Effects of linalool on respiratory neuron activity in the brainstem-spinal cord preparation from newborn rats.

Linalool and linalyl acetate are major components of lavender essential oil. These substances possess many biological activities, such as anti-inflammatory activity, analgesic and anxiolytic effects, and anticonvulsant properties, and they also induce modulation of neuronal activity in the autonomic nervous system. However, there are no reports of the direct effects of linalool on respiratory activity. In the present study, we analyzed the effects of linalool and linalyl acetate on central respiratory activity in the brainstem-spinal cord preparation isolated from newborn rats. Linalool dose-dependently decreased the rate of respiratory activity. This effect was reversed by bicuculline, suggesting that linalool enhanced inhibitory synaptic connections via GABAA receptors. In addition, linalool reduced the coefficient of variation of inspiratory burst intervals and thus could work to stabilize the respiratory rhythm. Linalyl acetate did not cause inhibitory effects as observed in linalool treatment. Linalool depressed burst activity of pre-inspiratory neurons in the medullary respiratory networks and increased the amplitude of inspiratory inhibitory postsynaptic potentials of pre-inspiratory neurons. We concluded that linalool caused inhibitory effects on respiratory rhythm generation mainly through activation of presynaptic GABAA receptors of pre-inspiratory neurons.

Involvement of cannabinoid receptors in depression of the putative nociceptive response in spinal cord preparations isolated from neonatal rats.

A metabolite of acetaminophen, AM404, which is an anandamide transporter inhibitor, induces analgesia mainly via activation of transient receptor potential channel 1 in the spinal cord, although the role of cannabinoid receptors remains to be studied. The ventral root reflex response induced by stimulation of the dorsal root in in vitro preparations of rat spinal cord is useful to assess the effect of analgesics. We analyzed the effects of AM404 and cannabinoid receptor antagonist AM251 on reflex responses in lumbar spinal cord preparations from newborn rats and found that the amplitude of the slow ventral root potential after administration of 10 µM AM404 was not significantly changed, whereas 10 µM AM251 significantly increased the amplitude. Administration of the cannabinoid receptor 1 agonist WIN55,212-2 (10 µM) did not significantly affect the reflex response. We suggest that endogenous cannabinoids in the spinal cord are involved in the antinociceptive mechanism through suppressive effects.

Effects of α2-adorenoceptor agonist dexmedetomidine on respiratory rhythm generation of newborn rats.

Dexmedetomidine, an α2-adrenoceptor agonist which has a slight side effect on breathing, is clinically used as an analgesic and sedative agent. Previous studies have shown depressing or modest effects of α2-adorenoceptor agonists on respiratory rhythm generation in newborn rat preparation in vitro. In contrast, it was recently reported that dexmedetomidine induced long-lasting activation of respiratory rhythm in brainstem-spinal cord preparation isolated from neonatal mice. In the present study, we examined whether dexmedetomidine induces any effects on respiratory rhythm in brainstem-spinal cord preparation isolated from newborn rats. We also examined the effects of dexmedetomidine on reflex response in the spinal cord, which is presumed to be an indication of nociceptive response. We found that the administration of dexmedetomidine, at the range of 0.1-10µM, dose-dependently depressed respiratory rhythm and that the inhibitory effect was reversed by atipamezole, an α2-adorenoceptor antagonist. Spinal cord reflex responses were depressed by the application of dexmedetomidine at the range of 0.1-1nM, a lower concentration than that affecting respiratory rhythm. The inhibitory effect was also reversed by atipamezole. Our findings provide neuronal mechanisms that support the clinical use of dexmedetomidine, which shows sedative and antinociceptive effects with minimal side effects on breathing.

Midline section of the medulla abolishes inspiratory activity and desynchronizes pre-inspiratory neuron rhythm on both sides of the medulla in newborn rats.

Each half of the medulla contains respiratory neurons that constitute two generators that control respiratory rhythm. One generator consists of the inspiratory neurons in the pre-Bötzinger complex (preBötC); the other, the pre-inspiratory (Pre-I) neurons in the parafacial respiratory group (pFRG), rostral to the preBötC. We investigated the contribution of the commissural fibers, connecting the respiratory rhythm generators located on the opposite side of the medulla to the generation of respiratory activity in brain stem-spinal cord preparation from 0- to 1-day-old rats. Pre-I neuron activity and the facial nerve and/or first lumbar (L1) root activity were recorded as indicators of the pFRG-driven rhythm. Fourth cervical ventral root (C4) root and/or hypoglossal (XII) nerve activity were recorded as indicators of preBötC-driven inspiratory activity. We found that a midline section that interrupted crossed fibers rostral to the obex irreversibly eliminated C4 and XII root activity, whereas the Pre-I neurons, facial nerve, and L1 roots remained rhythmically active. The facial and contralateral L1 nerve activities were synchronous, whereas right and left facial (and right and left L1) nerves lost synchrony. Optical recordings demonstrated that pFRG-driven burst activity was preserved after a midline section, whereas the preBötC neurons were no longer rhythmic. We conclude that in newborn rats, crossed excitatory interactions (via commissural fibers) are necessary for the generation of inspiratory bursts but not for the generation of rhythmic Pre-I neuron activity.