Tomoshige Koga

Neurons in the nucleus of the solitary tract mediating inputs from emetic vagal afferents and the area postrema to the pattern generator for the emetic act in dogs

Roles of neurons in the nucleus of the solitary tract corresponding to the area subpostrema (mNST) for the retching reflex were investigated in decerebrate, paralyzed dogs. Retching was defined as rhythmic coactivation of the phrenic and abdominal muscle nerves. Retching which had been induced by stimulation of the left and right abdominal vagus nerves was impaired by cooling the left and right mNSTs, respectively. This result indicates that the mNST neurons mediate activities of emetic vagal afferents. All 40 non-respiratory neurons in the mNST, which had excitatory response to pulse train stimulation of the vagus nerve, were also activated by continuous stimulation of the vagus nerve to provoke retching. During provoked retching, however, these neurons did not exhibit any activities modulated in association with retching. The average latency of responses of these neurons to the pulse train stimulation (306.5 ms) was significantly shorter than that of the inspiratory neurons in the lateral NST and the adjacent reticular formation. Discharge frequencies of these neurons in the mNST gradually increased after administration of apomorphine (6/10) and glutamate (14/14) to the 4th ventricle. Antidromic responses to stimulation of the Bötzinger complex were observed in some (20/289) of the mNST neurons. These findings suggest that neurons in the mNST mediate the information from both the abdominal vagal afferents and the area postrema and drive the pattern generator for retching and vomiting, which is assumed to be located in the Bötzinger complex.

Differences in autonomic responses between subjects with and without nausea while watching an irregularly oscillating video

Prodromal signs such as cardiac rhythm disturbance and changes in gastric motility are generally induced before and during nausea in humans. These autonomic reactions were compared in subjects who were or were not experiencing nausea. Nausea was induced by having the subjects view a movie of oscillating pictures. Seventeen healthy volunteers were asked to relax their muscles and watch the movie. Electrogastrogram (EGG), electrocardiogram (ECG), palmar and metopic perspiration, digital blood flow and thoracic movement related to respiration were simultaneously measured while the subjects viewed the movie. A total of 11 of 17 subjects complained of nausea after watching the movie. The characteristic changes in their autonomic responses during exposure to the movie were as follows. The power of the EGG, heart rate and metopic perspiration significantly increased compared to those before watching the movie. The respiratory cycle gradually increased during and even after watching the movie. In contrast, no significant changes in the power of the EGG, heart rate and metopic perspiration were observed in the remaining six subjects who did not experience nausea. The role of the autonomic nervous system in nausea is discussed. These results suggest that these symptoms regarding the sympathetic nervous system could actually be defensive reactions against the sensation of nausea.

The Bötzinger complex as the pattern generator for retching and vomiting in the dog

To clarify the location of the pattern generator for the emetic act, the bulb was systematically stimulated and partially cut in decerebrate, paralyzed dogs. Stimulation of the following bulbar structures elicited the activities which could be recognized as retching and vomiting in the following muscle nerves. The bulbar structures were: the intra-bulbar bundle of the vagal afferents, the solitary tract and the medial subdivision of its nucleus (NTS), the area postrema, the commissural nucleus, the raphe area at the obex level, and the longitudinal reticular column which consists of 3 areas--the area between the caudal parts of the solitary complex (SC) and the nucleus ambiguus, the area ventromedial to the rostral part of the nucleus and the area dorsomedial to the retrofacial nucleus (RFN) which may correspond to the Bötzinger complex (BOT). The muscle nerves were: the phrenic branches to the dome and hiatal parts of the diaphragm, the abdominal muscle nerve, the pharyngo-esophageal branch of the vagus nerve, the mylohyoid muscle nerve, and the recurrent nerve branches to the adductors and abductor of the glottis. Emetic responses to stimulation of the vagal ventral trunk and the rostral SC still remained after cutting of the bilateral SCs at about 1 mm rostral to the obex, but disappeared after cutting at about 3.5 mm rostral to the obex. After the rostral cuts, stimulation of the SC part caudal to the cuts and the reticular column still induced the emetic act. Emetic responses to stimulation of the caudal SC remained after transection of the bulb at the rostral end of the RFN, but disappeared after transection at its caudal end or after partial cutting of the caudal BOT. The following hypothesis was proposed from these results. Emetic vagal afferents enter the rostral bulb, then descend through the SC to the area subpostrema. Subpostrema neurons project through the reticular column to the pattern generator of the emetic act in the BOT and activate it.

Non-respiratory neurons in the Bötzinger complex exhibiting appropriate firing patterns to generate the emetic act in dogs

This work was performed to prove the hypothesis that the pattern generator for the emetic act exists in the Bötzinger complex (BOT) and is driven by vagal afferents via the subpostrema portion of the nucleus of the solitary tract (mNST). Non-respiratory neurons (78) intermingling with BOT respiratory neurons in decerebrate dogs responded to pulse train stimulation of vagal afferents with a mean latency of 387 ms. During retching induced by vagal stimulation, one-half of the non-respiratory neurons exhibited high frequency burst firings synchronous with each retch (SH-firing, SH-neurons) and one-third of these neurons showed similar firings synchronous with the periods between retches (BH-firing, BH-neurons). Two-thirds of the SH-neurons and one-half of the BH-neurons fired with gradually augmenting frequencies (augmenting firing) during the period prior to retching, which may correspond to the period of prodromal signs of vomiting. Three SH-neurons were observed at fictive expulsion: all 3 exhibited burst firings concomitant with expulsion. During cooling block of transmission in the mNST, stimulation of the vagus nerve ipsilateral to the cooling failed to induce not only retching but also augmenting firing and SH-firing in all 11 BOT SH-neurons observed. In contrast, contralateral vagal stimulation induced retching and neuronal firings which had been observed before the cooling. These results support the hypothesis mentioned above. Respiratory firings were changed during retching in all BOT respiratory neurons observed. Respiratory firings were depressed during retching in the majority (15/25) of inspiratory (I) neurons and in a few expiratory (E) neurons (6/45). SH-firing was exhibited by 3 I- and 13 E-neurons. A few (2) I- and half (23) E-neurons showed BH-firing. These results indicate that all BOT respiratory neurons participate in central patterning of the emetic act.

The central pattern generator for vomiting may exist in the reticular area dorsomedial to the retrofacial nucleus in dogs

Abstract There is some controversy over whether or not a discrete site that integrates vomiting activities in somatic and autonomic nerves is present in the medulla oblongata. On the basis of our previous studies, we hypothesized that the temporal patterns of muscle contractions in vomiting are generated by a central pattern generator in the retrofacial area of the rostral medulla. To investigate this hypothesis further, the effects of electrical and chemical lesions of the medullary area were observed in decerebrate paralyzed dogs. Efferent activities of the phrenic and abdominal muscle nerves were recorded to recognize fictive vomiting. The right half of the medulla oblongata was transversely severed about 3 mm rostral to the obex. Fictive vomiting responses to vagal stimulation still appeared after hemisection in all 11 dogs. In addition, stimulation of the contralateral reticular area dorsomedial to the retrofacial nucleus produced fictive vomiting even after hemisection. An electrical lesion or injection of kainic acid (0.5–1.0 µl) was applied at the point where reticular stimulation induced fictive vomiting. After this destruction, no activities that corresponded to fictive vomiting could be induced by stimulation of vagal afferents or the reticular site. Salivation was decreased by hemisection, and decreased further, but was not completely abolished, with destruction of the reticular area. Kainic acid is known to selectively destroy neural cell bodies. Therefore, we concluded that neuronal somata in the reticular formation dorsomedial to the retrofacial nucleus play an essential role in the central patterning of vomiting activities in peripheral motor nerves.

The site of the anti-emetic action of tachykinin NK1 receptor antagonists may exist in the medullary area adjacent to the semicompact part of the nucleus ambiguus

Abstract NK1 receptor antagonists have been shown to act centrally and to produce a broad-spectrum anti-emetic action. To determine precisely the site of this action, we microinjected GR205171, an NK1 receptor antagonist, into the left medulla oblongata in decerebrate paralyzed dogs. The right medulla was transected 2.5 mm rostral to the obex to eliminate the emetic function of that half. Fictive retching induced by vagal stimulation was still observed after each of 32 injections (0.5–5 μg in 1–30 μl) in the area ventrolateral to the solitary complex in six dogs. Retching was also observed for 30 min or more after all but 2 of 30 injections (0.5–1 μg in 0.5–1 μl) in the area dorsal to the retrofacial nucleus in 17 dogs. In contrast, retching disappeared within 5–30 min after each of 20 injections (0.5–1 μg in 1 μl) in the area adjacent to the semicompact part of the nucleus ambiguus (scAMB) in 15 dogs. The threshold dose for abolition of the retching response was examined in seven dogs and was about 0.1 ng in 1 μl. The maximum velocity of salivation occurred before the onset of retching and significantly decreased after its abolition. These results suggest that the site of the anti-emetic action of NK1 receptor antagonists may lie in a limited area adjacent to the scAMB, and that neurons in the site induce prodromal signs and retching in a sequential manner.

Association of sarcopenia with swallowing problems, related to nutrition and activities of daily living of elderly individuals

[Purpose] The purpose of the current study was to clarify problems associated with swallowing, related to nutrition and activities of daily living (ADL), in elderly individuals with sarcopenia. [Subjects and Methods] Seventy-seven subjects were assigned to a sarcopenia or a non-sarcopenia group according to a definition used by the European Working Group on Sarcopenia in Older People. Analyses were conducted including and excluding subjects with a central nervous system disorders in order to focus on the influence of sarcopenia. The swallowing ability, ADL, and nutrition levels were compared between the 2 groups. [Results] Swallowing function as well as ADL and nutrition levels were significantly lower in the sarcopenia group than in the non-sarcopenia group. [Conclusion] It is important to include dimensions of swallowing, nutrition, and ADL in the assessment and treatment of swallowing problems in elderly individuals with sarcopenia.

The tachykinin NK1 receptor antagonist GR205171 prevents vagal stimulation-induced retching but not neuronal transmission from emetic vagal afferents to solitary nucleus neurons in dogs

Tachykinin NK1 receptor antagonists injected into the medulla oblongata are known to abolish vomiting induced by vagal afferent stimulation. Emetic vagal afferents have been shown to synapse with neurons in the medial solitary nucleus (mNTS), which suggests that substance P is a transmitter in the synapse. To examine this possibility, the effects of GR205171, an NK1 receptor antagonist, on retching and mNTS neuronal responses to the stimulation of abdominal vagal afferents were investigated in decerebrate dogs. GR205171 (0.05-0.7 mg kg-1, i.v.) abolished retching induced by either vagal or mNTS stimulation within 5 min. Firing of mNTS neurons in response to pulse-train and sustained vagal stimulation did not change even after the abolition of retching. Similarly, GR205171 did not have any effects on mNTS evoked potentials induced by pulse-train vagal stimulation. In about 20% of mNTS neurons, the peak firing frequency was facilitated to about 150% with repetitive pulse-train vagal stimulation. This facilitation remained even after the abolition of retching. Administration of GR205171 (1 mg ml-1, 30 microliters) into the 4th ventricle abolished retching, with latencies in excess of 120 min These results suggest that substance P does not participate in synaptic transmission between emetic vagal afferents and mNTS neurons in dogs.

Capsaicin in the 4th ventricle abolishes retching and transmission of emetic vagal afferents to solitary nucleus neurons.

Systemic tachykinin NK1 receptor antagonists and resiniferatoxin are known to abolish vomiting mediated by vagal afferents. Emetic vagal afferents have been shown to make synaptic contact with neurons in the medial solitary nucleus. These results suggest that substance P participates in the synapse as a mediator. To examine this possibility, the effects of 4th-ventricular application of capsaicin (0.033-33 mM, 20-30 microl) and resiniferatoxin (1.6-160 microM, 20-30 microl) on the activity of neurons in the medial solitary nucleus and fictive retching induced by vagal stimulation were observed in paralyzed decerebrate dogs. Capsaicin (33 mM) and resiniferatoxin (160 microM) initially increased the neuronal firing and occasionally produced retching, then abolished both neuronal and retching responses. However, stimulation of the medial solitary nucleus continued to provoke retching. Field potential changes in the medial solitary nucleus evoked by pulse-train vagal stimulation decreased in amplitude, but did not disappear. Latencies of neuronal firing and evoked potentials were about 300 ms. These results suggest that emetic vagal afferents are capsaicin-sensitive C fibers which may have substance P as an excitatory transmitter or modulator.

Area postrema mediates gastric motor response induced by apomorphine in rats

The effects of apomorphine administration on the autonomic responses were investigated in rats. Distinctive gastric motor responses were observed after the intravenous administration of apomorphine (0.1 mg/kg body weight). Gastric motor responses in the distal stomach induced by apomorphine administration were classified into two types. One type involved inhibition of phasic contractions which appeared just after the administration of apomorphine. The other involved an increase in the frequency of small phasic contractions accompanied by increased gastric tone appearing with a relatively longer delay. No relaxation was observed in either the proximal or distal stomach. These gastric motor responses showed a dose-response effect to the amount of apomorphine administered (0.002-0.1 mg/kg body weight). In addition, submandibular salivary secretion was observed in response to the intravenous administration of apomorphine at a dose of 3 or 10 mg/kg body weight. Pretreatment with domperidone (1 or 2 mg/kg body weight) or the ablation of the area postrema (AP) abolished the gastric motor response and salivary secretion induced by the administration of apomorphine. In conclusion, rats showed definitive autonomic phenomena in response to the administration of apomorphine. Dopamine 2-like receptors situated in the AP mediate apomorphine-induced autonomic phenomena in rats.