Painful mechanical stimuli activate multiple peripheral sensory afferent subtypes simultaneously, including nociceptors and low-threshold mechanoreceptors (LTMRs). Using an optogenetic approach, we ...demonstrate that LTMRs do not solely serve as touch receptors but also play an important role in acute pain signaling. We show that selective activation of neuropeptide Y receptor-2-expressing (Npy2r) myelinated A-fiber nociceptors evokes abnormally exacerbated pain, which is alleviated by concurrent activation of LTMRs in a frequency-dependent manner. We further show that spatial summation of single action potentials from multiple NPY2R-positive afferents is sufficient to trigger nocifensive paw withdrawal, but additional simultaneous sensory input from LTMRs is required for normal well-coordinated execution of this reflex. Thus, our results show that combinatorial coding of noxious and tactile sensory input is required for normal acute mechanical pain signaling. Additionally, we established a causal link between precisely defined neural activity in functionally identified sensory neuron subpopulations and nocifensive behavior and pain.
•Identification of an A-fiber nociceptor subpopulation that mediates pinprick pain•Tactile sensory input alleviates A-fiber nociceptor-evoked pain•Tactile sensory input is required for nociceptive reflex coordination•Pinprick-evoked paw withdrawal reflex is triggered independently of firing frequency
Arcourt et al. utilize optogenetics to decipher the role of touch receptors and nociceptors in pain signaling. This approach reveals that tactile sensory input has an analgesic effect on acute pain and is required for normal coordination of nocifensive behavior.
Mechanical allodynia is a major symptom of neuropathic pain whereby innocuous touch evokes severe pain. Here we identify a population of peripheral sensory neurons expressing TrkB that are both ...necessary and sufficient for producing pain from light touch after nerve injury in mice. Mice in which TrkB-Cre-expressing neurons are ablated are less sensitive to the lightest touch under basal conditions, and fail to develop mechanical allodynia in a model of neuropathic pain. Moreover, selective optogenetic activation of these neurons after nerve injury evokes marked nociceptive behavior. Using a phototherapeutic approach based upon BDNF, the ligand for TrkB, we perform molecule-guided laser ablation of these neurons and achieve long-term retraction of TrkB-positive neurons from the skin and pronounced reversal of mechanical allodynia across multiple types of neuropathic pain. Thus we identify the peripheral neurons which transmit pain from light touch and uncover a novel pharmacological strategy for its treatment.
Itch, the unpleasant sensation that elicits a desire to scratch, is mediated by specific subtypes of cutaneous sensory neuron. Here, we identify a subpopulation of itch‐sensing neurons based on their ...expression of the receptor tyrosine kinase Ret. We apply flow cytometry to isolate Ret‐positive neurons from dorsal root ganglia and detected a distinct population marked by low levels of Ret and absence of isolectin B4 binding. We determine the transcriptional profile of these neurons and demonstrate that they express neuropeptides such as somatostatin (Sst), the NGF receptor TrkA, and multiple transcripts associated with itch. We validate the selective expression of Sst using an Sst‐Cre driver line and ablated these neurons by generating mice in which the diphtheria toxin receptor is conditionally expressed from the sensory neuron‐specific Avil locus. Sst‐Cre::AviliDTR mice display normal nociceptive responses to thermal and mechanical stimuli. However, scratching behavior evoked by interleukin‐31 (IL‐31) or agonist at the 5HT1F receptor is significantly reduced. Our data provide a molecular signature for a subpopulation of neurons activated by multiple pruritogens.
Synopsis
This study shows that a subset of DRG neurons expressing the tyrosine kinase Ret and somatostatin function as itch receptor and mediate 5HT1f receptor agonist‐induced scratching in mice.
Flow cytometric analysis of peripheral sensory neurons is used to isolate multiple Ret‐positive subsets.
Transcriptional profiling of sensory neurons with low levels of Ret and an absence of IB4 binding reveals co‐expression of somatostatin (Sst), interleukin‐31 (IL‐31) and serotonin receptor 5HT1f.
Ablation of Sst‐positive neurons reduces scratching responses to IL‐31 and 5HT1f agonists in vivo.
This study shows that a subset of DRG neurons expressing the tyrosine kinase Ret and somatostatin function as itch receptor and mediate 5HT1f receptor agonist‐induced scratching in mice.
Itch-a major symptom of many chronic skin diseases-can exacerbate inflammation by provoking scratching and subsequent skin damage. Here, we show that activation, via near infrared illumination, of a ...phototoxic agent that selectively targets itch-sensing cells can reduce itch-associated behaviours in mice. We generated a SNAP-tagged interleukin-31 (IL-31) ligand derivative (IL-31
) that selectively binds receptors on itch-associated cells, without evoking IL-31-receptor signalling or scratching, and conjugated it to the photosensitizer IRDye 700DX phthalocyanine. Subcutaneous injection of IL-31
-IR700 in mice followed by near infrared illumination resulted in the long-term reversal of the scratching behaviour evoked by the pruritogenic IL-31, an effect that was associated with the selective retraction of itch-sensing neurons in the skin. We also show that a topical preparation of IL-31
-IR700 reversed the behavioural and dermatological indicators of disease in mouse models of atopic dermatitis and of the genetic skin disease familial primary localized cutaneous amyloidosis. Targeted photoablation may enable itch control for the treatment of inflammatory skin diseases.
TREM2 is a transmembrane protein expressed exclusively in microglia in the brain that regulates inflammatory responses to pathological conditions. Proteolytic cleavage of membrane TREM2 affects ...microglial function and is associated with Alzheimer’s disease, but the consequence of reduced TREM2 proteolytic cleavage has not been determined. Here, we generate a transgenic mouse model of reduced Trem2 shedding (Trem2-Ile-Pro-Asp IPD) through amino-acid substitution of an ADAM-protease recognition site. We show that Trem2-IPD mice display increased Trem2 cell-surface-receptor load, survival, and function in myeloid cells. Using single-cell transcriptomic profiling of mouse cortex, we show that sustained Trem2 stabilization induces a shift of fate in microglial maturation and accelerates microglial responses to Aβ pathology in a mouse model of Alzheimer’s disease. Our data indicate that reduction of Trem2 proteolytic cleavage aggravates neuroinflammation during the course of Alzheimer’s disease pathology, suggesting that TREM2 shedding is a critical regulator of microglial activity in pathological states.
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•Generation of a transgenic mouse model of reduced TREM2 shedding•Sustained TREM2 stabilization aggravates neuroinflammation to Aβ pathology•TREM2 shedding regulates microglial activity in healthy and pathological states
Dhandapani et al. show that TREM2 shedding plays a critical role in promoting microglial maturation and response to Aβ pathology. Sustained reduction of TREM2 proteolytic cleavage induces a shift of fate in microglial maturation and aggravates neuroinflammation early on in a mouse model of Alzheimer’s disease.
Rational design and fabrication of electrocatalysts with outstanding performances and long-term durabilities are highly challenging for overall water-splitting reactions. Herein, interfacially ...engineered CoS@NiV-LDH heterostructures are fabricated by a simple top-down approach and used as bifunctional electrocatalysts for overall water splitting. Experimental results proved that the creation of an interface between pristine CoS and NiV-LDH can optimize the electronic structure of the active sites by transferring electrons from the NiV-LDH site to CoS, which boosts the formation of the NiOOH active phase, enhancing the catalytic performance in a 1 M KOH solution. While coupled with the heterostructure CoS@NiV-LDH as the anode and cathode, it demands a cell voltage of just 1.57 V to attain a current density of 10 mA cm–2 with remarkable stability for 70 h. Density functional theory (DFT) calculations reveal improved catalytic activity toward the oxygen evolution reaction (OER) for CoS@NiV-LDH with a lower energy barrier originating from the charge transfer-induced synergistic mechanism at the CoS and NiV-LDH interface. Moreover, the observed downshift of the d-band center for the CoS@NiV-LDH heterostructure explains their enhanced performance toward the hydrogen evolution reaction (HER), facilitating the H* adsorption/desorption process.
Abstract
Background
Corticotrophin-releasing hormone (CRH) is the major regulator of adrenocorticotrophic hormone (ACTH) secretion from the anterior pituitary and acts via CRH-1 receptors (CRH-1R). ...Corticotropinoma though autonomous, still retain their responsiveness to CRH and hence, we hypothesize that in vivo detection of CRH-1 receptors on pituitary adenoma using Gallium-68 (68Ga)-tagged CRH can indicate the functionality of adenoma, and combining it with positron emission tomography-computed tomography (PET-CT) can provide requisite anatomical information.
Methods
Subjects with ACTH-dependent Cushing’s syndrome (CS) (n = 27, 24 with Cushing’s disease CD, 3 with ectopic CS ECS) underwent 68Ga CRH PET-CT. Two nuclear medicine physicians read these images for adenoma delineation and superimposed them on magnetic resonance imaging (MRI) sella. The information provided was used for intraoperative navigation and compared with operative and histopathological findings.
Findings
68Ga CRH PET-CT correctly delineated corticotropinoma in all the 24 cases of CD, including the 10 cases with adenoma size < 6mm (4 cases were negative on MRI). Corticotropinoma location on 68Ga CRH PET fusion images with MRI were concordant with operative findings and were further confirmed on histopathology. There was no tracer uptake in the pituitary in 2 patients with ECS, while, in another, the diffuse uptake in pituitary suggested ectopic CRH production.
Conclusion
68Ga CRH PET-CT represents a novel, noninvasive molecular imaging, targeting CRH receptors that not only delineate corticotropinoma and provides the surgeon with valuable information for intraoperative tumor navigation, but also helps in differentiating a pituitary from an extra-pituitary source of ACTH-dependent CS.
Funding
None.
Abstract
Biologically important bisindolylmethanes are synthesized in a domino fashion by using an iron(II) chloride–(±)-1,1′-binaphthyl-2,2′-diamine FeCl
2
–(±)-BINAM complex as the catalyst. This ...method proceeds via oxidation of a primary alcohol into the corresponding aldehyde followed by nucleophilic addition of an indole in the presence of the catalyst. A reaction intermediate is synthesized separately and converted into the bisindolylmethane product under the same reaction conditions as support for the proposed mechanism.
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