: 31154660
DOI: 10.4414/smw.2019.20061 -
Journal of Anatomy Aug 2015Mechanotransduction by proprioceptive sensory organs is poorly understood. Evidence was recently shown that muscle spindle and hair follicle primary afferents... (Review)
Review
Mechanotransduction by proprioceptive sensory organs is poorly understood. Evidence was recently shown that muscle spindle and hair follicle primary afferents (lanceolates) constantly release glutamate from synaptic-like vesicles (SLVs) within the terminals. The secreted glutamate activates a highly unusual metabotropic glutamate receptor (mGluR) to modulate the firing rate (spindles) and SLV recycling (lanceolates). This receptor has yet to be isolated and sequenced. To further investigate this receptor's pharmacology, ligands selective for classical mGluRs have been recently characterised for their ability to alter stretch-evoked spindle firing and SLV endocytosis in these different endings. Here, it is described how the results of these screens facilitated the development of novel compounds to be used in the process of isolating and sequencing of this non-canonical mGluR. This study shows how the compounds were tested for their ability to alter stretch-evoked afferent firing in muscle spindles and SLV endocytosis in the lanceolate endings of hair follicles to ensure they maintained their ability to bind to the receptor. For the development of novel compounds, kainate was chosen as the parent ligand due to its potency and ease of chemical modification. Novel kainate derivatives were then synthesised and tested to find potent analogues suitable for 'click-chemistry', an established technique for relatively quick, cheap, stereospecific and high-yield chemical modifications (Angewandte Chemie (International ed. in English), 40, 2001, pp2004). Of the novel kainate analogues developed, unfortunately ZCZ49 and ZCZ50 lost the ability to produce a significant change in spindle stretch-evoked firing. However, ZCZ90 was as potent as kainate, increasing firing by a similar margin at 1 μm (n = 8; P < 0.001). The addition of either a biotin or a fluorescein side group to ZCZ90, using the click-chemistry technique, did not affect the potency and hence these compounds will be used in further studies of the receptor. As well as the development of these compounds, the study found not only many similarities, but also some key differences between the two types of primary mechanosensory endings investigated. These differences must be taken into account in further study. However, they also present an intriguing opportunity for these receptors to be targeted selectively to modulate ending sensitivity as treatments for muscle spasm in multiple sclerosis and spinal cord injury, and possibly even baroreceptor firing to treat hypertension.
Topics: Animals; Endocytosis; Hair Follicle; Mammals; Mechanotransduction, Cellular; Molecular Sequence Data; Muscle Spindles; Neurons, Afferent; Proprioception; Pyridinium Compounds; Quaternary Ammonium Compounds; Receptors, Metabotropic Glutamate; Synaptic Vesicles
PubMed: 26053109
DOI: 10.1111/joa.12319 -
Pain Apr 2016
Review
Topics: Afferent Pathways; Humans; Keratinocytes; Neurons, Afferent; Skin; Skin Physiological Phenomena
PubMed: 26982514
DOI: 10.1097/j.pain.0000000000000490 -
The Journal of Comparative Neurology Dec 2022Anatomical tracing studies examining the vagal system can conflate details of sensory afferent and motor efferent neurons. Here, we used a serotype of adeno-associated...
Anatomical tracing studies examining the vagal system can conflate details of sensory afferent and motor efferent neurons. Here, we used a serotype of adeno-associated virus that transports retrogradely and exhibits selective tropism for vagal afferents, to map their soma location and central termination sites within the nucleus of the solitary tract (NTS). We examined the vagal sensory afferents innervating the trachea, duodenum, stomach, or heart, and in some animals, from two organs concurrently. We observed no obvious somatotopy in the somata distribution within the nodose ganglion. The central termination patterns of afferents from different organs within the NTS overlap substantially. Convergence of vagal afferent inputs from different organs onto single NTS neurons is observed. Abdominal and thoracic afferents terminate throughout the NTS, including in the rostral NTS, where the 7th cranial nerve inputs are known to synapse. To address whether the axonal labeling produced by viral transduction is so widespread because it fills axons traveling to their targets, and not just terminal fields, we labeled pre and postsynaptic elements of vagal afferents in the NTS . Vagal afferents form multiple putative synapses as they course through the NTS, with each vagal afferent neuron distributing sensory signals to multiple second-order NTS neurons. We observe little selectivity between vagal afferents from different visceral targets and NTS neurons with common neurochemical phenotypes, with afferents from different organs making close appositions with the same NTS neuron. We conclude that specific viscerosensory information is distributed widely within the NTS and that the coding of this input is probably determined by the intrinsic properties and projections of the second-order neuron.
Topics: Animals; Motor Neurons; Neurons, Afferent; Nodose Ganglion; Rats; Solitary Nucleus; Vagus Nerve
PubMed: 35988033
DOI: 10.1002/cne.25398