Expression of Fos protein in brainstem after application of l-menthol to the rat nasal mucosa.
ABSTRACT There are two functional pathways for the nasotrigeminal reflex: the spinal nucleus of trigeminal nerve (SPV) to the Kölliker-Fuse (KF) nucleus and the nucleus of solitary tract (NTS) to the lateral parabrachial nucleus (PBl). Although stimulation of the nasal mucosa by cool temperature induces respiratory depression, it is still unknown whether these nuclei are activated. In the present study, we examined the expression of Fos protein in rat brainstem neurons after nasal application of l-menthol, which is known to activate cold-sensitive nasal receptors. Application of l-menthol, but not paraffin oil, decreased the respiratory rate from 99.7+/-15.6 to 78.5+/-7.3 min(-1). Furthermore, a significantly higher density of Fos-immunoreactive cells was observed in the SPV and KF in the l-menthol rats than in the controls. In the SPV, the density of Fos-immunoreactive cells was highest at approximately 0.5mm rostral to the obex in both the l-menthol (48.5+/-11.5 cells/section) and paraffin oil (26.0+/-9.6 cells/section) groups. In the KF, the mean density of Fos-immunoreactive cells was highest at approximately 5.0mm rostral to the obex in both groups (l-menthol: 67.8+/-14.0 cells/section, control: 41.0+/-12.7 cells/section). The present study suggests that the SPV-KF pathway is important for the cold-induced respiratory depression.
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ABSTRACT: Somatosensory neurons detect environmental stimuli, converting external cues into neural activity that is relayed first to second-order neurons in the spinal cord. The detection of cold is proposed to be mediated by the ion channels TRPM8 and TRPA1. However, there is significant debate regarding the role of each channel in cold-evoked pain, complicating their potential as drug targets for conditions such as cold allodynia and hyperalgesia. To address this debate, we generated mice lacking functional copies of both channels and examined behaviors and neural activity in response to painful cold and noxious cooling compounds. Whereas normal mice display a robust preference for warmth over cold, both TRPM8-null (TRPM8(-/-)) and TRPM8/TRPA1 double-knockout mice (DKO) display no preference until temperatures reach the extreme noxious range. Additionally, in contrast to wildtype mice that avoid touching cold surfaces, mice lacking TRPM8 channels display no such avoidance and explore noxious cold surfaces, even at 5 degrees C. Furthermore, nocifensive behaviors to the cold-mimetic icilin are absent in TRPM8(-/-) and DKO mice, but are retained in TRPA1-nulls (TRPA1(-/-)). Finally, neural activity, measured by expression of the immediate-early gene c-fos, evoked by hindpaw stimulation with noxious cold, menthol, or icilin is reduced in TRPM8(-/-) and DKO mice, but not in TRPA1(-/-) animals. Thus our results show that noxious cold signaling is exclusive to TRPM8, mediating neural and behavioral responses to cold and cold-mimetics, and that TRPA1 is not required for acute cold pain in mammals.Pain 08/2010; 150(2):340-50. · 5.64 Impact Factor
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ABSTRACT: Menthol is known as an agonist for cold-sensitive transient receptor potential channels (TRPM8) and also as a direct modulator of GABA channels. We examined the effects of menthol on respiratory rhythm generation in the brainstem-spinal cord preparations isolated from newborn rats. Menthol decreased respiratory rhythm dose-dependently (0.1-1 mM). Effects of menthol were reversed by the GABAA antagonist, bicuculline. Menthol caused pronounced reduction in the driving potential of pre-inspiratory but not inspiratory neurons. Expression of the TRPM8 channel protein was not detected in the respiratory related region of the rostral ventrolateral medulla by immunohistochemistry. The results suggest that the potent inhibitory action of menthol on burst generation of pre-inspiratory neurons is because of direct activation of tonic GABA channels by menthol.Neuroreport 09/2010; 21(17):1095-9. · 1.40 Impact Factor
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ABSTRACT: Nasal mucosa has an extraordinary nerve supply with unique geometry that encompasses complex physiology. Among these, side-specific predilections to the respiratory and autonomic centers are the interesting issues that have been raised about the consequences of the nasal irritations. The aim of the study was an evaluation of how intranasal stimulation influences lung mechanics and determines whether unilateral stimulation produces side-specific partitioning responses. Tracheotomized-paralyzed rats received unilateral air-puff stimulation. Inspiratory pressure- volume (P-V) curve was obtained. Low frequency forced oscillation technique (FOT) was used to detect changes in central and peripheral airways. Mean airway pressure significantly increased to >10 cmH2O in the presence of 5cmH2O of positive end-expiratory pressure. Elastance was significantly changed, and significant higher airway resistance (Raw) and lower reactance (Xrs) were noticed in peripheral airways following different side of stimulation. Calculated inspiratory P-V curve showed significant deviations in transitional, rising and maximal pressures following stimulations. Transitional left-side shifting was observed following right side stimulation, whereas left side stimulation shifted the curve to the right. May be altered respiratory mechanics is the consequences of bimodal pressure-volume relationships observed in central and peripheral airways following nasal stimulation.Acta medica Iranica 01/2014; 54(8):631-638.