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Trends in Neurosciences Mar 2023Chronic pain caused by injury or disease of the nervous system (neuropathic pain) has been linked to persistent electrical hyperactivity of the sensory neurons... (Review)
Review
Chronic pain caused by injury or disease of the nervous system (neuropathic pain) has been linked to persistent electrical hyperactivity of the sensory neurons (nociceptors) specialized to detect damaging stimuli and/or inflammation. This pain and hyperactivity are considered maladaptive because both can persist long after injured tissues have healed and inflammation has resolved. While the assumption of maladaptiveness is appropriate in many diseases, accumulating evidence from diverse species, including humans, challenges the assumption that neuropathic pain and persistent nociceptor hyperactivity are always maladaptive. We review studies indicating that persistent nociceptor hyperactivity has undergone evolutionary selection in widespread, albeit selected, animal groups as a physiological response that can increase survival long after bodily injury, using both highly conserved and divergent underlying mechanisms.
Topics: Humans; Animals; Nociceptors; Sensory Receptor Cells; Neuralgia; Adaptation, Physiological
PubMed: 36610893
DOI: 10.1016/j.tins.2022.12.007 -
Advances in Nutrition (Bethesda, Md.) Jul 2014It is well established that food intake behavior and energy balance are regulated by crosstalk between peripheral organ systems and the central nervous system (CNS), for... (Review)
Review
It is well established that food intake behavior and energy balance are regulated by crosstalk between peripheral organ systems and the central nervous system (CNS), for instance, through the actions of peripherally derived leptin on hindbrain and hypothalamic loci. Diet- or obesity-associated disturbances in metabolic and hormonal signals to the CNS can perturb metabolic homeostasis bodywide. Although interrelations between metabolic status and diet with CNS biology are well characterized, afferent networks (those sending information to the CNS from the periphery) have received far less attention. It is increasingly appreciated that afferent neurons in adipose tissue, the intestines, liver, and other tissues are important controllers of energy balance and feeding behavior. Disruption in their signaling may have consequences for cardiovascular, pancreatic, adipose, and immune function. This review discusses the diverse ways that afferent neurons participate in metabolic homeostasis and highlights how changes in their function associate with dysmetabolic states, such as obesity and insulin resistance.
Topics: Animals; Diet; Energy Intake; Energy Metabolism; Feeding Behavior; Homeostasis; Humans; Insulin Resistance; Metabolic Diseases; Neurons, Afferent; Obesity
PubMed: 25022988
DOI: 10.3945/an.113.005439 -
Journal of Anatomy Nov 2022Primary sensory neurons are a heterogeneous population of cells able to respond to both innocuous and noxious stimuli. Like most neurons they are highly... (Review)
Review
Primary sensory neurons are a heterogeneous population of cells able to respond to both innocuous and noxious stimuli. Like most neurons they are highly compartmentalised, allowing them to detect, convey and transfer sensory information. These compartments include specialised sensory endings in the skin, the nodes of Ranvier in myelinated axons, the cell soma and their central terminals in the spinal cord. In this review, we will highlight the importance of these compartments to primary afferent function, describe how these structures are compromised following nerve damage and how this relates to neuropathic pain.
Topics: Axons; Ganglia, Spinal; Neurons; Neurons, Afferent; Spinal Cord
PubMed: 34528255
DOI: 10.1111/joa.13544 -
American Journal of Physiology.... Sep 2019The distal colon is innervated by the splanchnic and pelvic nerves, which relay into the thoracolumbar and lumbosacral spinal cord, respectively. Although the peripheral...
The distal colon is innervated by the splanchnic and pelvic nerves, which relay into the thoracolumbar and lumbosacral spinal cord, respectively. Although the peripheral properties of the colonic afferent nerves within these pathways are well studied, their input into the spinal cord remain ill defined. The use of dual retrograde tracing from the colon wall and lumen, in conjunction with in vivo colorectal distension and spinal neuronal activation labeling with phosphorylated MAPK ERK 1/2 (pERK), allowed us to identify thoracolumbar and lumbosacral spinal cord circuits processing colonic afferent input. In the thoracolumbar dorsal horn, central projections of colonic afferents were primarily labeled from the wall of the colon and localized in laminae I and V. In contrast, lumbosacral projections were identified from both lumen and wall tracing, present within various dorsal horn laminae, collateral tracts, and the dorsal gray commissure. Nonnoxious in vivo colorectal distension evoked significant neuronal activation (pERK-immunoreactivity) within the lumbosacral dorsal horn but not in thoracolumbar regions. However, noxious in vivo colorectal distension evoked significant neuronal activation in both the thoracolumbar and lumbosacral dorsal horn, with the distribution of activated neurons correlating to the pattern of traced projections. Dorsal horn neurons activated by colorectal distension were identified as possible populations of projection neurons or excitatory and inhibitory interneurons based on their neurochemistry. Our findings demonstrate how colonic afferents in splanchnic and pelvic pathways differentially relay mechanosensory information into the spinal cord and contribute to the recruitment of spinal cord pathways processing non-noxious and noxious stimuli. In mice, retrograde tracing from the colon wall and lumen was used to identify unique populations of afferent neurons and central projections within the spinal cord dorsal horn. We show that there are pronounced differences between the spinal cord regions in the distribution pattern of colonic afferent central projections and the pattern of dorsal horn neuron activation evoked by colorectal distension. These findings demonstrate how colonic afferent input influences spinal processing of colonic mechanosensation.
Topics: Afferent Pathways; Animals; Colon; Male; Mice, Inbred C57BL; Neurons, Afferent; Posterior Horn Cells; Spinal Cord
PubMed: 31188624
DOI: 10.1152/ajpgi.00013.2019 -
Journal of Neurophysiology Dec 2019Semicircular canal afferent neurons transmit information about head rotation to the brain. Mathematical models of how they do this have coevolved with concepts of how... (Review)
Review
Semicircular canal afferent neurons transmit information about head rotation to the brain. Mathematical models of how they do this have coevolved with concepts of how brains perceive the world. A 19th-century "camera" metaphor, in which sensory neurons project an image of the world captured by sense organs into the brain, gave way to a 20th-century view of sensory nerves as communication channels providing inputs to dynamical control systems. Now, in the 21st century, brains are being modeled as Bayesian observers who infer what is happening in the world given noisy, incomplete, and distorted sense data. The semicircular canals of the vestibular apparatus provide an experimentally accessible, low-dimensional system for developing and testing dynamical Bayesian generative models of sense data. In this review, we summarize advances in mathematical modeling of information transmission by semicircular canal afferent sensory neurons since the first such model was proposed nearly a century ago. Models of information transmission by vestibular afferent neurons may provide a foundation for developing realistic models of how brains perceive the world by inferring the causes of sense data.
Topics: Animals; Models, Biological; Neurons, Afferent; Semicircular Canals; Vestibule, Labyrinth
PubMed: 31693427
DOI: 10.1152/jn.00087.2019 -
The Journal of Physiology Feb 2023Tactile sensitivity is affected by age, as shown by the deterioration of spatial acuity assessed with the two-point discrimination task. This is assumed to be partly a...
Tactile sensitivity is affected by age, as shown by the deterioration of spatial acuity assessed with the two-point discrimination task. This is assumed to be partly a result of age-related changes of the peripheral somatosensory system. In particular, in the elderly, the density of mechanoreceptive afferents decreases with age and the skin tends to become drier, less elastic and less stiff. To assess to what degree mechanoreceptor density, skin hydration, elasticity and stiffness can account for the deterioration of tactile spatial sensitivity observed in the elderly, several approaches were combined, including psychophysics, measurements of finger properties, modelling and simulation of the response of first-order tactile neurons. Psychophysics confirmed that the Elderly group has lower tactile acuity than the Young group. Correlation and commonality analysis showed that age was the most important factor in explaining decreases in behavioural performance. Biological elasticity, hydration and finger pad area were also involved. These results were consistent with the outcome of simulations showing that lower afferent density and lower Young's modulus (i.e. lower stiffness) negatively affected the tactile encoding of stimulus information. Simulations revealed that these changes resulted in a lower build-up of task-relevant stimulus information. Importantly, the reduction in discrimination performance with age in the simulation was less than that observed in the psychophysical testing, indicating that there are additional peripheral as well as central factors responsible for age-related changes in tactile discrimination. KEY POINTS: Ageing effects on tactile perception involve the deterioration of spatial sensitivity, although the contribution of central and peripheral factors is not clear. We combined psychophysics, measurements of finger properties, modelling and simulation of the response of first-order tactile neurons to investigate to what extent skin elasticity, stiffness, hydration, finger pad area and afferent density can account for the lower spatial sensitivity observed in the elderly. Correlation and commonality analysis revealed that age was the most important factor to predict behavioural performance. Skin biological elasticity, hydration and finger pad area contributed to a lesser extent. The simulation of first-order tactile neuron responses indicated that reduction in afferent density plays a major role in the deterioration of tactile spatial acuity. Simulations also showed that lower skin stiffness and lower afferent density affect the build-up of stimulus information and the response of SA1 (i.e. type 1 slowly adapting fibres) and RA1 (i.e. type 1 rapidly adapting fibres) afferent fibres.
Topics: Humans; Aged; Skin; Touch; Touch Perception; Mechanoreceptors; Aging; Neurons, Afferent
PubMed: 36533658
DOI: 10.1113/JP283174 -
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 -
Experimental Brain Research Feb 2000This review considers whether the vestibular system includes separate populations of sensory axons innervating individual organs and giving rise to distinct central... (Review)
Review
This review considers whether the vestibular system includes separate populations of sensory axons innervating individual organs and giving rise to distinct central pathways. There is a variability in the discharge properties of afferents supplying each organ. Discharge regularity provides a marker for this diversity since fibers which differ in this way also differ in many other properties. Postspike recovery of excitability determines the discharge regularity of an afferent and its sensitivity to depolarizing inputs. Sensitivity is small in regularly discharging afferents and large in irregularly discharging afferents. The enhanced sensitivity of irregular fibers explains their larger responses to sensory inputs, to efferent activation, and to externally applied galvanic currents, but not their distinctive response dynamics. Morphophysiological studies show that regular and irregular afferents innervate overlapping regions of the vestibular nuclei. Intracellular recordings of EPSPs reveal that some secondary vestibular neurons receive a restricted input from regular or irregular afferents, but that most such neurons receive a mixed input from both kinds of afferents. Anodal currents delivered to the labyrinth can result in a selective and reversible silencing of irregular afferents. Such a functional ablation can provide estimates of the relative contributions of regular and irregular inputs to a central neuron's discharge. From such estimates it is concluded that secondary neurons need not resemble their afferent inputs in discharge regularity or response dynamics. Several suggestions are made as to the potentially distinctive contributions made by regular and irregular afferents: (1) Reflecting their response dynamics, regular and irregular afferents could compensate for differences in the dynamic loads of various reflexes or of individual reflexes in different parts of their frequency range; (2) The gating of irregular inputs to secondary VOR neurons could modify the operation of reflexes under varying behavioral circumstances; (3) Two-dimensional sensitivity can arise from the convergence onto secondary neurons of otolith inputs differing in their directional properties and response dynamics; (4) Calyx afferents have relatively low gains when compared with irregular dimorphic afferents. This could serve to expand the stimulus range over which the response of calyx afferents remains linear, while at the same time preserving the other features peculiar to irregular afferents. Among those features are phasic response dynamics and large responses to efferent activation; (5) Because of the convergence of several afferents onto each secondary neuron, information transmission to the latter depends on the gain of individual afferents, but not on their discharge regularity.
Topics: Animals; Auditory Pathways; Axons; Excitatory Postsynaptic Potentials; Humans; Neurons, Afferent; Reflex, Vestibulo-Ocular; Vestibule, Labyrinth
PubMed: 10706428
DOI: 10.1007/s002210050033 -
Molecular Pain 2023The role of Aβ-afferents in somatosensory function is often oversimplified as low threshold mechanoreceptors (LTMRs) with large omission of Aβ-afferent involvement in...
The role of Aβ-afferents in somatosensory function is often oversimplified as low threshold mechanoreceptors (LTMRs) with large omission of Aβ-afferent involvement in nociception. Recently, we have characterized Aβ-afferent neurons which have large diameter somas in the trigeminal ganglion (TG) and classified them into non-nociceptive and nociceptive-like TG afferent neurons based on their electrophysiological properties. Here, we extend our previous observations to further characterize electrophysiological properties of trigeminal Aβ-afferent neurons and investigate their mechanical and chemical sensitivity by patch-clamp recordings from large-diameter TG neurons in ex vivo TG preparations of adult male and female rats. Based on cluster analysis of electrophysiological properties, trigeminal Aβ-afferent neurons can be classified into five discrete types (type I, IIa, IIb, IIIa, and IIIb), which responded differentially to mechanical stimulation and sensory mediators including serotonin (5-HT), acetylcholine (ACh) and adenosine triphosphate (ATP). Notably, type I neuron action potential (AP) was small in amplitude, width was narrow in duration, and peak dV/dt repolarization was great with no deflection observed, whereas discretely graded differences were observed for type IIa, IIb, IIIa, and IIIb, as AP increased in amplitude, width broadened in duration, and peak dV/dt repolarization reduced with the emergence of increasing deflection. Type I, IIa, and IIb neurons were mostly mechanically sensitive, displaying robust and rapidly adapting mechanically activated current (I) in response to membrane displacement, while IIIa and IIIb, conversely, were almost all mechanically insensitive. Interestingly, mechanical insensitivity coincided with increased sensitivity to 5-HT and ACh. Together, type I, IIa and IIb display features of LTMR Aβ-afferent neurons while type IIIa and type IIIb show properties of nociceptive Aβ-afferent neurons.
Topics: Rats; Male; Female; Animals; Serotonin; Neurons, Afferent; Nociceptors; Mechanoreceptors; Neurons; Action Potentials; Trigeminal Ganglion
PubMed: 36526445
DOI: 10.1177/17448069221148958 -
Neuron Feb 2006Somatosensory stimuli are encoded by molecularly and anatomically diverse classes of dorsal root ganglia (DRG) neurons. In this issue of Neuron, three papers demonstrate... (Review)
Review
Somatosensory stimuli are encoded by molecularly and anatomically diverse classes of dorsal root ganglia (DRG) neurons. In this issue of Neuron, three papers demonstrate that the Runx transcription factors, Runx1 and Runx3, respectively regulate the molecular identities and spinal terminations of TrkA+ nociceptive neurons and TrkC+ proprioceptive neurons. These findings emphasize the importance of intrinsic genetic programs in generating the diversity of DRG neurons and specifying the circuits into which they incorporate.
Topics: Animals; Cell Differentiation; Core Binding Factor alpha Subunits; Neurons, Afferent; Receptor, trkA
PubMed: 16446135
DOI: 10.1016/j.neuron.2006.01.013