The origin of the vomiting response: a neuroanatomical hypothesis.

The connections of area postrema include a set of nuclei with a common topographical location immediately deep to the ependyma or pia mater. These nuclei are all within two principal synapses of the area postrema and can be reached by more than one route from it. There is direct evidence that, like the area postrema, a number of these nuclei participate in vomiting. It is suggested that the paraventricular system may act as a distributed pattern generator for the several processes known to be integrated in the emetic response. It is also suggested that the other functions of the paraventricular nuclei, mainly homeostatic in mammals, have all evolved from a prototypical behaviour pattern of escape from, and subsequent avoidance of, noxious stimuli. Thus, through this system of nuclei, blood pressure, respiration, gastrointestinal motility and secretion, fluid and electrolyte balance, and the ingestion of food may all be influenced by noxious situations.

Effects of partial truncal vagotomy on intragastric pressure responses to vagal stimulation and gastric distension in ferrets.

Changes in intragastric pressure after dorsal truncal vagotomy, investigated by stimulation of the surviving vagal branches and by step inflation of the stomach, were divided into an early phase lasting five days, and a late phase continuing for at least three months. During the early phase the amplitude of vagal evoked contraction was diminished but the resting pressure and the response to gastric inflation were increased. After the fifth day vagal evoked contractions doubled in amplitude but the resting pressure and the response to step inflation of the stomach returned to control levels. Ventral vagotomy did not produce any substantial changes. Alterations to gastric and body weight, or to the relation between resting pressure and evoked contraction and relaxation were excluded as causes of the enhanced vagal effectiveness. Sprouting of axons into denervated territory occurred too late to explain the changes, but an increase in synaptic density within the innervated territory has not been ruled out.

Variation of the ferret skull (Mustela putorius furo L.) in relation to stereotaxic landmarks.

The ferret skull was investigated to identify reliable extracranial landmarks for stereotaxy. The skulls of 56 ferrets of both sexes were measured in a stereotaxic apparatus. Neither body weight nor an index of skull length proved to be reliable predictors of intracranial location. Sutures fused too early in life for lambda and bregma to be useful as landmarks in adult ferrets. The position of extracranial features was used to predict the position of intracranial features. For rostral intracranial features, the supraorbital processes were found to be the best predictors. Although the occipital crest was not the best predictor for posterior structures, it was the most practical. Using these landmarks, the prediction of intracranial location could be improved by more than 30%. Sexual dimorphism was found for all features examined except those nearest the interaural line. Female skulls were significantly smaller than male skulls and had less prominent sagittal and occipital crests. Males showed a substantial variation in the structures surrounding the pituitary gland. Fitches were also found to differ from albinos in having a more marked development of the sagittal crest.

Quantification of branched neuronal projections labelled by retrograde fluorescent tracing. A study of olivo-cerebellar projections.

A method for estimating the number of branched and unbranched neurones projecting from a nucleus to two target sites is presented, based on the retrograde transport of fluorescent tracers. The method initially involves stereological corrections for the size of cytoplasm and nuclei respectively labelled by the two tracers. A second correction is applied to account for doubly labelled cells whose cytoplasm, but not nuclei, are in the plane of section. Finally, the detection rates of the two tracers are determined and appropriate corrections are applied. The projection from the medial accessory olive to the cerebellar vermis was studied using true blue and diamidino yellow to illustrate the method. Application of the method increased the number of branched neurones detected by 18.5%. Of the total increase, 48.4% was due to the correction for size, 9.2% to the correction for doubly labelled cells with nuclei outside the plane of the section and 42.4% to the correction for detection rates. There was no significant masking of one tracer by another, but true blue enhanced the fluorescence of diamidino yellow.

Gastric tone modifies the responses to extrinsic neural stimuli in the anaesthetized ferret.

To determine the relation between resting intragastric pressure and neuronally evoked motility responses, the stomach of the anaesthetized ferret was inflated with two volumes within the physiological range. Vagal evoked contractions decreased as the resting pressure was increased. The decrease affected responses to high, but not low, intensity stimulation of the vagus. Vagal evoked relaxation of the stomach increased as a linear function of resting pressure. Atropine lowered the resting pressure in vagotomized ferrets but did not alter the relation between vagal evoked relaxation and resting pressure. Intra-arterial acetylcholine evoked a contraction followed by a relaxation. The contraction was reduced at higher resting pressures but the relaxation increased. Hexamethonium had no effect on the contraction but substantially reduced the relaxation. Stimulation of the greater splanchnic nerve evoked two responses. The first, direct relaxation of the stomach (independent of cholinergic activity), bore the same relation to resting pressure as vagal evoked relaxation. The second, inhibition of vagal evoked contraction, had no relation to resting pressure. The degree of reduction in the amplitude of vagal evoked contraction by an immediately preceding vagal stimulation decreased at higher resting pressures. This was the opposite of vagal evoked relaxation. The capacity of stimulation of one cervical vagus to evoke a response as large as that from stimulation of two cervical vagi was shown to depend on the use of near-maximal levels of stimulation. At low levels of stimulation the responses to two vagi were additive, and at the lowest levels there was facilitation. It was concluded that the effect of resting pressure on the amplitude of evoked contractions was mediated mainly by smooth muscle, although modulation of the quantities of transmitter released from nerves could play a minor part. The practical implications of manipulating resting pressure by changes in volume were discussed. In particular, the manipulation of resting pressure as a method of differentiating the mechanisms of central nervous influence on gastric motility was compared to surgical and pharmacological nerve block.

Characteristics of the vagally driven non-adrenergic, non-cholinergic inhibitory innervation of ferret gastric corpus.

This paper reports a quantitative in vivo study on the vagal activation of the intramural non-adrenergic, non-cholinergic inhibitory nerves in the ferret gastric corpus. The nature of the inhibitory neurotransmitter was also investigated. In the atropinized, guanethidine-treated, urethane-anaesthetized ferret, electrical stimulation (10 s at 20 V, 1-20 Hz, 0.5 ms pulses) of the cervical vagi produced a prompt fall in intracorpus pressure that was related to the stimulus frequency. The maximal response was achieved at 10 Hz. The time taken for the intracorpus pressure to return to pre-stimulus levels after a 10 s period of stimulation was related to the stimulus frequency; at 10 Hz the pressure took approximately 11 min to recover. In contrast to studies in the cat (Martinson & Muren, 1963), there was no detectable difference in the electrical threshold for activation of the vagal excitatory and vagal inhibitory fibres. The nature of the vagal non-adrenergic, non-cholinergic inhibitory neurotransmitter was investigated using a variety of antagonists and agonists. Adenosine triphosphate (ATP), adenosine, alpha beta-methylene ATP and beta gamma-methylene ATP all contracted the corpus in the presence of vagotomy, atropine, guanethidine and indomethacin. The vagally induced fall in corpus pressure was not blocked by high doses of alpha beta-methylene ATP. A variety of peptides were investigated for their effects on corpus pressure in the presence of atropine, guanethidine and vagotomy. Bombesin, pentagastrin, substance P, cholecystokinin octapeptide (CCK-8) and bradykinin all produced an increase in intracorpus pressure. Neurotensin and vasoactive intestinal polypeptide (VIP) both decreased intracorpus pressure, and of the two VIP most closely mimicked the response to vagal activation of the non-cholinergic, non-adrenergic inhibitory neurones. The results provide support for the involvement of a peptide (possibly VIP) rather than a purine in the vagally driven decrease in intracorpus pressure in the ferret.

Quantitative analysis of the topographical organization of olivocerebellar projections in the rat.

The inferior olivary projection to anterior and posterior regions of the cerebellar vermis was studied in the rat using the retrograde fluorescent double-labelling technique in combination with a computerized data collection system. A technique for quantifying and statistically analysing the point-to-point (or nucleotopic) organization of the projection is presented. It was found that one group of neurones in the medial accessory olivary nucleus projected to cerebellar lobules 6 or 7, and second group projected to lobules 4 or 5, while a third sent collaterals to both areas. In the rostral part of the nucleus these three groups were spatially separated (P less than 0.05), whereas caudally they were intermingled. It is concluded that a double-labelling method has distinct advantages over a single-tracer technique (such as horseradish peroxidase) in the investigation of the topographic organization of neuronal projections. Quantitative analysis is used here to overcome the problems presented by collateralization, inter-animal variation and the accurate representation of results from a series of animals.

Interactions between splanchnic and vagus nerves in the control of mean intragastric pressure in the ferret.

To determine whether splanchnic nerves relax the stomach by direct or indirect mechanisms, ramp inflations of the stomach, section and electrical stimulation of the vagus and greater splanchnic nerves, and step inflations of the duodenum were used. A high threshold, sustained inhibition of the gastric pressure response to ramp inflation was mediated by the vagus. Prior splanchnectomy increased vagal inhibition. The greater splanchnic nerves had no effect on gastric responses to inflation, although after vagotomy they were shown to be mediators of a low threshold, powerful but transient inhibition of the stomach. This was not dependent on intrinsic neurones with nicotinic receptors. Electrical stimulation of the greater splanchnic nerves produced a relaxation of the stomach, the magnitude of which was determined by resting pressure. Splanchnically mediated relaxation was not abolished by atropine, nor was it reduced by concurrent vagal stimulation. At submaximal levels of vagal stimulation the two nerves had a partially additive effective on relaxation. Duodenal inflation had an effect on intracorpus pressure similar to that of electrical stimulation of the greater splanchnic nerves on intragastric pressure. Reflex relaxation of the corpus evoked by duodenal distension was decreased by atropine but greatly increased by atropine coupled with vagotomy. These changes were caused by variations in resting pressure. It was concluded that the principal effect of splanchnic nerves on mean gastric pressure is direct and does not depend on inhibition of cholinergic neurones either centrally or peripherally. Evidence is presented for central interactions between the vagus and the greater splanchnic nerves in the anaesthetized ferret.

Variation between different samples of SITS with respect to axonal transport and toxicity.

Retrograde axonal transport of the fluorescent compound SITS has been described as occurring only from axon terminals and not from axons of passage. Injection of 4 different commercially available samples of SITS into terminations of cerebellar pathways in the rat revealed that only one sample produced retrogradely labelled neurones. Chemical analysis suggested that this was due to a unique fluorescent component (not SITS). This sample also contained other fluorescent components one of which, present in two other samples, produced paroxysmal motor disturbances. All of the samples examined contained several other fluorescent compounds.

The role of vagal and intramural inhibitory reflexes in the regulation of intragastric pressure in the ferret.

1. The step inflation technique combined with nerve section and pharmacological receptor blockade was used to determine the gastric distribution of the vagal inhibitory fibres and their role in the regulation of intragastric pressure in the anaesthetized ferret.2. Under the conditions described the predominant effect of the vagus was inhibitory. The dorsal abdominal vagus mediated more inhibition than the ventral vagal trunk. There was partial overlap in the inhibitory effects of the two trunks but, in contrast to excitatory effects, this overlap was less than complete.3. No evidence was found to indicate that the intramural inhibitory neurones (demonstrated pharmacologically) could be activated by a local distensive stimulus or that local inhibitory reflexes played an independent role in the regulation of intragastric pressure. The vago-vagal inhibitory reflexes play the major (possibly the only) part in the over-all regulation of intragastric pressure.4. After a step gastric inflation (50 ml. in < 3 sec) the time taken for the intragastric pressure to fall to 1/e of the peak pressure was a function of the number of inflations; the time decreased with increased number of inflations. It was apparently unaffected by nerve lesions.5. The intragastric pressure in response to an inflation, besides being a function of the neural reflexes evoked, was also related to the gastric weight and hence the size of the animal.6. The sum of the prevailing intragastric pressure and the response to vagal stimulation (10 Hz, 10 sec) was similar, irrespective of the intragastric fluid volume (10-80 ml.).7. The volume of fluid in the corpus was shown to be a major determinant of the contraction produced in response to vagal stimulation: as the corpus volume increased the corpus contraction decreased but the relaxation that follows the contraction increased. A similar effect was observed with intra-arterial ACh which implies that the response to stimulation was modified directly by the degree of stretch of the smooth muscle cells. Inhibitory effects were not apparent unless the stomach was moderately inflated.8. The relative roles of the vagal reflexes, intramural reflexes and the smooth muscle in the regulation of intragastric pressure are discussed in the light of the above observations.

The role of the vagus and splanchnic nerves in the regulation of intragastric pressure in the ferret.

1. The role of the vagus and splanchnic nerves in the regulation of intragastric pressure was investigated by quantifying the effect of nerve section on the response to a standard fluid inflation of the stomach. An opportunity was also taken to compare the responses to a step and physiological ramp inflation of the same volume (50 ml). 2. The peak pressure at the end ot the step inflation (13.6 +/- 1.0 cmH2O) was twice that for a ramp inflation (6.2 +/- 0.4 cmH2O). 5 min after the peak the pressures were similar (4.8 +/- 0.3 cmH2O; 4.7 +/- 0.3 cmH2O) for both. 3. Vagotomy produced a significant increase in the intragastric pressure response for both the peak and plateau levels of the step and ramp inflations. 4. Atropine produced a statistically significant decrease in the pressure response to both step and ramp inflation. 5. Splanchnic nerve section produced an increase in the intragastric pressure response to both step and ramp inflations although the values failed to reach the 5% significance level. However, following vagotomy or atropine, section of the splanchnic nerves produced a statistically significant increase in the pressure response to inflation. 6. These results indicate that the vagal cholinergic excitatory and vagal non-cholinergic, non-adrenergic inhibitory fibres are activated at physiological levels of gastric inflation and play a role in the regulation of intragastric pressure. The splanchnic nerves also play a role although in the intact animal they are suppressed by the action of the vagus nerve.

Peripheral functional organisation of vagally evoked gastric motor responses in the ferret.

The aims of the present study were to determine the relative amplitudes of intragastric motor responses evoked by different vagal branches and to establish whether the effects of acute or chronic vagotomy could be predicted from these data. Intragastric pressure responses to electrical stimulation of the vagus were measured in urethane-anaesthetised ferrets and acute or chronic vagotomies were performed. The results show that the left and right cervical vagi were equipotential and fully overlaped each other. Their contributions to the dorsal trunk were equipotential and fully overlapping and so were their contributions to the ventral trunk. The dorsal trunk was more effective than the ventral trunk and there was total functional overlap between these two trunks. Vagal evoked gastric motor responses of the ferret are apparently organised in a different way from vagally induced acid secretion or hormone release in the cat. Acute removal of a trunk led to a reduction in evoked responses that was not linear function of the effect of stimulation of that trunk. In contrast, chronic removal caused a relative increase in evoked responses that ws inversely related to the decrease caused by acute removal. The implications of total functional overlap and neuromuscular reorganisation after chronic vagotomy are discussed.

The clinical reliability of brain stem auditory evoked responses.

Auditory evoked responses thought to originate in the brain stem were investigated in patients with and without good evidence of brain stem pathology, and in healthy volunteers. The purpose of the investigation was to find a method of quantifying these evoked responses which would be clinically useful. The best quantitative measure was the latencies of certain peaks in the evoked response considered in combination. This measure indicated abnormal brain stem evoked responses in 64% of patients with good independent evidence of brain stem pathology; 23% of patients with equivocal independent evidence of brain stem pathology; and 0% of healthy volunteers.