Biology subjects

Nagi, S. S.

Publications and source records attributed to Nagi, S. S..

12 recordsLinked to original sources

bioRxiv2026

Rapid peripheral reprogramming of myelinated afferents drives human hyperalgesia

A small burn can render a large area of skin painfully tender. This widespread hyperalgesia protects injured tissue and is typically attributed to altered spinal cord mechanisms. Whether peripheral sensory afferents directly interact to contribute to hyperalgesia remains unclear. Using single-unit microneurography, we recorded cutaneous afferents before and after inducing localized TRPV1-mediated inflammatory flare. This triggered minutes-scale reweighting of transcriptomically defined TRPV1- afferents, with divergent effects among myelinated (A{beta}-range) classes: tactile receptors showed reduced responsiveness, whereas mechano-nociceptors underwent sensitization. These changes paralleled diminished tactile sensitivity and intensified mechanical pain. Recruitment of mechanically silent branches in A{beta}-range mechano-nociceptors produced wide-field amplification of peripheral nociceptive signaling beyond the inflamed site. These findings suggest that rapid peripheral crosstalk from TRPV1+ afferents reprograms TRPV1- A{beta}-afferents and drives human hyperalgesia.

neuroscience↗

bioRxiv2025

Central role for fast nociceptors in mechanical nocifensive behavior and sensitization

Nociceptors, primary afferent nerve fibers that signal noxious stimuli, are broadly divided into slowly conducting unmyelinated C fibers and fast-conducting myelinated A fibers. Whereas C-nociceptors have been extensively studied, considerably less is known about the function of A-nociceptors. To address this gap, we developed an intersectional genetic approach for robust and selective interrogation and manipulation of mechanically responsive A-nociceptors (A-MNs) in mice. Optogenetic A-MN stimulation induced rapid and precise withdrawal reflexes as well as place aversion and facial expression changes consistent with pain affect, while inhibition strongly impaired mechanical nociceptive withdrawal reflexes, demonstrating that A-MNs are necessary and sufficient for rapid avoidance of noxious mechanical stimuli. Prolonged A-MN activation induced mechanical allodynia and central sensitization. In a rare individual lacking thickly myelinated A{beta} fibers, mechanical withdrawal reflexes were completely absent, and pain perception reduced. Together, these findings identify fast-conducting mechano-nociceptors as essential drivers of nocifensive behaviors in mice and humans.

neuroscience↗

bioRxiv2025

A Reference Atlas of the Human Dorsal Root Ganglion

Somatosensory perception largely emerges from diverse peripheral sensory neurons whose cell bodies reside in dorsal root ganglia (DRG). Damage or dysfunction of DRG neurons is a major cause of chronic pain and sensory loss. In mice, deep single-cell transcriptomic profiling and genetically defined models have offered important clues into DRG function, but in humans, the cellular and molecular landscape of DRG neurons remains less understood. Here, we constructed a reference cell atlas of the human DRG by profiling transcriptomes of cells and nuclei from 126 donors sampled across cervical, thoracic, and lumbar DRGs. This atlas resolves 22 neuronal subtypes, including known and previously unrecognized subtypes linked to nociception, mechanosensation, thermosensation, and proprioception, as well as 10 types of non-neuronal cells. Cross-species integration, spatial transcriptomics, and microneurography enabled cell-type-specific comparisons of soma size and conduction velocity between species. Human DRG somata are larger across all cell types than their mouse counterparts, and the conduction velocities of human hair follicle innervating A-fibers are faster than in mice, suggesting a functional shift in rapid mechanical detection in humans. This integrated human DRG reference cell atlas provides a resource for exploring new molecular and physiological features of human DRG, which could help identify new strategies for treating chronic pain and other diseases of the peripheral nervous system.

neuroscience↗

bioRxiv2025

A fast nociceptive subsystem mediating rapid reflexive behavior but not affective pain

Spinal nociceptive withdrawal reflexes are widely believed to rely on unmyelinated and thinly myelinated nociceptive fibers that also signal affective and motivational aspects of pain. Here we discover a population of myelinated mechanoreceptive nociceptor that forms free nerve endings as well as circumferential endings around hair follicles, and exclusively terminate in the deep spinal dorsal horn. Optogenetic activation of these fibers triggers rapid withdrawal reflexes that are precise and selective for the targeted limb, while silencing increases the threshold of mechanical nociceptive withdrawal reflexes. By contrast, optogenetic stimulation of the fibers is not associated with place aversion nor with changes in facial expression. Thus, we conclude that this nerve fiber population is uniquely positioned to rapidly respond to mechanical threats via selective withdrawal of the targeted body part, whereas other fast and slow nociceptive pathways are required for affective-motivational aspects of pain.

neuroscience↗

bioRxiv2023

PIEZO2-dependent rapid pain system in humans and mice.

The PIEZO2 ion channel is critical for transducing light touch into neural signals but is not considered necessary for transducing acute pain in humans. Here, we discovered an exception - a form of mechanical pain evoked by hair pulling. Based on observations in a rare group of individuals with PIEZO2 deficiency syndrome, we demonstrated that hair-pull pain is dependent on PIEZO2 transduction. Studies in control participants showed that hair-pull pain triggered a distinct nocifensive response, including a nociceptive reflex. Observations in rare A{beta} deafferented individuals and nerve conduction block studies in control participants revealed that hair-pull pain perception is dependent on A{beta} input. Single-unit axonal recordings revealed that a class of cooling-responsive myelinated nociceptors in human skin is selectively tuned to painful hair-pull stimuli. Further, we pharmacologically mapped these nociceptors to a specific transcriptomic class. Finally, using functional imaging in mice, we demonstrated that in a homologous nociceptor, Piezo2 is necessary for high-sensitivity, robust activation by hair-pull stimuli. Together, we have demonstrated that hair-pulling evokes a distinct type of pain with conserved behavioral, neural, and molecular features across humans and mice.

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bioRxiv2023

Human foot outperforms the hand in mechanical pain discrimination

Tactile discrimination has been extensively studied, but mechanical pain discrimination remains poorly characterised. Here, we measured the capacity for mechanical pain discrimination using a twoalternative forced choice paradigm, with force-calibrated indentation stimuli (Semmes-Weinstein monofilaments) applied to the hand and foot dorsa of healthy human volunteers. In order to characterise the relationship between peripheral neural and perceptual processes, we recorded singleunit activity from myelinated (A) and unmyelinated (C) mechanosensitive nociceptors in the skin using microneurography. At the perceptual level, we found that the foot was better at discriminating noxious forces than the hand, which stands in contrast to that for innocuous force discrimination, where the hand performed better than the foot. This observation of superior mechanical pain discrimination on the foot compared to the hand could not be explained by the responsiveness of single primary afferents. We found no significant difference in the discrimination performance of either the myelinated or unmyelinated class of nociceptors between skin regions. This suggests the possibility that other factors such as skin biophysics, receptor density or central mechanisms may underlie these regional differences. Significance StatementStandard clinical practice for diagnosing neuropathies and pain disorders often involves assessing thresholds for pain or light touch. The ability to discriminate between different stimulus intensities is a separate but equally important sensory function, however this is not typically assessed in the clinic, and so studying this may provide insights into pain signalling mechanisms. Here, we investigated the ability of healthy individuals to discriminate between different forces of painful indentation. We found that the foot was better at this than the hand. This difference could not be explained by the firing activity of peripheral nociceptors (pain-signalling neurons) between the two regions, suggesting that mechanisms other than nociceptor sensitivity are involved.

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bioRxiv2023

The role of cutaneous Aβ fibers in human nocifensive functions: Nerve block study on painful withdrawal reflex responses

The nociceptive withdrawal reflex (NWR) is a protective limb withdrawal response triggered by painful stimuli, used to assess spinal nociceptive excitability. Conventionally, the NWR is understood as having two reflex responses: a short-latency A{beta}-mediated response, considered tactile, and a longer-latency A{delta}-mediated response, considered nociceptive. However, nociceptors with conduction velocities similar to A{beta} tactile afferents have been identified in human skin. In this study, we investigated the effect of a preferential conduction block of A{beta} fibers on pain perception and NWR signaling evoked by intradermal electrical stimulation in healthy participants. We recorded a total of 198 NWR responses in the intact condition, and no dual reflex responses occurred within our latency bandwidth (50-150 ms). The current intensity required to evoke the NWR was magnitude higher than the perceptual pain threshold, indicating that NWR did not occur before pain was felt. In the block condition, when the A{beta}-mediated tuning fork sensation was lost while A{delta}-mediated nonpainful cooling was still detectable (albeit reduced), we observed that the reflex was abolished. Further, short-latency electrical pain intensity at pre-block thresholds was greatly reduced, with any residual pain sensation having a longer latency. Although electrical pain was unaffected at suprathreshold current intensities, the reflex could not be evoked despite a two-fold increase in the pre-block current intensity and a five-fold increase in the pre-block pulse duration. These observations lend support to the possible involvement of A{beta}-fiber inputs in pain and reflex signaling.

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bioRxiv2023

Mechanoreceptive Aβ primary afferents discriminate naturalistic social touch inputs at a functionally relevant time scale

Interpersonal touch is an important part of our social and emotional interactions. How these physical, skin-to-skin touch expressions are processed in the peripheral nervous system is not well understood. From single-unit microneurography recordings in humans, we evaluated the capacity of six subtypes of cutaneous afferents to differentiate perceptually distinct social touch expressions. By leveraging conventional statistical analyses and classification analyses using convolutional neural networks and support vector machines, we found that single units of multiple A{beta} subtypes, especially slowly adapting type II (SA-II) and fast adapting hair follicle afferents (HFA), can reliably differentiate the skin contact of those expressions at accuracies similar to those perceptually. Rapidly adapting field (Field) afferents exhibit lower accuracies, whereas C-tactile (CT), fast adapting Pacinian corpuscles (FA-II), and muscle spindle (MS) afferents can barely differentiate the expressions, despite responding to the stimuli. We then identified the most informative firing patterns of SA-II and HFA afferents spike trains, which indicate that an average duration of 3-4 s of firing provides sufficient discriminative information. Those two subtypes also exhibit robust tolerance to shifts in spike-timing of up to 10 ms. A greater shift in spike-timing, however, drastically compromises an afferents discrimination capacity, and can change a firing patterns envelope to resemble that of another expression. Altogether, the findings indicate that SA-II and HFA afferents differentiate the skin contact of social touch at time scales relevant for such interactions, which is 1-2 orders of magnitude longer than those relevant for discriminating non-social touch inputs.

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bioRxiv2023

Single-Soma Deep RNA sequencing of Human DRG Neurons Reveals Novel Molecular and Cellular Mechanisms Underlying Somatosensation

The versatility of somatosensation arises from heterogeneous dorsal root ganglion (DRG) neurons. However, soma transcriptomes of individual human DRG (hDRG) neurons - critical information to decipher their functions - are lacking due to technical difficulties. Here, we developed a novel approach to isolate individual hDRG neuron somas for deep RNA sequencing (RNA-seq). On average, >9,000 unique genes per neuron were detected, and 16 neuronal types were identified. Cross-species analyses revealed remarkable divergence among pain-sensing neurons and the existence of human-specific nociceptor types. Our deep RNA-seq dataset was especially powerful for providing insight into the molecular mechanisms underlying human somatosensation and identifying high potential novel drug targets. Our dataset also guided the selection of molecular markers to visualize different types of human afferents and the discovery of novel functional properties using single-cell in vivo electrophysiological recordings. In summary, by employing a novel soma sequencing method, we generated an unprecedented hDRG neuron atlas, providing new insights into human somatosensation, establishing a critical foundation for translational work, and clarifying human species-specific properties.

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bioRxiv2022

Investigations into an overlooked early component of painful nociceptive withdrawal reflex responses in humans

IntroductionThe role of pain as a warning system necessitates a rapid transmission of information from the periphery for the execution of appropriate motor responses. The nociceptive withdrawal reflex (NWR) is a physiological response to protect the limb from a painful stimulus and is often considered an objective measure of spinal nociceptive excitability. The NWR is commonly defined by its latency in the presumed Ad-fiber range consistent with the canonical view that "fast pain" is signaled by Ad nociceptors. We recently demonstrated that human skin is equipped with ultrafast (A{beta} range) nociceptors. Here, we investigated the short-latency component of the reflex and explored the relationship between reflex latency and pain perception. MethodsWe revisited our earlier work on NWR measurements in which, following convention, only those reflex responses were selected that were in the presumed Ad range (taken to be latencies [≥]90 ms in that study). In our current analysis, we expanded the time window to search for shorter latency responses and compared those with pain ratings. ResultsIn both cohorts, we found an abundance of recordings with short-latency reflex responses. In nearly 90% of successful recordings, only single reflex responses (not dual) were seen which allowed us to compare pain ratings to reflex latencies. We found that shorter latency reflexes were just as painful as those in the conventional latency range. DiscussionWe found a preponderance of short-latency painful reflex responses. Based on this finding, we suggest that short-latency responses must be considered in future studies. We predict these might be signaled by the ultrafast nociceptors, warranting further investigation.

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bioRxiv2019

Tactile sensory channels over-ruled by frequency decoding system that utilizes spike pattern regardless of receptor type

The established view is that vibrotactile stimuli evoke two qualitatively distinctive cutaneous sensations, flutter (frequencies < 60 Hz) and vibratory hum (frequencies > 60 Hz), subserved by two distinct receptor types (Meissners and Pacinian corpuscle, respectively) which may engage different neural processing pathways or channels and fulfill quite different biological roles. In psychological and physiological literature those two systems have been labelled as Pacinian and non-Pacinian channels. However, we present evidence that low-frequency spike trains in Pacinian afferents can readily induce a vibratory percept with the same low frequency attributes as sinusoidal stimuli of the same frequency thus demonstrating a universal frequency decoding system. We achieved this using brief low-amplitude pulsatile mechanical stimuli to selectively activate Pacinian afferents. This indicates that spiking pattern, regardless of receptor type, determines vibrotactile frequency perception. This mechanism may underlie the constancy of vibrotactile frequency perception across different skin regions innervated by distinct afferent types.

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bioRxiv2019

Regionally diffuse muscle pain-hypersensitivity in humans during acute muscle pain

BackgroundWe have previously shown that an intramuscular infusion of 5% hypertonic saline (HS) produces a painful response to normally innocuous stimuli applied to overlying and adjacent skin regions. In the current study, we explored whether a similar interaction could be observed between adjacent, contralateral and remote muscles. Indeed, widespread muscle pain-hypersensitivity is a hallmark of chronic pain conditions such as fibromyalgia.\n\nMethods5% HS was infused into the flexor carpi ulnaris (FCU) muscle to develop a stable baseline pain (n=30). In separate experiments, each of the three test locations (n=10 per site), the adjacent abductor digiti minimi (ADM), contralateral FCU and contralateral tibialis anterior (TA) (part 1-3, respectively), 50L of 0.9% normal saline (NS) was infused (in triplicate) prior to, during and following HS-induced muscle pain.\n\nResultsUnder control conditions (no background pain), the infusion of NS was imperceptible by all subjects. In the presence of HS-induced background pain (FCU), in part 1 the NS co-infusion into ADM increased overall pain by 17%. This was replicated in the contralateral FCU (part 2) with a 12% pain increase, and in the TA (part 3) with a 15% pain increase in response to the NS co-infusions. Notably, over 80% of subjects perceived the NS-induced increase in pain at the HS-infusion location (FCU) rather than the NS-infusion location (adjacent, contralateral and remote).\n\nConclusionsIntramuscular infusion of HS results in pain-hypersensitivity to sub-perceptual stimulation of muscle afferents in a somatotopically unrestricted manner, indicating the involvement of a central (likely supra-spinal) mechanism.\n\nSignificanceThis work provides evidence for a regionally diffuse type of pain hypersensitivity, manifesting as a painful response to normally sub-perceptual stimulation in the context of acute experimentally induced muscle pain. This phenomenon may provide parallels to clinically relevant painful conditions and neuropathies.

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