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In 1884 Henry Head was a 23-year-old medical student at Cambridge when he interrupted his medical studies to do research with Ewald Hering at the ‘German’ University in Prague. Hering had previously supervised a year's work by Josef Breuer which led to the classic paper on the control of breathing through the vagus nerves (Breuer, 1868). This paper established the Breuer-Hering inflation and deflation reflexes but was full of unanswered questions. Head answered many of them. He took 3 years over the research, and then a further 2 years before publication (Head, 1889a,b). This slowness and care were typical of Head. When he wrote a paper he read and corrected it five times; than placed it on a shelf for a year before rereading it and submitting it for publication. Happy days! Head split ‘On the Regulation of Respiration’ into two papers, ‘Experimental’ and ‘Theoretical’ they occupy 81 pages in Volume 10 of The Journal of Physiology. They are written with great clarity and precision and with meticulous attention to detail. They analyse the way in which lung volume changes in rabbits affect breathing via vagal reflexes. While no-one can doubt their nutrient value and digestibility they taste, nonetheless, like a large dollop of suet pudding. Yet buried in them are two sparkling little gems, well worth discovering. Head took advantage of the method of Gad (1880) of reversibly blocking the vagus nerves by cold, so that controls could be done before and after blockade. And, more importantly, he established a method of recording diaphragm contraction from an isolated xiphisternal muscle slip (‘Head's diaphragm slip preparation’). Previous methods allowed the stimulus of a lung volume change to interfere with what was being measured—lung volume changes – unless one observed movements of the nares, a very indirect alternative. (Head was certainly an innovator. He made and used a cuffed endobronchial tube of rabbit size, 50 years before it was reintroduced by anaesthetists for humans. A ‘woodcut’ illustrates this in his ‘Experimental’ paper. Will J Physiol still accept woodcuts?) The first of the two gems is a single page describing the discovery of the ‘paradoxical reflex’. When the vagus nerves were recovering from cold block, inflation of the lungs no longer inhibited inspiration (the Breuer-Hering inflation reflex, Fig. 1A), but strongly augmented it (Fig. 1B): ‘The strength of the inspiratory contractions is not increased but their duration is prolonged and … a tonic inspiratory contraction appears during the inflation’. Vagal section or further cooling abolished the response. He called the reflex ‘this paradoxical effect’ and said ‘I am totally at a loss to account for its appearance’. Earlier Breuer had said ‘It happened occasionally that, quite contrary to expectation, an animal responded to distension of the lung by air inflation with an inspiration instead of an expiration’; and ‘Obviously, in such animals only reactions that are entirely consistent merit attention’. Head found consistency and gave the reaction his attention. He had also discovered one of the few examples of positive feedbacks in the nervous system. Figure 1 Redrawings from Head (1889a) made by Cross (1961) Fifty years later the sensory mechanism of the paradoxical reflex was analysed by Larrabee & Knowlton (1946). They showed that it was mediated by rapidly adapting pulmonary stretch receptors (RARs) in the lungs, with properties quite distinct from those of the slowly adapting receptors (SARs) responsible for the Breuer-Hering inflation reflex. Later it was shown to be important in the first breath of babies (Cross, 1961) and in causing augmented breaths that reverse the tendency of the lungs to collapse during quiet breathing (Davies & Roumy, 1982). The second gem is the solution to a question left open by Breuer. He had shown that inflation of the lungs inhibits and deflation stimulates inspiration (the inflation and deflation Breuer-Hering reflexes), thus establishing the mechanism of the vagal reflex control of the pattern of breathing. But he didn't know if this was one or two reflexes. Since inflation could activate a reflex pathway and deflation could lessen the tonic activity of that pathway, only one afferent pathway was needed. Of the two hypotheses—one or two reflexes—Breuer concluded: ‘In the present state of this investigation I dare not proffer a definite suggestion as to which of these hypotheses is the correct one. I hope to come closer to a conclusion by further experimentation’. These further experiments were either not done or not reported. Breuer slid down a slippery slope to become the founder of psychoanalysis. But Head answered the question. ‘If both lungs are allowed to collapse suddenly by puncturing the thorax a much stronger inspiratory effort is produced than if both vagi were divided and yet … both operations equally remove the inhibitory stimuli normally passing up the vagi from the lungs’. ‘I think it is difficult to explain these differences unless we assume that collapse of the lungs below the normal volume produced an actual inspiratory stimulus’. He tucked these comments away in his ‘Theoretical’ paper. Identification of both the paradoxical and the deflation reflex were made possible by the use of the diaphragm slip preparation and vagal cooling. Again, it took 50 years before Larrabee & Knowlton (1946) and later workers analysed the mechanisms and significance of this separate deflation reflex. They showed that the same sensory receptors in the lungs, the RARs, mediated both reflexes. They were activated by both lung inflations and deflations, and reflexly caused inspiratory activity. I have selected less than two pages of Head's 81 page-long papers as having much importance today. I suspect that, if Head were alive today, he would agree. After Prague he returned to complete his medical studies at University College London, and then moved to the London Hospital and the Institute of Neurology, Queen Square, to become the most distinguished British neurologist of the 20th Century. His work with Hering may have been a hiccough in his career as a neurologist, but it was very important to him. It taught him scientific method and critique. He acknowledged the influence of Hering in the preface to his great book on aphasia by dedicating it to him. We should remember Head for his contributions to respiratory physiology even if he himself seemed rather unaware of their significance.

In 1970 Paintal described the J reflex, the inhibition of somatic muscle by stimulation of type J receptors in the alveolar walls of cats. Twenty years earlier he had begun studying these receptors, and named them ‘juxta-pulmonary capillary receptors’, or J receptors. They are now usually called pulmonary C fibre receptors, since they are one group in a population of airway receptors with non-myelinated afferent fibres, a population that includes bronchial, tracheal and laryngeal groups, probably together with nasal groups, and possibly pharyngeal and oral receptors. The evidence for the J reflex in cats is compelling. Deshpande & Devanandan (1970) showed that stimulation of C fibre receptors in cats depressed the somatic muscle stretch reflex. Kalia (1973) and Ginzel et al. (1971) showed that stimulation of C fibre receptors, whether the cats were anaesthetized, conscious or mesencephalic, led to a profound decrease in skeletal muscle stretch reflex (Fig. 1) and, if the cats were walking, to its attenuation or abolition. Paintal (1970) suggested that the reflex was present in man, and speculated that it would be a major factor in limiting severe exercise. The evidence was indirect: in cats the reflex is known to inhibit muscle tone and the pulmonary receptors are stimulated by an increase in pulmonary capillary pressure and flow. These pulmonary vascular changes also occur in human exercise and, therefore, it is argued, skeletal muscle force would be inhibited in exercising humans by the J reflex, and therefore limit the exercise. This important mechanism has never been established or refuted, until the paperby Gandevia et al. (1998) in this issue of The Journal of Physiology. They show that activation of C fibre receptors in humans by injections of lobeline, claimed to be a selective stimulant, increased the size of the H reflex in soleus and the size of EMG responses evoked in arm muscles by transcranial magnetic stimulation. The injections neither decreased the force of sustained contractions of the elbow flexors at submaximal or maximal levels, nor disrupted walking. The injections were known to be effective because they caused severe respiratory discomfort and cardiorespiratory responses including cough. In other words the skeletal muscle responses were precisely the opposite of what had been shown in the cat and what had been anticipated for human exercise. Figure 1 Records from an anaesthetized, atropinized cat Our understanding of the C fibre reflex in exercising humans is made more complicated by the extensive studies of Coleridge & Coleridge (1984). Working mainly with anaesthetized dogs and cats, they and others showed that activation of the receptors causes powerful reflex broncho- and laryngoconstriction, airway mucus secretion and mucosal vasodilatation, as well as confirming the hypopnoea, hypotension and bradycardia reported by Paintal (1970). And yet very few of these changes are seen in human exercise, even when extreme. In fact ventilation, blood pressure and heart rate all increase, laryngoconstriction seems unlikely, and there is no evidence for mucus secretion or mucosal vasodilatation. Another paradox relates to cough. This has never been shown with C fibre stimulation in experimental animals, anaesthetized or not; in fact in cats the cough reflex is inhibited (Tatar et al. 1988). Yet cough is a characteristic response to C fibre stimulation in relaxed humans, following some seconds after what is often intense laryngeal discomfort. This pattern suggests it may be a behavioural response to discomfort rather than a direct reflex. In exercise the cough may be suppressed or even absent. The tightness, even pain, felt in the chest during severe exercise, at least in unfit physiologists, may indicate that C fibre receptors are being stimulated. A further problem lies in the fact that, both in experimental animals and humans, the stimuli to C fibre receptors have mostly been intravascular injections of drugs, such as phenyl diguanide, capsaicin and lobeline. These drugs are not specific and probably not very selective. There are many examples of their different actions on lung receptors and reflexes in cats, rabbits and dogs. It is therefore quite unjustifiable to assume any similarity between their actions in humans and in cats. A clue to the different responses in cats and humans may lie in a neglected observation by Kalia (1970). She showed that in cats the J reflex was abolished by bilateral lesions involving the caudate nuclei, but if both cingulate gyri were destroyed the reflex inhibition was consistently reversed to an augmentation. Thus the cat brain has reflex pathways, activated by C fibre receptors, which can either increase or decrease the strength of skeletal muscle contractions. The balance between these two pathways may determine whether stretch reflexes are enhanced or inhibited; perhaps more appropriate to an experimental approach, different physiological conditions, e.g. other afferent nervous activities, could adjust the balance. The search for the J reflex in man should move towards situations where these tuning processes can be tested, as Gandevia et al. (1998) suggest. In 1868, Breuer & Hering described the inflation and deflation reflexes that bear their names; they also thought they had identified a third reflex from the lungs which was not volume dependent but which increased the frequency of breathing. They stated their intention to study this reflex further, but if they did they never published their results. (Breuer took up psychoanalysis and Hering was too busy as a Head of Department.) Fifty-five years ago Paintal studied this reflex and stimulated a vast flow of research that established its complexity and importance. It is good that there are still problems to be solved.

1. In pentobarbitone-anaesthetized dogs the nasal vasculature was perfused on both sides, and nasal vascular and airflow resistances were measured together with blood pressure, heart rate and tidal airflow. 2. Capsaicin was injected intravenously to stimulate lung C-fibre receptors, and veratrine to stimulate pulmonary stretch receptors and cardiac receptors. Injections with both drugs were repeated after pulmonary denervation and after cervical vagosympathectomy. 3. Intravenous capsaicin caused hypotension, bradycardia and rapid shallow breathing, together with a decrease in nasal vascular resistance and little change in nasal airways resistance. Denervation showed that these effects came from lung reflexes, presumably from C-fibre receptors. 4. Intravenous veratrine caused similar effects to capsaicin before denervations, presumably due to stimulation of slowly adapting pulmonary stretch receptors. Left atrial injections of veratrine caused hypotension, bradycardia and hyperpnoea, together with an increase in nasal vascular resistance and little change in nasal airways resistance. Thus cardiac receptors seem to increase nasal vascular resistance. 5. Injections of capsaicin and veratrine into the nasal circulation decreased nasal vascular resistance, with a stimulation of breathing and changes in blood pressure. Denervations indicated that these were a combination of local and reflex actions.

1. The dog trachea has a copious subepithelial vasculature supplied at the cranial end by arteries from the superior thyroid artery. The parasympathetic innervation is partly in the superior laryngeal nerves, stimulation of which causes vasodilatation on both sides. 2. Section of these nerves causes a small dilatation, suggesting that there is no significant resting parasympathetic dilator tone. 3. The dilator response to nerve stimulation is about halved when atropine is given, indicating a cholinergic mechanism. 4. The residual vasodilatation on nerve stimulation in the presence of atropine is reduced but not abolished by hexamethonium, suggesting that an antidromic vasodilator pathway can be activated. 5. Stimulation of the nerves increased tracheal mucosal thickness at the same time as vascular resistance decreased. Thus vasodilator mechanisms of parasympathetic origin may contribute to tracheal mucosal swelling and hyperaemia. 6. There is considerable vascular anastomosis between the two sides of the trachea, and possibly also a crossing-over of the parasympathetic innervation.

A method for the collection of rabbit nasal washings to analyse outputs of mucous glycoproteins is described. The radiolabels sodium [35S]sulphate and [3H]glucose are bound to the glycoproteins. The release of bound 35S and 3H was enhanced by cervical sympathetic nerve stimulation. Adrenoceptor agonists (phenylephrine, dobutamine and salbutamol) given I.V. increased the output of 35S, and the last two drugs increased the output of 3H. The blocking effects of thymoxamine and propranolol on these responses are described. Pilocarpine (given I.V. or intranasally) produced large increases in 35S release; histamine had little effect. Irritants (ammonia and cigarette smoke) and diluted serum or plasma, given intranasally, produced large increases in 3H output, and sometimes enhanced 35S release. Radiolabelled nasal washings fractionated on Sepharose CL-4B gel chromatography columns formed two peaks, with most of the radioactivity in the high molecular weight (mucous glycoprotein) peak.

1. The whole trachea of the ferret has been isolated in vitro in an organ bath and used to study the transport of bovine serum albumin (BSA) and two dextrans (70,000 and 9000 Da) from external buffer solution to air-filled lumen, assessed by fluorescent-labelled tracers. 2. In control conditions, when mucus secretion was not stimulated by drugs, the concentration of albumin in the lumen was over half that in the buffer, and about six times greater than those of the two dextrans. 3. Methacholine and phenylephrine caused large increases in mucus secretion and albumin output and decreases in albumin concentration. The responses were proportional to drug concentration. We concluded that albumin output is increased but diluted with submucosal gland secretion. 4. Salbutamol caused a small increase in mucus secretion and large increases in output and concentration of albumin. The concentration of albumin became greater than that in the external buffer medium. The responses were proportional to concentration of salbutamol. 5. Histamine increased mucus secretion and albumin output and concentration. 6. None of the four drugs increased the output of dextran-70,000. Methacholine and phenylephrine increased the output of dextran-9000, but to a far less extent than for albumin. 7. Cooling the trachea and buffer to 4 degrees C almost abolished the stimulation of mucus and albumin outputs due to methacholine. 8. Increasing the concentration of albumin external to the trachea did not proportionally increase albumin secretion, the logarithmic relationship suggesting saturation of an active transport system. 9. We conclude that albumin is secreted by active transport into the tracheal lumen, and that the rate of transport can be augmented by salbutamol to build up a higher concentration in the lumen than in the external buffer.

1. We have recorded afferent activity from ;single fibres' dissected from the superior laryngeal nerve of anaesthetized cats.2. Units which responded to gentle mechanical stimulation of the larynx epithelium were chosen for study.3. Receptors with myelinated fibres were grouped according to their spontaneous activity. Group 1 fibres had little or no spontaneous activity: group 2 fibres had constant and continuous spontaneous activity.4. Group 1 fibres had a wide range of adaptation rates. Their conduction velocities lay between 3.0 and 30 m/sec. The receptors were generally stimulated by ammonia and distilled water and often by CS riot control agent, 5 and 10% CO(2), 200 ppm SO(2), and cigarette smoke. Histamine, phenyl diguanide, graphite dust, 100 ppm SO(2) and saline drops did not generally excite the fibres.5. Group 2 fibres were slowly adapting. Their conduction velocities ranged between 8.0 and 26.5 m/sec. Ammonia usually, and distilled water sometimes, excited these fibres while 5 and 10% CO(2) mixtures inhibited them. A minority of group 2 fibres were pH sensitive, inhibited by acids and stimulated by alkaline buffers. Cigarette smoke had complex actions, either excitation, inhibition or, at different times, both. Histamine, P.d.g., CS, SO(2), saline drops and dust had no action on these fibres.6. Recordings were made from one unmyelinated fibre (conduction velocity 1.9 m/sec) which responded to stroking of the epithelium with a thread and to histamine, P.d.g. and ammonia vapour applied to the epithelium.7. We consider the site, method of excitation and reflex actions of the different receptors described.

1. With pentobarbitone-anaesthetized cats we have elicited cough reflexes from the tracheobronchial tree and the larynx, and the aspiration and sneeze reflexes from the nasopharynx and the nose respectively. The reflexes were induced by mechanical stimulation of the mucosa, before and during activation of pulmonary C-fibre receptors by intravenous injections of capsaicin or phenylbiguanide. 2. During the 20-30 s apnoea due to C-fibre stimulation, the cough reflex from both sites and the sneeze reflex were completely abolished, whereas the aspiration reflex response was approximately halved. Reflex contractions of genioglossus muscle still occurred at this time, but were far weaker than in the control state. 3. During the rapid shallow breathing that immediately followed apnoea due to C-fibre receptor stimulation, the defensive reflexes recovered: the aspiration and sneeze reflexes fully and the cough reflexes to about half of the control response. 4. Acute hypotension due to haemorrhage, of a size considerably greater than that due to stimulation of the pulmonary C-fibre receptors, caused no significant inhibition of the cough reflex from the tracheobronchial tree. 5. We conclude that the pulmonary C-fibre reflex powerfully inhibits airway defensive reflexes, and that its activation is unlikely to contribute positively to coughing induced by aerosols of capsaicin and similar agents.

1. With pentobarbitone-anaesthetized dogs, the cranial tracheal arteries have been independently perfused on both sides, to measure vascular resistance. Blood pressure and contractions of tracheal muscle were also measured. 2. Capsaicin was injected intravenously to stimulate lung C-fibre receptors. In breathing and in paralysed artificially ventilated dogs it decreased tracheal vascular resistance and blood pressure, and contracted tracheal muscle. The effects were abolished or far smaller after bilateral cervical vagosympathectomy. 3. Veratrine was injected intravenously to stimulate slowly adapting pulmonary stretch receptors and cardiac receptors. In breathing and in artificially ventilated dogs it lowered tracheal vascular resistance and blood pressure, and had variable effects on tracheal muscle tone. The vascular effects were prevented by vagotomy. 4. Veratrine injected into the left atrium caused similar vascular changes to intravenous administration. The changes were prevented by vagotomy. Veratrine causes a tracheal vasodilatation by action on cardiac receptors. 5. Inflation of the lungs in artificially ventilated dogs, to stimulate slowly adapting pulmonary stretch receptors, had no effect on tracheal vascular resistance but decreased blood pressure and tracheal muscle tone, the latter being prevented by vagotomy. 6. Bilateral carotid arterial occlusion, to decrease the discharge in carotid sinus baroreceptors, had no effect on tracheal vascular resistance but increased blood pressure and contracted tracheal muscle, the last two responses being greatly reduced by cutting the sinus nerves. 7. It is concluded that stimulation of lung C-fibre and cardiac receptors causes a reflex tracheal vasodilatation, but that no changes in the tracheal vascular bed occur with stimulation of slowly adapting pulmonary stretch receptors or inhibition of carotid sinus baroreceptors.