Characterisation of sleep apneas and respiratory circuitry in mice lacking CDKL5.

CDKL5 deficiency disorder is a rare genetic disease caused by mutations in the CDKL5 gene. Central apneas during wakefulness have been reported in patients with CDKL5 deficiency disorder. Studies on CDKL5-knockout mice, a CDKL5 deficiency disorder model, reported sleep apneas, but it is still unclear whether these events are central (central sleep apnea) or obstructive (obstructive sleep apnea) and may be related to alterations of brain circuits that modulate breathing rhythm.

M muscarinic receptors mediate acetylcholine-induced suppressant effects on the cough reflex in the caudal nucleus tractus solitarii of the rabbit.

It has been shown that muscarinic acetylcholine receptors (mAChRs) located within the caudal nucleus tractus solitarii (cNTS) mediate a cholinergic inhibitory control mechanism of the cough reflex. Thus, identification of the involved mAChR subtypes could be of considerable interest for novel therapeutic strategies. In pentobarbital sodium-anesthetized, spontaneously breathing rabbits we investigated the contribution of different mAChR subtypes in the modulation of mechanically and chemically induced cough reflex.

Somatic points for cough and urge to cough in chronic coughers.

In patients with chronic cough and age-matched control subjects, we attempted to evoke coughing and/or an urge to cough (UTC) by finger pressure along the sternocleidomastoid and sternum, on the lower cervical or first dorsal vertebrae, the jugular notch as well as with maximum neck extension and flexion These mechanical actions were ineffective in controls but reproducibly evoked coughing or UTC in about 50% of chronic coughers; sternal and spinal responses were abolished temporarily by local cooling. The results may disclose a novel paradigm of cough sensitisation possibly involving central convergence of somatic and visceral neural stimuli.

The lamprey respiratory network: Some evolutionary aspects.

Breathing is a complex behaviour that involves rhythm generating networks. In this review, we examine the main characteristics of respiratory rhythm generation in vertebrates and, in particular, we describe the main results of our studies on the role of neural mechanisms involved in the neuromodulation of the lamprey respiration. The lamprey respiratory rhythm generator is located in the paratrigeminal respiratory group (pTRG) and shows similarities with the mammalian preBötzinger complex.

Neural mechanisms underlying respiratory regulation within the preBötzinger complex of the rabbit.

The preBötzinger complex (preBötC) is a medullary area essential for normal breathing and widely recognized as necessary and sufficient to generate the inspiratory phase of respiration. It has been studied mainly in rodents. Here we report the main results of our studies revealing the characteristics of the rabbit preBötC identified by means of neuronal recordings, D,L-homocysteic acid microinjections and histological controls.

Activation of μ-opioid receptors differentially affects the preBötzinger Complex and neighbouring regions of the respiratory network in the adult rabbit.

The role of the different components of the respiratory network in the mediation of opioid-induced respiratory depression is still unclear. We investigated the contribution of the preBötzinger Complex (preBötC) and the neighbouring Bötzinger Complex (BötC) and inspiratory portion of the ventral respiratory group (iVRG) in anesthetized, vagotomized, paralyzed and artificially ventilated adult rabbits making use of bilateral microinjections (30-50 nl) of the μ-opioid receptor agonist [D-Ala, N-Me-Phe, Gly-ol]-enkephalin (DAMGO). Dose-dependent effects were observed.

Key role of 5-HT receptors in the modulation of the neuronal network underlying the respiratory rhythm generation in lampreys.

In mammals, 5-HTexcitatory respiratory effects imply 5-HT receptor-mediated disinhibition of pre-Bötzinger complex neurons. In the lamprey, 5-HT receptors are involved in the neural control of locomotion, but their role in the respiratory regulation, particularly at the level of the putative respiratory rhythm generator, the paratrigeminal respiratory group (pTRG), is not known. We here investigate the respiratory function of inhibitory 5-HT receptors within the pTRG of the isolated brainstem of the adult lamprey.

Breathing stimulation mediated by 5-HT and 5-HT receptors within the preBötzinger complex of the adult rabbit.

Serotonin (5-HT) has been reported to play excitatory effects on respiration by acting on preBötzinger complex (preBötC) neurons in neonatal or juvenile rodents. However, whether its action is circumscribed to the preBötC and present in other animal species, particularly in adult preparations, is unknown. We investigated the respiratory role of 5-HT within the preBötC and neighbouring respiration-related regions.

Inhibitory modulation of the cough reflex by acetylcholine in the caudal nucleus tractus solitarii of the rabbit.

A cholinergic system has been described in the nucleus tractus solitarii (NTS). However, no information is available on the role played by acetylcholine (ACh) in the modulation of the cough reflex within the caudal NTS that has an important function in cough regulation. We addressed this issue making use of bilateral microinjections (30-50 nl) of 10 mM ACh combined with 5 mM physostigmine as well as of 10 mM mecamylamine or 10 mM scopolamine into the caudal NTS of pentobarbital sodium-anesthetized, spontaneously breathing rabbits.

ATP and astrocytes play a prominent role in the control of the respiratory pattern generator in the lamprey.

Key Points: The paratrigeminal respiratory group (pTRG) is responsible for the respiratory pattern generation in the lamprey. The role of ATP and astrocytes, known to control respiratory activity in mammals, was investigated in the lamprey respiratory network. ATP microinjected into the pTRG induces a biphasic response consisting of marked increases in respiratory frequency mediated by P2X receptors followed by a decrease in the respiratory motor output due to the ATP metabolite adenosine.

GABAA- and glycine-mediated inhibitory modulation of the cough reflex in the caudal nucleus tractus solitarii of the rabbit.

Cough-related sensory inputs from rapidly adapting receptors (RARs) and C fibers are processed by second-order neurons mainly located in the caudal nucleus tractus solitarii (NTS). Both GABAA and glycine receptors have been proven to be involved in the inhibitory control of second-order cells receiving RAR projections. We investigated the role of these receptors within the caudal NTS in the modulation of the cough reflex induced by either mechanical or chemical stimulation of the tracheobronchial tree in pentobarbital sodium-anesthetized, spontaneously breathing rabbits.

Downregulation of the cough reflex by aclidinium and tiotropium in awake and anesthetized rabbits.

Long-acting muscarinic receptor antagonists (LAMAs) have been reported to attenuate cough in preclinical and clinical studies. The present study was performed on rabbits to compare aclidinium and tiotropium efficacy in the downregulation of the cough reflex. This reflex was evoked by citric acid inhalation in unanesthetized animals and by both citric acid inhalation and mechanical stimulation of the tracheobronchial tree in anesthetized animals 90 min following the inhalation of each drug (nebulizer output always at 1 mL/min).

Inhibitory control of ascending glutamatergic projections to the lamprey respiratory rhythm generator.

Neurons within the vagal motoneuron region of the lamprey have been shown to modulate respiratory activity via ascending excitatory projections to the paratrigeminal respiratory group (pTRG), the proposed respiratory rhythm generator. The present study was performed on in vitro brainstem preparations of the lamprey to provide a characterization of ascending projections within the whole respiratory motoneuron column with regard to the distribution of neurons projecting to the pTRG and related neurochemical markers. Injections of Neurobiotin were performed into the pTRG and the presence of glutamate, GABA and glycine immunoreactivity was investigated by double-labeling experiments.

The cough reflex is upregulated by lisinopril microinjected into the caudal nucleus tractus solitarii of the rabbit.

We have previously shown that cough potentiation induced by intravenous administration of the AT1 receptor antagonist losartan is lower than that induced by the ACE inhibitor lisinopril in anesthetized and awake rabbits. Since losartan and lisinopril cross the blood-brain barrier, their central action on the cough reflex can be hypothesized. Mechanical stimulation of the tracheobronchial tree and citric acid inhalation were used to induce cough reflex responses in pentobarbital sodium-anesthetized, spontaneously breathing rabbits.

Inhibitory control of the cough reflex by galanin receptors in the caudal nucleus tractus solitarii of the rabbit.

The caudal nucleus tractus solitarii (NTS) is the main central station of cough-related afferents and a strategic site for the modulation of the cough reflex. The similarities between the characteristics of central processing of nociceptive and cough-related inputs led us to hypothesize that galanin, a neuropeptide implicated in the control of pain, could also be involved in the regulation of the cough reflex at the level of the NTS, where galanin receptors have been found. We investigated the effects of galanin and galnon, a nonpeptide agonist at galanin receptors, on cough responses to mechanical and chemical (citric acid) stimulation of the tracheobronchial tree.

Neural mechanisms underlying respiratory rhythm generation in the lamprey.

The isolated brainstem of the adult lamprey spontaneously generates respiratory activity. The paratrigeminal respiratory group (pTRG), the proposed respiratory central pattern generator, has been anatomically and functionally characterized. It is sensitive to opioids, neurokinins and acetylcholine.

GABAergic and glycinergic inputs modulate rhythmogenic mechanisms in the lamprey respiratory network.

We have previously shown that GABA and glycine modulate respiratory activity in the in vitro brainstem preparations of the lamprey and that blockade of GABAA and glycine receptors restores the respiratory rhythm during apnoea caused by blockade of ionotropic glutamate receptors. However, the neural substrates involved in these effects are unknown. To address this issue, the role of GABAA, GABAB and glycine receptors within the paratrigeminal respiratory group (pTRG), the proposed respiratory central pattern generator, and the vagal motoneuron region was investigated both during apnoea induced by blockade of glutamatergic transmission and under basal conditions through microinjections of specific antagonists.

Suppression of the cough reflex by α 2-adrenergic receptor agonists in the rabbit.

The α 2-adrenergic receptor agonist clonidine has been shown to inhibit citric acid-induced cough responses in guinea pigs when administered by aerosol, but not orally. In contrast, oral or inhaled clonidine had no effect on capsaicin-induced cough and reflex bronchoconstriction in humans. In addition, intravenous administration of clonidine has been shown to depress fentanyl-induced cough in humans.

Proton magnetic resonance spectroscopy in the evaluation of patients with acute Charcot neuro-osteoarthropathy.

Objective: To evaluate whether bone marrow proton magnetic resonance spectroscopy (MRS) might provide a quantitative parameter able to assess disease activity in acute Charcot neuro-osteoarthropathy (CN).

Methods: Ten diabetic patients with stage 0 CN were prospectively evaluated at clinical onset and during treatment follow-up. The MRS lipid spectrum was analysed and a lipid polyunsaturation index (PUI) was calculated.

Neuronal mechanisms of respiratory pattern generation are evolutionary conserved.

A brainstem region, the paratrigeminal respiratory group (pTRG), has been suggested to play a crucial role in the respiratory rhythm generation in lampreys. However, a detailed characterization of the pTRG region is lacking. The present study performed on isolated brainstem preparations of adult lampreys provides a more precise localization of the pTRG region with regard to both connectivity and neurochemical markers.

Modulation of the cough reflex by GABA(A) receptors in the caudal ventral respiratory group of the rabbit.

We have previously shown that the caudal ventral respiratory group (cVRG) is a possible site of action of some antitussive drugs and plays a crucial role in determining both the expiratory and inspiratory components of the cough motor pattern. In addition, it has been reported that medullary expiratory neurons of the cVRG are subject to potent GABAergic gain modulation. This study was devoted to investigate the role of cVRG GABA(A) receptors in the control of baseline respiratory activity and cough responses to mechanical and chemical (citric acid) stimulation of the tracheobronchial tree.

Suppression of the cough reflex by inhibition of ERK1/2 activation in the caudal nucleus tractus solitarii of the rabbit.

The caudal nucleus tractus solitarii (cNTS), the predominant site of termination of cough-related afferents, has been shown to be a site of action of some centrally acting antitussive agents. A role of ERK1/2 has been suggested in acute central processing of nociceptive inputs. Because pain and cough share similar features, we investigated whether ERK1/2 activation could also be involved in the central transduction of tussive inputs.