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The roles of Aβ low-threshold mechanoreceptors (LTMRs) in transmitting mechanical hyperalgesia and in alleviating chronic pain have been of great interest but remain contentious. Here we utilized intersectional genetic tools, optogenetics, and high-speed imaging to specifically examine functions of Split Cre labeled mouse Aβ-LTMRs in this regard. Genetic ablation of Split Cre - Aβ-LTMRs increased mechanical nociception but not thermosensation in both acute and chronic inflammatory pain conditions, indicating a modality-specific role in gating mechanical nociception. Local optogenetic activation of Split Cre -Aβ-LTMRs triggered nociception after tissue inflammation, whereas their broad activation at the dorsal column still alleviated mechanical hypersensitivity of chronic inflammation. Taking all data into consideration, we propose a model, in which Aβ-LTMRs play distinctive local and global roles in transmitting or alleviating mechanical hyperalgesia of chronic pain, respectively. Our model suggests a strategy of global activation plus local inhibition of Aβ-LTMRs for treating mechanical hyperalgesia. The mechanism underlying mechanical hyperalgesia is not fully understood. Here authors show opposing roles of tactile afferents in mechanical nociception using mouse pain models.

Vincristine is an important chemotherapy drug to treat various types of cancer, but it induces peripheral neuropathy, leading to numbness and mechanical allodynia in the hands and feet of patients. The peripheral neuropathy is a dose-limiting toxicity of vincristine chemotherapy. How vincristine treatment causes numbness and mechanical allodynia remains incompletely understood. In the present study, we utilized Nav1.8-ChR2 transgenic mice in which Nav1.8-ChR2-positive and Nav1.8-ChR2-negative mechanoreceptors could be characterized using the opto-electrophysiological method. Nav1.8-ChR2-negative Aβ- and Aδ-fiber mechanoreceptors are primarily low-threshold mechanoreceptors (LTMRs). On the other hand, Nav1.8-ChR2-positive Aβ- and Aδ-fiber mechanoreceptors are mainly high-threshold mechanoreceptors (HTMRs). We have shown that the mechanical threshold of Nav1.8-ChR2-negative Aβ-fiber mechanoreceptors, but not Nav1.8-ChR2-negative Aδ-fiber mechanoreceptors, were increased significantly in the animals treated with vincristine. In contrast, the mechanical threshold of Nav1.8-ChR2-positive Aβ-fiber mechanoreceptors were significantly reduced following vincristine treatment. Vincristine treatment did not significantly affect the mechanical sensitivity of Nav1.8-ChR2-positive Aδ- and C-fiber mechanoreceptors. Vincristine treatment also did not affect the opto-sensitivity of Nav1.8-ChR2-positive Aβ-, Aδ-, and C-fiber mechanoreceptors. Our findings suggest that mechanical sensitivity is decreased in Aβ-fiber LTMRs and increased in Aβ-HTMRs following vincristine treatment, providing insights into vincristine-induced numbness and mechanical allodynia.

Nav1.8-positive afferent fibers are mostly nociceptors playing a role in mediating thermal and mechanical pain, but mechanoreceptors within these afferents have not been fully investigated. In this study, we generated mice expressing channel rhodopsin 2 (ChR2) in Nav1.8-positive afferents (Nav1.8 ChR2 ), which showed avoidance responses to mechanical stimulation and nocifensive responses to blue light stimulation applied to hindpaws. Using ex vivo hindpaw skin-tibial nerve preparations made from these mice, we characterized properties of mechanoreceptors on Nav1.8 ChR2 -positive and Nav1.8 ChR2 -negative afferent fibers that innervate the hindpaw glabrous skin. Of all Aβ-fiber mechanoreceptors, small portion was Nav1.8 ChR2 -positive. Of all Aδ-fiber mechanoreceptors, more than half was Nav1.8 ChR2 -positive. Of all C-fiber mechanoreceptors, almost all were Nav1.8 ChR2 -positive. Most Nav1.8 ChR2 -positive Aβ-, Aδ-, and C-fiber mechanoreceptors displayed slowly adapting (SA) impulses in response to sustained mechanical stimulation, and their mechanical thresholds were high in the range of high threshold mechanoreceptors (HTMRs). In contrast, sustained mechanical stimulation applied to Nav1.8 ChR2 -negative Aβ- and Aδ-fiber mechanoreceptors evoked both SA and rapidly adapting (RA) impulses, and their mechanical thresholds were in the range of low threshold mechanoreceptors (LTMRs). Our results provide direct evidence that in the mouse glabrous skin, most Nav1.8 ChR2 -negative Aβ-, Aδ-fiber mechanoreceptors are LTMRs involving in the sense of touch, whereas Nav1.8 ChR2 -positive Aβ-, Aδ-, and C-fiber mechanoreceptors are mainly HTMRs involving in mechanical pain.

Sensing cooling temperatures is achieved by primary afferent endings located in the skin and is essential for the survival of animals. TRPM8 channels, primarily expressed in cutaneous C-fibers, have been established as receptors for cooling temperatures, sensing innocuous cooling from the normal skin temperature near 30°C to 17°C, and noxious cooling below 17°C. A cooling sensation is also felt when skin temperatures are first elevated to higher temperatures, for example, noxious heat, and then cool down to the normal skin temperature near 30°C. It is currently not clear what types of cutaneous afferent fibers are involved in sensing the cooling from a high heat to the normal skin temperature. Cutaneous Aβ-fiber low-threshold mechanoreceptors (Aβ-LTMRs) are primarily involved in the sense of touch and are thought to play no role in cooling sensation. In the present study, we conducted the opto-electrophysiological recordings from the skin-nerve preparations made from the hindpaw glabrous skin of Nav1.8-ChR2 transgenic mice. In these transgenic mice, Nav1.8-ChR2-negative Aβ-fiber mechanoreceptors are primarily Aβ-LTMRs, and Nav1.8-ChR2-positive Aβ-fiber mechanoreceptors are mainly high-threshold mechanoreceptors (Aβ-HTMRs). Neither Aβ-LTMRs nor Aβ-HTMRs responded to temperature rising from 30°C to the noxious heat of 43°C. However, a subpopulation of Aβ-LTMRs, but not Aβ-HTMRs, robustly fires action potential impulses in response to the temperature drop from 43°C to 30°C. This finding reveals for the first time that a subpopulation of Aβ-LTMRs senses the cooling for a temperature drop from noxious heat to normal skin temperature.

Nav1.8-positive afferent fibers are mostly nociceptors playing a role in mediating thermal and mechanical pain, but mechanoreceptors within these afferents have not been fully investigated. In this study, we generated mice expressing channel rhodopsin 2 (ChR2) in Nav1.8-positive afferents (Nav1.8 ), which showed avoidance responses to mechanical stimulation and nocifensive responses to blue light stimulation applied to hindpaws. Using ex vivo hindpaw skin-tibial nerve preparations made from these mice, we characterized properties of mechanoreceptors on Nav1.8 -positive and Nav1.8 -negative afferent fibers that innervate the hindpaw glabrous skin. Of all Aβ-fiber mechanoreceptors, small portion was Nav1.8 -positive. Of all Aδ-fiber mechanoreceptors, more than half was Nav1.8 -positive. Of all C-fiber mechanoreceptors, almost all were Nav1.8 -positive. Most Nav1.8 -positive Aβ-, Aδ-, and C-fiber mechanoreceptors displayed slowly adapting (SA) impulses in response to sustained mechanical stimulation, and their mechanical thresholds were high in the range of high threshold mechanoreceptors (HTMRs). In contrast, sustained mechanical stimulation applied to Nav1.8 -negative Aβ- and Aδ-fiber mechanoreceptors evoked both SA and rapidly adapting (RA) impulses, and their mechanical thresholds were in the range of low threshold mechanoreceptors (LTMRs). Our results provide direct evidence that in the mouse glabrous skin, most Nav1.8 -negative Aβ-, Aδ-fiber mechanoreceptors are LTMRs involving in the sense of touch, whereas Nav1.8 -positive Aβ-, Aδ-, and C-fiber mechanoreceptors are mainly HTMRs involving in mechanical pain.

The roles of Aβ low-threshold mechanoreceptors (LTMRs) in transmitting mechanical hyperalgesia and in alleviating chronic pain have been of great interest but remain contentious. Here we utilized intersectional genetic tools, optogenetics, and high-speed imaging to specifically examine functions of Split Cre labeled Aβ-LTMRs in this regard. Genetic ablation of Split Cre -Aβ-LTMRs increased mechanical pain but not thermosensation in both acute and chronic inflammatory pain conditions, indicating their modality-specific role in gating mechanical pain transmission. Local optogenetic activation of Split Cre -Aβ-LTMRs triggered nociception after tissue inflammation, whereas their broad activation at the dorsal column still alleviated mechanical hypersensitivity of chronic inflammation. Taking all data into consideration, we propose a new model, in which Aβ-LTMRs play distinctive local and global roles in transmitting and alleviating mechanical hyperalgesia of chronic pain, respectively. Our model suggests a new strategy of global activation plus local inhibition of Aβ-LTMRs for treating mechanical hyperalgesia.The roles of Aβ low-threshold mechanoreceptors (LTMRs) in transmitting mechanical hyperalgesia and in alleviating chronic pain have been of great interest but remain contentious. Here we utilized intersectional genetic tools, optogenetics, and high-speed imaging to specifically examine functions of Split Cre labeled Aβ-LTMRs in this regard. Genetic ablation of Split Cre -Aβ-LTMRs increased mechanical pain but not thermosensation in both acute and chronic inflammatory pain conditions, indicating their modality-specific role in gating mechanical pain transmission. Local optogenetic activation of Split Cre -Aβ-LTMRs triggered nociception after tissue inflammation, whereas their broad activation at the dorsal column still alleviated mechanical hypersensitivity of chronic inflammation. Taking all data into consideration, we propose a new model, in which Aβ-LTMRs play distinctive local and global roles in transmitting and alleviating mechanical hyperalgesia of chronic pain, respectively. Our model suggests a new strategy of global activation plus local inhibition of Aβ-LTMRs for treating mechanical hyperalgesia.

We recently used Nav1.8-ChR2 mice in which Nav1.8-expressing afferents were optogenetically tagged to classify mechanosensitive afferents into Nav1.8-ChR2-positive and Nav1.8-ChR2-negative mechanoreceptors. We found that the former were mainly high threshold mechanoreceptors (HTMRs), while the latter were low threshold mechanoreceptors (LTMRs). In the present study, we further investigated whether the properties of these mechanoreceptors were altered following tissue inflammation. Nav1.8-ChR2 mice received a subcutaneous injection of saline or Complete Freund’s Adjuvant (CFA) in the hindpaws. Using the hind paw glabrous skin-tibial nerve preparation and the pressure-clamped single-fiber recordings, we found that CFA-induced hind paw inflammation lowered the mechanical threshold of many Nav1.8-ChR2-positive Aβ-fiber mechanoreceptors but heightened the mechanical threshold of many Nav1.8-ChR2-negative Aβ-fiber mechanoreceptors. Spontaneous action potential impulses were not observed in Nav1.8-ChR2-positive Aβ-fiber mechanoreceptors but occurred in Nav1.8-ChR2-negative Aβ-fiber mechanoreceptors with a lower mechanical threshold in the saline goup, and a higher mechanical threshold in the CFA group. No significant change was observed in the mechanical sensitivity of Nav1.8-ChR2-positive and Nav1.8-ChR2-negative Aδ-fiber mechanoreceptors and Nav1.8-ChR2-positive C-fiber mechanoreceptors following hind paw inflammation. Collectively, inflammation significantly altered the functional properties of both Nav1.8-ChR2-positive and Nav1.8-ChR2-negative Aβ-fiber mechanoreceptors, which may contribute to mechanical allodynia during inflammation.

Different neural contributions to motor learning might be involved when different error sizes of perturbation are introduced. Although the corticospinal drive contributes to abrupt gait adaptation processes, no studies have investigated whether cortical involvement during gait differs between perturbations applied abruptly and gradually. This study aimed to investigate the differences in oscillatory common neural drives to ankle muscles during gait between abrupt and gradual adaptations, using coherence analyses of paired surface electromyographic (EMG) recordings. Sixteen healthy young adults performed the treadmill gait with perturbation resisting forward movement of the swing leg for 10 min under two conditions: abrupt (a large perturbation from the beginning of the adaptation period) and gradual (a series of small perturbations that gradually increased). Swing phase duration and step length showed significantly greater asymmetry in the abrupt condition than in the gradual condition in the early adaptation period (p < 0.01), despite no significant differences in gait symmetries between the two conditions in the early post-adaptation period. EMG–EMG coherence calculated from the tibialis anterior muscle in the beta band (15–35 Hz) on the perturbed side was significantly higher in the early adaptation period in the abrupt condition (p < 0.05), but not in the gradual condition. There were significant relationships between changes in temporal gait symmetry and EMG–EMG coherence during the different adaptation periods between the two conditions (p < 0.05). The abrupt large perturbation seems to require a cortical involvement, whereas a gradual adaptation with small gait asymmetry requires no modulation of cortical involvement.

Proopiomelanocortin (POMC), a precursor with multiple bioactive peptides, is expressed by keratinocytes and regulates various pathophysiological responses, including pruritus associated with atopic dermatitis (AD). In the skin, POMC is extracellularly processed into peptides like α-melanocyte-stimulating hormone (α-MSH); however, the processing and functional role of β-endorphin (β-END) remain unclear. Here, we investigated the molecular form and biological activity of β-END generated in the context of AD. We analyzed skin extracts from AD lesions using immunoprecipitation and MALDI-TOF MS, identifying β-END(1–9), a truncated peptide, as a major derivative. To explore opioid receptor expression in fetal rat skin keratinocytes (FRSK) using RT-PCR. Delta opioid receptor (DOR) was detected in FRSK cells. Functional assays showed β-END(1–9) reduced cAMP levels via DOR signaling, acting as a full agonist with about half the potency of methionine-enkephalin. To further explore its biological effects, DNA microarray analysis was conducted on β-END(1–9)-treated FRSK cells. Differential gene expression analysis revealed modulation of genes involved in collagen maturation and hyaluronic acid synthesis, suggesting roles in skin barrier function. Collectively, these findings suggest that POMC is processed into β-END(1–9) in atopic-inflammatory skin, and this peptide acts via DOR expressed in keratinocytes to promote the expression of skin-protective factors.