Highlights ► Trp channels underlie pain and itch. ► Noxious chemicals are not specific for pain versus itch. ► Primary afferents may be differentially wired to convey either pain or itch. ► ...Inhibition between somatosensory modalities sharpens acuity. ► Normally silent excitatory circuits are unmasked in injury and disease.
Menthol and other counterstimuli relieve itch, resulting in an antipruritic state that persists for minutes to hours. However, the neural basis for this effect is unclear, and the underlying ...neuromodulatory mechanisms are unknown. Previous studies revealed that Bhlhb5−/− mice, which lack a specific population of spinal inhibitory interneurons (B5-I neurons), develop pathological itch. Here we characterize B5-I neurons and show that they belong to a neurochemically distinct subset. We provide cause-and-effect evidence that B5-I neurons inhibit itch and show that dynorphin, which is released from B5-I neurons, is a key neuromodulator of pruritus. Finally, we show that B5-I neurons are innervated by menthol-, capsaicin-, and mustard oil-responsive sensory neurons and are required for the inhibition of itch by menthol. These findings provide a cellular basis for the inhibition of itch by chemical counterstimuli and suggest that kappa opioids may be a broadly effective therapy for pathological itch.
•Spinal B5-I interneurons function to inhibit itch•B5-I neurons release the kappa opioid dynorphin•Kappa opioid signaling bidirectionally modulates itch within the spinal cord•Spinal B5-I interneurons mediate the inhibition of itch by menthol
Kardon et al. identify a population of spinal interneurons that function to inhibit itch. Release of the kappa opioid dynorphin from these neurons mediates the inhibition of itch by chemical counterstimuli such as menthol, suggesting that kappa opioids may be a broadly effective therapy for pathological itch.
The lateral parabrachial nucleus (lPBN) is a major target of spinal projection neurons conveying nociceptive input into supraspinal structures. However, the functional role of distinct lPBN efferents ...in diverse nocifensive responses have remained largely uncharacterized. Here we show that that the lPBN is required for escape behaviors and aversive learning to noxious stimulation. In addition, we find that two populations of efferent neurons from different regions of the lPBN collateralize to distinct targets. Activation of efferent projections to the ventromedial hypothalamus (VMH) or lateral periaqueductal gray (lPAG) drives escape behaviors, whereas activation of lPBN efferents to the bed nucleus stria terminalis (BNST) or central amygdala (CEA) generates an aversive memory. Finally, we provide evidence that dynorphin-expressing neurons, which span cytoarchitecturally distinct domains of the lPBN, are required for aversive learning.
•The lPBN mediates escape and aversion to noxious stimuli•Spatially segregated neurons in the lPBN collateralize to distinct targets•Distinct output pathways give rise to separate aspects of the pain response
Chiang et al. reveal that neurons in spatially segregated regions of the lateral parabrachial nucleus collateralize to distinct targets and that activation of distinct efferents gives rise to separate components of the nocifensive response.
Pain information processing in the spinal cord has been postulated to rely on nociceptive transmission (T) neurons receiving inputs from nociceptors and Aβ mechanoreceptors, with Aβ inputs gated ...through feed-forward activation of spinal inhibitory neurons (INs). Here, we used intersectional genetic manipulations to identify these critical components of pain transduction. Marking and ablating six populations of spinal excitatory and inhibitory neurons, coupled with behavioral and electrophysiological analysis, showed that excitatory neurons expressing somatostatin (SOM) include T-type cells, whose ablation causes loss of mechanical pain. Inhibitory neurons marked by the expression of dynorphin (Dyn) represent INs, which are necessary to gate Aβ fibers from activating SOM+ neurons to evoke pain. Therefore, peripheral mechanical nociceptors and Aβ mechanoreceptors, together with spinal SOM+ excitatory and Dyn+ inhibitory neurons, form a microcircuit that transmits and gates mechanical pain.
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•Intersectional ablation of dorsal spinal excitatory and inhibitory neurons•SOM+ excitatory neurons are required to sense acute and chronic mechanical pain•Dyn+ neurons prevent Aβ fibers from activating SOM+ pain transmission neurons•Identification of spinal circuits that transmit and gate mechanical pain
Genetic manipulations in the spinal cord reveal the identity of neurons transmitting and gating pain. Spinal somastatin-positive excitatory neurons receive input from peripheral nociceptors and Aβ mechanoreceptors, which are in turns gated by dynorphin-expressing inhibitory neurons.
Opioids are a mainstay of treatment for pain worldwide. Pruritus, a common side effect of opioids, is a patient dissatisfier that limits their use in many clinical settings. Both parenteral and ...neuraxial administration of opioids frequently evoke pruritus. The ability of opioids to suppress pain while causing itch continues to perplex clinicians and researchers alike. Several mechanisms have been proposed to explain how opioids can give rise to pruritus, but specific knowledge gaps perpetuate debate. This review summarizes the clinical burden of opioid-induced pruritus and emphasizes recent discoveries of peripheral and central mechanisms for opioid-induced pruritus, particularly with respect to scientific and conceptual advances in spinal cord circuitry and mast cell biology. The mechanisms and effectiveness of existing medications used for clinical management of pruritus will be evaluated, and we will highlight the emerging preclinical utility of selective κ-opioid receptor agonists, such as nalfurafine, for the management of opioid-induced pruritus.
In Duchenne muscular dystrophy (DMD), a lack of functional dystrophin leads to myofiber instability and progressive muscle damage that results in fibrosis. While fibrosis is primarily characterized ...by an accumulation of extracellular matrix (ECM) components, there are changes in ECM architecture during fibrosis that relate more closely to functional muscle stiffness. One of these architectural changes in dystrophic muscle is collagen cross-linking, which has been shown to increase the passive muscle stiffness in models of fibrosis including the mdx mouse, a model of DMD. We tested whether the intraperitoneal injections of beta-aminopropionitrile (BAPN), an inhibitor of the cross-linking enzyme lysyl oxidase, would reduce collagen cross-linking and passive stiffness in young and adult mdx mice compared to saline-injected controls. We found no significant differences between BAPN treated and saline treated mice in collagen cross-linking and stiffness parameters. However, we observed that while collagen cross-linking and passive stiffness scaled positively in dystrophic muscles, collagen fiber alignment scaled with passive stiffness distinctly between muscles. We also observed that the dystrophic diaphragm showed the most dramatic fibrosis in terms of collagen content, cross-linking, and stiffness. Overall, we show that while BAPN was not effective at reducing collagen cross-linking, the positive association between collagen cross-linking and stiffness in dystrophic muscles still show cross-linking as a viable target for reducing passive muscle stiffness in DMD or other fibrotic muscle conditions.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Although transcription factors that repress gene expression play critical roles in nervous system development, their mechanism of action remains to be understood. Here, we report that the ...Olig-related transcription factor Bhlhb5 (also known as Bhlhe22) forms a repressor complex with the PR/SET domain protein, Prdm8. We find that Bhlhb5 binds to sequence-specific DNA elements and then recruits Prdm8, which mediates the repression of target genes. This interaction is critical for repressor function since mice lacking either Bhlhb5 or Prdm8 have strikingly similar cellular and behavioral phenotypes, including axonal mistargeting by neurons of the dorsal telencephalon and abnormal itch-like behavior. We provide evidence that Cadherin-11 functions as target of the Prdm8/Bhlhb5 repressor complex that must be repressed for proper neural circuit formation to occur. These findings suggest that Prdm8 is an obligate partner of Bhlhb5, forming a repressor complex that directs neural circuit assembly in part through the precise regulation of Cadherin-11.
► Bhlhb5 binds sequence-specific DNA and recruits Prdm8 to mediate repression ► Prdm8 is an obligate partner of Bhlhb5 ► Mice lacking either factor have axonal mistargeting and abnormal itch-like behavior ► Cadherin-11 is a target of the Bhlhb5/Prdm8 repressor
Ross et al. report that the Olig-related transcription factor Bhlhb5 forms a repressor complex with the PR/SET domain protein Prdm8. This complex ensures precise regulation of target genes such as Cadherin-11 and is essential for proper neuronal development.
The impact of different neuronal populations on local cerebral blood flow (CBF) regulation is not well known and insight into these relationships could enhance the interpretation of brain function ...and dysfunction from brain imaging data. We investigated the role of sub-types of inhibitory neuron activity on the regulation of CBF using optogenetics, laser Doppler flowmetry and different transgenic mouse models (parvalbumin (PV), vasoactive intestinal peptide (VIP), somatostatin (SOM) and nitric oxide synthase (NOS)). Whisker stimulation was used to verify that typical CBF responses were obtained in all mice. Photo-stimulation of SOM-cre and NOS-cre mice produced significant increases in CBF that were similar to whisker responses. In NOS-cre mice, CBF responses scaled with the photo-stimulus pulse duration and frequency. In SOM-cre mice, CBF increases were followed by decreases. In VIP-cre mice, photo-stimulation did not consistently produce significant changes in CBF, while slower increases in CBF that peaked 14–18 s after stimulation onset were observed in PV-cre mice. Control experiments performed in non-expressing regions showed no changes in CBF. These findings suggest that dysfunction in NOS or SOM neurons can have a significant impact on vascular responses that are detected by brain imaging methods like functional magnetic resonance imaging (fMRI).
Facial expression is widely used as a measure of pain in infants; whether nonhuman animals display such pain expressions has never been systematically assessed. We developed the mouse grimace scale ...(MGS), a standardized behavioral coding system with high accuracy and reliability; assays involving noxious stimuli of moderate duration are accompanied by facial expressions of pain. This measure of spontaneously emitted pain may provide insight into the subjective pain experience of mice.
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