Dermal macrophages control tactile perception under physiological conditions via NGF signaling.

We demonstrated previously that sorting nexin 25 (SNX25) in nerve-associated macrophages plays critical roles in pain sensation by regulating tissue NGF content under both physiological and neuropathic conditions. In the present study, we apply the SNX25-NGF paradigm to tactile perception by showing that Snx25 mice or macrophage-specific Snx25 conditional knock-out (mcKO) mice had weaker responses to tactile stimuli in normal conditions. Snx25 mcKO mice responded poorly to transcutaneous electrical stimuli at a frequency of 5 Hz (C fiber responses), but normally to stimuli at a frequency of 250 Hz (Aδ fiber responses) or of 2000 Hz (Aβ fiber responses).

Anterior cingulate cross-hemispheric inhibition via the claustrum resolves painful sensory conflict.

The anterior cingulate cortex (ACC) responds to noxious and innocuous sensory inputs, and integrates them to coordinate appropriate behavioral reactions. However, the role of the projections of ACC neurons to subcortical areas and their influence on sensory processing are not fully investigated. Here, we identified that ACC neurons projecting to the contralateral claustrum (ACC) preferentially respond to contralateral mechanical sensory stimulation.

Effects of inflammation on the properties of Nav1.8-ChR2-positive and Nav1.8-ChR2-negative afferent mechanoreceptors in the hindpaw glabrous skin of mice.

We recently used Nav1.8-ChR2 mice in which Nav1.8-expressing afferents were optogenetically tagged to classify mechanosensitive afferents into Nav1.

ASICs mediate fast excitatory synaptic transmission for tactile discrimination.

Tactile discrimination, the ability to differentiate objects' physical properties such as texture, shape, and edges, is essential for environmental exploration, social interaction, and early childhood development. This ability heavily relies on Merkel cell-neurite complexes (MNCs), the tactile end-organs enriched in the fingertips of humans and the whisker hair follicles of non-primate mammals. Although recent studies have advanced our knowledge on mechanical transduction in MNCs, it remains unknown how tactile signals are encoded at MNCs.

Electrical stimulation mitigates muscle degradation shift in gene expressions during 12-h mechanical ventilation.

Ventilator-induced diaphragm dysfunction (VIDD), a dysfunction of the diaphragm muscle caused by prolonged mechanical ventilation (MV), is an important factor that hinders successful weaning from ventilation. We evaluated the effects of electrical stimulation of the diaphragm muscle (pulsed current with off-time intervals) on genetic changes during 12 h of MV (E-V12). Rats were divided into four groups: control, 12-h MV, sham operation, and E-V12 groups.

Optogenetic inhibition of spinal inhibitory neurons facilitates mechanical responses of spinal wide dynamic range neurons and causes mechanical hypersensitivity.

Inhibitory interneurons in the spinal dorsal horn (DH) play a major role in regulating innocuous and noxious information. Reduction in inhibitory synaptic transmission is thought to contribute to the development of touch-evoked pain (allodynia), a common symptom of neuropathic pain. However, it is not fully understood how inhibitory neurons in the DH regulate sensory responses in surrounding neurons and modulate sensory transmission.

Hippocampal ensemble dynamics and memory performance are modulated by respiration during encoding.

During offline brain states, such as sleep and memory consolidation, respiration coordinates hippocampal activity. However, the role of breathing during online memory traces remains unclear. Here, we show that respiration can be recruited during online memory encoding.

An electrophysiological method for evaluation of topical antipruritic drugs on itch-related neuronal activities in the spinal cord in hairless mice.

To evaluate the effects of antipruritic drugs, it is important to determine whether the neural responses induced by physiological itch stimuli are suppressed. Although there are several behavioral assessments for topical antipruritic drugs applied to the skin, there are few established methods at neuronal levels using in vivo electrophysiological recordings for predicting local efficacy of antipruritic drugs for cutaneous application. To establish an assessment of topical antipruritic drugs applied to skin using in vivo extracellular recording from neurons in the superficial dorsal horn, we examined the relationships between itch-related biting behavior and spinal neuronal responses elicited by intradermal injection of pruritogen serotonin (5-HT) in hairless mice.

Voltage-gated calcium channel subunit αδ-1 in spinal dorsal horn neurons contributes to aberrant excitatory synaptic transmission and mechanical hypersensitivity after peripheral nerve injury.

Neuropathic pain, an intractable pain symptom that occurs after nerve damage, is caused by the aberrant excitability of spinal dorsal horn (SDH) neurons. Gabapentinoids, the most commonly used drugs for neuropathic pain, inhibit spinal calcium-mediated neurotransmitter release by binding to αδ-1, a subunit of voltage-gated calcium channels, and alleviate neuropathic pain. However, the exact contribution of αδ-1 expressed in SDH neurons to the altered synaptic transmission and mechanical hypersensitivity following nerve injury is not fully understood.

Properties of Nav1.8-positive and Nav1.8-negative afferent mechanoreceptors in the hindpaw glabrous skin of mice.

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.

Dermal macrophages set pain sensitivity by modulating the amount of tissue NGF through an SNX25-Nrf2 pathway.

Cross-talk between peripheral neurons and immune cells is important in pain sensation. We identified Snx25 as a pain-modulating gene in a transgenic mouse line with reduced pain sensitivity. Conditional deletion of Snx25 in monocytes and macrophages, but not in peripheral sensory neurons, in mice (Snx25 mice) reduced pain responses in both normal and neuropathic conditions.

Structural and functional properties of spinal dorsal horn neurons after peripheral nerve injury change overtime via astrocyte activation.

Chronic pain remains challenging to treat, despite numerous reports of its pathogenesis, including neuronal plasticity in the spinal dorsal horn (SDH). We hypothesized that understanding plasticity only at a specific time point after peripheral nerve injury (PNI) is insufficient to solve chronic pain. Here, we analyzed the temporal changes in synaptic transmission and astrocyte-neuron interactions in SDH after PNI.

Angular Tuning Properties of Low Threshold Mechanoreceptors in Isolated Rat Whisker Hair Follicles.

Angular tuning is preferential sensory response to a directional stimulus and is observed in the whisker tactile system. In whisker hair follicles, there are at least three types of low threshold mechanoreceptors (LTMRs): rapidly adapting (RA), slowly adapting type 1 (SA1), and slowly adapting type 2 (SA2). These LTMRs display angular tuning but their properties remain incompletely studied.

Tmem45b is essential for inflammation- and tissue injury-induced mechanical pain hypersensitivity.

Persistent mechanical pain hypersensitivity associated with peripheral inflammation, surgery, trauma, and nerve injury impairs patients' quality of life and daily activity. However, the molecular mechanism and treatment are not yet fully understood. Herein, we show that chemical ablation of isolectin B4-binding (IB4) afferents by IB4-saporin injection into sciatic nerves completely and selectively inhibited inflammation- and tissue injury-induced mechanical pain hypersensitivity while thermal and mechanical pain hypersensitivities were normal following nerve injury.

Excess intracellular ATP causes neuropathic pain following spinal cord injury.

Intractable neuropathic pain following spinal cord injury (NP-SCI) reduces a patient's quality of life. Excessive release of ATP into the extracellular space evokes neuroinflammation via purinergic receptor. Neuroinflammation plays an important role in the initiation and maintenance of NP.

Long-term selective stimulation of transplanted neural stem/progenitor cells for spinal cord injury improves locomotor function.

In cell transplantation therapy for spinal cord injury (SCI), grafted human induced pluripotent stem cell-derived neural stem/progenitor cells (hiPSC-NS/PCs) mainly differentiate into neurons, forming synapses in a process similar to neurodevelopment. In the developing nervous system, the activity of immature neurons has an important role in constructing and maintaining new synapses. Thus, we investigate how enhancing the activity of transplanted hiPSC-NS/PCs affects both the transplanted cells themselves and the host tissue.

Anesthesia and surgery induce a functional decrease in excitatory synaptic transmission in prefrontal cortex neurons, and intraoperative administration of dexmedetomidine does not elicit the synaptic dysfunction.

Postoperative delirium (POD), a syndrome of confusion and inattention, frequently occurs after anesthesia and surgery. The prefrontal cortex (PFC) plays key roles in executive functions and cognitive controls. However, the neuropathogenesis of POD in the PFC remains largely unknown.

A subset of spinal dorsal horn interneurons crucial for gating touch-evoked pain-like behavior.

A cardinal, intractable symptom of neuropathic pain is mechanical allodynia, pain caused by innocuous stimuli via low-threshold mechanoreceptors such as Aβ fibers. However, the mechanism by which Aβ fiber-derived signals are converted to pain remains incompletely understood. Here we identify a subset of inhibitory interneurons in the spinal dorsal horn (SDH) operated by adeno-associated viral vectors incorporating a neuropeptide Y promoter (AAV-NpyP) and show that specific ablation or silencing of AAV-NpyP SDH interneurons converted touch-sensing Aβ fiber-derived signals to morphine-resistant pain-like behavioral responses.

Correction to: Ascending noradrenergic excitation from the locus coeruleus to the anterior cingulate cortex.

An amendment to this paper has been published and can be accessed via the original article.

L-bupivacaine Inhibition of Nociceptive Transmission in Rat Peripheral and Dorsal Horn Neurons.

Background: Although the widely used single L-enantiomers of local anesthetics have less toxic effects on the cardiovascular and central nervous systems, the mechanisms mediating their antinociceptive actions are not well understood. The authors hypothesized that significant differences in the ion channel blocking abilities of the enantiomers of bupivacaine would be identified.

Methods: The authors performed electrophysiologic analysis on rat dorsal root ganglion neurons in vitro and on spinal transmissions in vivo.

Involvement of cannabinoid type 1 receptor in fasting-induced analgesia.

The endocannabinoid system (ECS) is known to modulate not only food intake but also pain, especially via the cannabinoid type 1 receptor (CB1R) expressed throughout the central nervous system and the peripheral tissues. Our previous study demonstrated that fasting produces an analgesic effect in adult male mice, which is reversed by intraperitoneal (i.p.

Anti-nociceptive and anxiolytic effects of systemic flupirtine and its direct inhibitory actions on in vivo neuronal mechanical sensory responses in the adult rat anterior cingulate cortex.

Flupirtine is a non-opioid centrally acting analgesic that has been in clinical use, and is reported to act on neuronal ion channels and neurotransmitter receptors. However, its action on emotional aspects of pain is still unknown. In this study, we examined whether flupirtine has anxiolytic action and assayed its direct actions on the anterior cingulate cortex (ACC) at the single neuronal and synaptic levels.

Ascending noradrenergic excitation from the locus coeruleus to the anterior cingulate cortex.

Anterior cingulate cortex (ACC) plays important roles in sensory perception including pain and itch. Neurons in the ACC receive various neuromodulatory inputs from subcortical structures, including locus coeruleus noradrenaline (LC-NA) neurons. Few studies have been reported about synaptic and behavioral functions of LC-NA projections to the ACC.

Responsiveness of lumbosacral superficial dorsal horn neurons during the voiding reflex and functional loss of spinal urethral-responsive neurons in streptozotocin-induced diabetic rats.

Aims: Sensory information from the lower urinary tract (LUT) is conveyed to the spinal cord to trigger and co-ordinate micturition. However, it is not fully understood how spinal dorsal horn neurons are excited during the voiding reflex. In this study, we developed an in vivo technique allowing recording of superficial dorsal horn (SDH) neurons concurrent with intravesical pressure (IVP) during the micturition cycle in both normal and diabetic rats.