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Orexins are produced in hypothalamic areas and orexin-containing neurons are distributed in widespread areas of the central nervous system. Orexins regulate several physiological functions such as arousal, food intake and autonomic control. The presence of orexin-containing neuron terminals and orexin receptors has been confirmed in the nucleus tractus solitarius (NTS), which receives primary afferent fibers from peripheral organs including baroreceptors. However, the neuronal effects of orexin-1 receptor (OX 1 R) activation were not examined. Here, we aimed to determine the effects of OX 1 R activation on excitatory synaptic transmission. OX 1 R activation increased the frequency of spontaneous excitatory synaptic currents (sEPSCs). This effect was blocked by the prior application of L-NAME. In contrast, the amplitude of evoked excitatory postsynaptic currents (eEPSCs) was suppressed by OX 1 R activation, and this effect was prevented by a cannabinoid receptor 1 blocker, AM251, but not by the pretreatment with L-NAME. Altogether, these results suggest that OX 1 R activation increases sEPSCs frequency by stimulating NO production, whereas it inhibits eEPSCs by releasing endocannabinoids in the NTS. Thus, OX 1 R activation had distinct effects on spontaneous and evoked excitatory synaptic transmissions in the NTS., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest, financial or otherwise., (Copyright © 2022 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

The present study evaluated the ability of progesterone to alleviate the synaptic transmission disturbed by hypoxia in the nucleus tractus solitarius (NTS). Hypoxia with N 2 inhibited spontaneous and tractus solitarius-evoked excitatory postsynaptic currents (sEPSCs and eEPSCs) in NTS neurons of the rat brainstem slice. An additional application of progesterone counteracted the hypoxia-induced inhibition of sEPSCs and eEPSCs without affecting the baseline currents. This effect of progesterone occurred rapidly and reversibly. Progesterone had neither effect on sEPSCs nor eEPSCs in normoxia. These results suggest that progesterone restores hypoxia-induced disturbance of the NTS glutamatergic transmission, presumably by a presynaptic, non-genomic mechanism., (Copyright © 2019 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

This study was performed to clarify mechanisms underlying pentazocine-induced ventilatory depression and antinociception. Spontaneous ventilation and hind leg withdrawal response against nociceptive thermal stimulation were simultaneously recorded in anesthetized rats. Pentazocine decreased minute volume resulting from depression of the ventilatory rate and tracheal airflow, and prolonged the latency of withdrawal response. Pre-treatment of β-funaltorexamine, but not nor-binaltorphimine, significantly attenuated pentazocine-induced ventilatory depression, while either antagonist weakened its analgesic potency. Comparing with effects of fentanyl and U50488, the present results suggest that ventilatory depression induced by pentazocine is mediated by mainly μ receptors and analgesia by both μ and κ receptors., (Copyright © 2016 Japanese Pharmacological Society. Production and hosting by Elsevier B.V. All rights reserved.)

Dextromethorphan (DEX) is a widely used non-opioid antitussive. However, the precise site of action and its mechanism were not fully understood. We examined the effects of DEX on AMPA receptor-mediated glutamatergic transmission in the nucleus tractus solitarius (NTS) of guinea pigs. Excitatory postsynaptic currents (evoked EPSCs: eEPSCs) were evoked in the second-order neurons by electrical stimulation of the tractus solitarius. DEX reversibly decreased the eEPSC amplitude in a concentration-dependent manner. The DEX-induced inhibition of eEPSC was accompanied by an increased paired-pulse ratio. Miniature EPSCs (mEPSCs) were also recorded in the presence of Cd(2+) or tetrodotoxin. DEX decreased the frequency of mEPSCs without affecting their amplitude. Topically applied AMPA provoked an inward current in the neurons, which was unchanged during the perfusion of DEX. BD1047, a σ-1-receptor antagonist, did not block the inhibitory effect of DEX on the eEPSCs, but antagonized the inhibition of eEPSCs induced by SKF-10047, a σ-1 agonist. Haloperidol, a σ-1 and -2 receptor ligand, had no influence on the inhibitory action of DEX. These results suggest that DEX inhibits glutamate release from the presynaptic terminals projecting to the second-order NTS neurons, but this effect of DEX is not mediated by the activation of σ receptors.

The role of platelet-derived growth factor (PDGF)-BB / PDGF receptor (PDGFR)-beta signal in inhibition of synaptic transmission by hypoxia is unclear. In the nucleus tractus solitarius neurons, hypoxia with N(2) or NaCN decreased the amplitude of excitatory postsynaptic currents (EPSCs) similarly in wild type (WT) and PDGFR-beta gene-knockout (KO) mice. Recovery of EP SCs after a high concentration of NaCN in KO mice was significantly faster than that in WT mice, while recovery after a low concentration of NaCN or N(2) was not different between both mice. These results suggest that the PDGF-BB / PDGFR-beta signal modulates the excitatory synaptic transmission during hypoxia.

The present study investigated whether the platelet-derived growth factor receptor (PDGFR)-beta-mediated mechanisms are involved in the hypoxic ventilatory response through modulating the N-methyl-D-aspartate (NMDA) function. The ventilatory changes during hypoxic challenge (10% O(2), 30 min) were measured plethysmographically in mice selectively lacking the PDGFR-beta in neurons (KO mice) and in control wild-type mice (WT mice) before and after blockade of NMDA receptors. In baseline breathing at rest, respiratory rate, tidal volume, and minute ventilation were similar between WT and KO mice. Hypoxia caused an increase of ventilation during the early period of exposure (an initial excitation), followed by a progressive decrease along with the exposure period (a late decline). The initial excitation occurred similarly in KO and WT mice, while the late decline was markedly attenuated in KO mice. Administration of an antagonist of NMDA receptors, dizocilpine (0.3 mg/kg, i.p.) decreased the initial excitation and hastened the late decline of hypoxic ventilatory response. Furthermore, the hypoxic ventilatory response in KO mice was indistinguishable from that in WT mice after blockade of NMDA receptors. The present study suggests that the PDGF-BB/PDGFR-beta signal axis contributes to the hypoxic ventilatory response by its inhibitory effect on the NMDA receptor-mediated function.

d-Pseudoephedrine (PSE) is one of the main ingredients of Ephedrae herba. Although PSE is widely applied for patients with a common cold and upper respiratory inflammation as a decongestant, the effects of PSE on cough have never been reported. In this study, we investigated the antitussive effects of intraperitoneal injection of PSE on the cough reflex induced by microinjection of citric acid into the larynx of guinea pigs. PSE decreased the number of cough reflexes dose-dependently (-18.3 +/- 5.0% at 20 mg/kg, P<0.05; -41.1 +/- 7.2% at 60 mg/kg, P<0.01). Furthermore, PSE (60 mg/kg) increased the threshold intensity for inducing fictive cough by electrical micro-stimulation of the nucleus tractus solitarius (+72.7 +/- 8.4%, P<0.01). On the afferent discharge of the superior laryngeal nerve, PSE suppressed the increases of amplitude and frequency when stimulated by citric acid at laryngeal mucosa. These results demonstrate that PSE possesses an antitussive effect that might be derived from both central and peripheral actions.