A descending pathway emanating from the periaqueductal gray mediates the development of cough-like hypersensitivity.
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ABSTRACT:
SUBMITTER: Chen Z
PROVIDER: S-EPMC8741493 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background and purposeThe midbrain periaqueductal grey (PAG) plays a central role in modulating pain through a descending pathway that projects indirectly to the spinal cord via the rostroventral medial medulla (RVM). While opioids are potent analgesics that target the PAG, their cellular actions on descending projection neurons are unclear.Experimental approachPatch clamp recordings in voltage- and current-clamp mode were made from acutely prepared PAG slices from animals that received retrograde tracer injections into the RVM.Key resultsThe μ-agonist DAMGO reduced GABAergic evoked inhibitory postsynaptic currents (IPSCs) in retro-labelled, RVM-projecting neurons to a greater extent than in unlabelled neurons. The κ-opioid agonist U69593 reduced evoked IPSCs to a similar extent in both neuronal groups, while the δ-opioid agonist deltorphin-II was without effect. DAMGO and U69593 both produced a reduction in the rate, but not amplitude of spontaneous miniature IPSCs and asynchronous evoked IPSCs in retro-labelled neurons. DAMGO and U69593 also suppressed glutamatergic EPSCs in retro-labelled and unlabelled neurons. The DAMGO inhibition of evoked EPSCs, however, was less than that for evoked IPSCs in retro-labelled, but not unlabelled neurons. In current clamp, DAMGO produced a depolarizing increase in evoked postsynaptic potentials in retro-labelled neurons, but directly inhibited unlabelled neurons.Conclusion and implicationsThese findings suggest that μ-opioids activate the descending analgesic pathway from the midbrain PAG by a combination of presynaptic disinhibition of RVM-projecting neurons and postsynaptic inhibition of presumptive interneurons.
| S-EPMC7174888 | biostudies-literature
Project description:Chronic cough is globally prevalent across all age groups. This disorder is challenging to treat because many pulmonary and extrapulmonary conditions can present with chronic cough, and cough can also be present without any identifiable underlying cause or be refractory to therapies that improve associated conditions. Most patients with chronic cough have cough hypersensitivity, which is characterized by increased neural responsivity to a range of stimuli that affect the airways and lungs, and other tissues innervated by common nerve supplies. Cough hypersensitivity presents as excessive coughing often in response to relatively innocuous stimuli, causing significant psychophysical morbidity and affecting patients' quality of life. Understanding of the mechanisms that contribute to cough hypersensitivity and excessive coughing in different patient populations and across the lifespan is advancing and has contributed to the development of new therapies for chronic cough in adults. Owing to differences in the pathology, the organs involved and individual patient factors, treatment of chronic cough is progressing towards a personalized approach, and, in the future, novel ways to endotype patients with cough may prove valuable in management.
| S-EPMC9244241 | biostudies-literature
Project description:Endogenous opioids generate analgesic signals in the periaqueductal gray (PAG). However, because cell types in the PAG are difficult to identify, its neuronal mechanism has remained poorly understood. To address this issue, we characterized PAG neurons by their electrical properties using differentially labeled GABAergic and output neurons in the PAG. We found that GABAergic neurons were mostly fast-spiking cells and could be further divided into two distinct classes: with or without low-threshold spikes (LTS) driven by T-type channels. In contrast, the PAG output neurons lacked LTS and showed heterogeneous firing patterns. To reveal the function of the LTS, we examined the mutant mice lacking the alpha1G T-type channels (alpha1G(-/-)). The mutant mice lacked LTS in the fast-spiking GABAergic neurons of the PAG and unexpectedly showed impaired opioid-dependent analgesia; a similar phenotype was reproduced in PAG-specific alpha1G-knockdown mice. Electrophysiological analyses revealed functional expression of mu-opioid receptors in the low threshold-spiking GABAergic neurons. These neurons in the mutant lacking LTS showed markedly enhanced discharge activities, which led to an augmented inhibition of output neurons. Furthermore, the impaired analgesia observed in alpha1G(-/-) mice was reversed by blocking local GABA(A) receptors. These results indicate that alpha1G T-type channels are critical for the opioidergic descending analgesia system in the PAG.
| S-EPMC2930412 | biostudies-literature
Project description:IntroductionResting state functional connectivity (FC) is widely used to assess functional brain alterations in patients with chronic pain. However, reports of FC accompanying tonic pain in pain-free persons are rare. A network we term the Descending Pain Modulatory Network (DPMN) is implicated in healthy and pathologic pain modulation. Here, we evaluate the effect of tonic pain on FC of specific nodes of this network: anterior cingulate cortex (ACC), amygdala (AMYG), periaqueductal gray (PAG), and parabrachial nuclei (PBN).MethodsIn 50 pain-free participants (30F), we induced tonic pain using a capsaicin-heat pain model. functional MRI measured resting BOLD signal during pain-free rest with a 32 °C thermode and then tonic pain where participants experienced a previously warm temperature combined with capsaicin. We evaluated FC from ACC, AMYG, PAG, and PBN with correlation of self-report pain intensity during both states. We hypothesized tonic pain would diminish FC dyads within the DPMN.ResultsOf all hypothesized FC dyads, only PAG and subgenual ACC was weakly altered during pain (F = 3.34; p = 0.074; pain-free>pain d = 0.25). After pain induction sACC-PAG FC became positively correlated with pain intensity (R = 0.38; t = 2.81; p = 0.007). Right PBN-PAG FC during pain-free rest positively correlated with subsequently experienced pain (R = 0.44; t = 3.43; p = 0.001). During pain, this connection's FC was diminished (paired t=-3.17; p = 0.0026). In whole-brain analyses, during pain-free rest, FC between left AMYG and right superior parietal lobule and caudate nucleus were positively correlated with subsequent pain. During pain, FC between left AMYG and right inferior temporal gyrus negatively correlated with pain. Subsequent pain positively correlated with right AMYG FC with right claustrum; right primary visual cortex and right temporo-occipitoparietal junction CONCLUSION: We demonstrate sACC-PAG tonic pain FC positively correlates with experienced pain and resting right PBN-PAG FC correlates with subsequent pain and is diminished during tonic pain. Finally, we reveal PAG- and right AMYG-anchored networks which correlate with subsequently experienced pain intensity. Our findings suggest specific connectivity patterns within the DPMN at rest are associated with subsequently experienced pain and modulated by tonic pain. These nodes and their functional modulation may reveal new therapeutic targets for neuromodulation or biomarkers to guide interventions.
| S-EPMC9250649 | biostudies-literature
Project description:Descending projections from sensory areas of the cerebral cortex are among the largest pathways in the brain, suggesting that they are important for subcortical processing. Although corticofugal inputs have been shown to modulate neuronal responses in the thalamus and midbrain, the behavioral importance of these changes remains unknown. In the auditory system, one of the major descending pathways is from cortical layer V pyramidal cells to the inferior colliculus in the midbrain. We examined the role of these neurons in experience-dependent recalibration of sound localization in adult ferrets by selectively killing the neurons using chromophore-targeted laser photolysis. When provided with appropriate training, animals normally relearn to localize sound accurately after altering the spatial cues available by reversibly occluding one ear. However, this ability was lost after eliminating corticocollicular neurons, whereas normal sound-localization accuracy was unaffected. The integrity of this descending pathway is therefore critical for learning-induced localization plasticity.
| S-EPMC3634157 | biostudies-literature
Project description:Background: Parkinson’s disease (PD) is a progressive, degenerative disease with early-stage pathology hypothesized to manifest in brainstem regions. Vocal deficits, including soft monotone speech, result in significant clinical and quality of life issues and are present in 90% of PD patients; yet, the underlying pathology mediating these significant voice deficits is unknown. The Pink1-/- rat is a valid model of early-onset PD that presents with analogous vocal communication deficits (e.g. reduced loudness). Previous work shows abnormal α-synuclein protein aggregation in the periaqueductal gray (PAG), a brain region critical and necessary to the modulation of mammalian vocal behavior. In this study, we used high-throughput RNA sequencing to examine gene expression within the PAG of both male and female Pink1-/- rats as compared to age-matched wildtype controls. We used a bioinformatic approach to (1) test the hypothesis that loss of Pink1 in the PAG will influence expression of genes that interact with Pink1, (2) highlight other key genes that relate to Mendelian PD, and (3) catalog molecular targets important for the production of rat vocalizations. Results: Knockout of the Pink1 gene resulted in differentially expressed genes for both male and female rats. Pathway analysis highlighted several significant metabolic pathways. Weighted gene co-expression network analysis (WGCNA) was used to identify gene nodes and their interactions in (A) males, (B) females, and (C) combined-sexes datasets. For each analysis, within the module containing the Pink1 gene, Pink1 itself was the central node with the highest number of interactions with other genes including solute carriers, glutamate metabotropic receptors, and genes associated with protein localization. Strong connections between Pink1 and Krt2 and Hfe were found in both males and female datasets. In females a number of modules were significantly correlated with vocalization traits. Of interest, gene enrichment of the key vocal Cyan module in females showed a significant number of neuromodulatory genes including Nts, Slc6a4, Slc10a4, Ndnf, and Gpr160, that may be responsible for the modulation of rat vocalizations. The top biological pathways within the female Cyan vocal module included the regulation of membrane depolarization, indolalkylamine metabolic process, and monoamine transport. Conclusions: Overall, this work supports the premise that gene expression changes in the PAG may contribute to the vocal behavioral and deficits observed in this PD rat model. Additionally, this dataset identifies genes that represent new therapeutic targets for PD voice disorders.
2020-05-21 | GSE150939 | GEO
Project description:Our previous works disclosed the contributing role of macrophage migration inhibitory factor (MIF) and dopaminergic inhibition by lysine dimethyltransferase G9a/Glp complex in peripheral nerve injury-induced hypersensitivity. We herein propose that the proinflammatory cytokine MIF participates in the regulation of neuropathic hypersensitivity by interacting with and suppressing the descending dopaminergic system. The lumbar spinal cord (L-SC) and ventral tegmental area (VTA) are two major locations with significant upregulation of MIF after chronic constriction injury (CCI) of the sciatic nerve, and they display time-dependent changes, along with a behavioral trajectory. Correspondingly, dopamine (DA) content shows the reverse characteristic change to MIF with a time-dependent curve in post-surgical behavior. The levels of both MIF and DA are reversed by the MIF tautomerase inhibitor ISO-1, and a negative relationship exists between MIF and DA. The reversed role of ISO-1 also affects tyrosine hydroxylase expression. Furthermore, CCI induces Th promoter CpG site methylation in the L-SC and VTA areas, and this effect could be abated by ISO-1 administration. G9a/SUV39H1 and H3K9me2/H3K9me3 enrichment within the Th promoter region following CCI in the L-SC and VTA was also decreased by ISO-1. In cultured dopaminergic neurons, rMIF enhanced the recruitment of G9a and SUV39H1, followed by an increase in H3K9me2/H3K9me3. These molecular changes correspondingly exhibited alterations in Th promoter CpG site methylation and pain behaviors. In summary, MIF functions as a braking factor in curbing dopaminergic descending inhibition in peripheral nerve injury-induced hypersensitivity by mediating Th gene methylation through G9a/SUV39H1-associated H3K9 methylation.
| S-EPMC5903823 | biostudies-literature
Project description:The induction of a coma by traumatic brain injury (TBI) is a crucial factor for poor clinical prognoses. We report that acupuncture at the hand 12 Jing-Well points (HTWP) improved consciousness and neurologic function in TBI rats. Gene chip analyses showed that HTWP acupuncture mostly activated genes modulating neuronal projections (P2rx7, P2rx3, Trpv1, Tacr1, and Cacna1d), protein secretion (Exoc1, Exoc3l1, Fgb, and Fgr), and dopamine (DA) receptor D3 (Drd3) in the ventral periaqueductal gray (vPAG), among which the expression rate of P2rx7 was the most obviously increased. Acupuncture also increased the expression and excitability of DA and P2RX7 neurons, and the DA neurons expressed P2RX7, P2RX3, and TRPV1 in the vPAG. Intracerebroventricular administration of P2RX7, P2RX3, or TRPV1 antagonists blocked acupuncture-induced consciousness, and the subsequent injection of a P2RX7 antagonist into the vPAG nucleus also inhibited this effect. Our findings provide evidence that acupuncture alleviates TBI-induced comas via DA neurons expressing P2RX7 in the vPAG, so as to reveal the cellular and molecular mechanisms of the improvement of TBI clinical outcomes by HTWP acupuncture.
| S-EPMC7838360 | biostudies-literature
Project description:The electroacupuncture-induced analgesic effect has been used widely to alleviate diverse pains. However, significant individual variations in analgesic effect of EA for both experiments and clinics were reported. According to the sensitivity of the analgesic response to EA stimulation, the subjects could be categorized into high responders (HR) and low responders (NR). However, the molecular mechanism of individual variability in the analgesic response to acupuncture stimulation is still uncertain. This study aims to investigate the potential gene expression in spinal dorsal horn induced by 2Hz/100Hz electroacupuncture in HR and NR rats. Rats were given 2Hz or 100Hz electroacupuncture for 30 min and using cDNA microarrays to compare different gene expression in dorsal horn. Transcriptome profiling analysis found that some co-regulated genes related with electroacupuncture or 2Hz or 100Hz fruqencies. These co-regulated genes were plasticity-related by GO analysis.
2016-03-21 | GSE58803 | GEO
Project description:The ventrolateral periaqueductal gray (VLPAG) is thought to be the main PAG column for bladder control. PAG neurons (especially VLPAG neurons) and neurons in the pontine micturition center (PMC) innervating the bladder detrusor have anatomical and functional synaptic connections. The prevailing viewpoint on neural control of the bladder is that PAG neurons receive information on the decision to void made by upstream brain regions, and consequently activate the PMC through their direct projections to initiate urination reflex. However, the exact location of the PMC-projecting VLPAG neurons, their activity in response to urination, and their whole-brain inputs remain unclear. Here, we identified the distribution of VLPAG neurons that may participate in control of the bladder or project to the PMC through retrograde neural tracing. Population Ca2+ signals of PMC-projecting VLPAG neurons highly correlated with bladder contractions and urination as shown by in vivo recording in freely moving animals. Using a RV-based retrograde trans-synaptic tracing strategy, morphological results showed that urination-related PMC-projecting VLPAG neurons received dense inputs from multiple urination-related higher brain areas, such as the medial preoptic area, medial prefrontal cortex, and lateral hypothalamus. Thus, our findings reveal a novel insight into the VLPAG for control of bladder function and provide a potential therapeutic midbrain node for neurogenic bladder dysfunction.
| S-EPMC9259957 | biostudies-literature