▪ Abstract The detection of painful stimuli occurs primarily at the peripheral terminals of specialized sensory neurons called nociceptors. These small-diameter neurons transduce signals of a chemical, mechanical, or thermal nature into action potentials and transmit this information to the central nervous system, ultimately eliciting a perception of pain or discomfort. Little is known about the proteins that detect noxious stimuli, especially those of a physical nature. Here we review recent advances in the molecular characterization of the capsaicin (vanilloid) receptor, an excitatory ion channel expressed by nociceptors, which contributes to the detection and integration of pain-producing chemical and thermal stimuli. The analysis of vanilloid receptor gene knockout mice confirms the involvement of this channel in pain sensation, as well as in hypersensitivity to noxious stimuli following tissue injury. At the same time, these studies demonstrate the existence of redundant mechanisms for the sensation ...

https://sites.oxy.edu/clint/physio/article/thevanilloidreceptor.pdf

The Vanilloid Receptor: A Molecular Gateway to the Pain Pathway

Natriuretic peptides are a family of structurally related but genetically distinct hormones/paracrine factors that regulate blood volume, blood pressure, ventricular hypertrophy, pulmonary hypertension, fat metabolism, and long bone growth. The mammalian members are atrial natriuretic peptide, B-type natriuretic peptide, C-type natriuretic peptide, and possibly osteocrin/musclin. Three single membrane-spanning natriuretic peptide receptors (NPRs) have been identified. Two, NPR-A/GC-A/NPR1 and NPR-B/GC-B/NPR2, are transmembrane guanylyl cyclases, enzymes that catalyze the synthesis of cGMP. One, NPR-C/NPR3, lacks intrinsic enzymatic activity and controls the local concentrations of natriuretic peptides through constitutive receptor-mediated internalization and degradation. Single allele-inactivating mutations in the promoter of human NPR-A are associated with hypertension and heart failure, whereas homozygous inactivating mutations in human NPR-B cause a form of short-limbed dwarfism known as acromesomelic dysplasia type Maroteaux. The physiological effects of natriuretic peptides are elicited through three classes of cGMP binding proteins: cGMP-dependent protein kinases, cGMP-regulated phosphodiesterases, and cyclic nucleotide-gated ion channels. In this comprehensive review, the structure, function, regulation, and biological consequences of natriuretic peptides and their associated signaling proteins are described.

/pdf/natriuretic-peptides-their-receptors-and-cyclic-guanosine-mm2sqziu0p.pdf

Natriuretic peptides, their receptors, and cyclic guanosine monophosphate-dependent signaling functions.

Capsaicin-sensitive sensory neurons convey to the central nervous system signals (chemical and physical) arising from viscera and the skin which activate a variety of visceromotor and neuroendocrine reflexes integrated at various levels (intramurally in peripheral organs, at level of prevertebral ganglia, spinal and supraspinal level). Much evidence is now available that peripheral terminals of certain sensory neurons, widely distributed in skin and viscera have the ability to release, upon adequate stimulation, their transmitter content. In addition to the well-known "axon reflex" arrangement, the capsaicin-sensitive sensory neurons have the ability to release the stored transmitter also from the same terminal which is excited by the environmental stimulus. The efferent function of these sensory neurons is realized through the direct and indirect (i.e. mediated by activation of other cells) effects of released mediators. The action of released transmitters on postjunctional elements covers a wide range of effects which may have a physiological or pathological relevance. Development of drugs capable of controlling the sensory-efferent functions of the capsaicin-sensitive sensory neurons represent a new and very promising area of research for pharmacological treatment of various human diseases.

The sensory-efferent function of capsaicin-sensitive sensory neurons

Objective To review available information on cough and angioneurotic edema associated with angiotensin-converting enzyme (ACE) inhibitors Data sources All relevant articles from 1966 through 1991 were identified mainly through MEDLINE search and article bibliographies Study selection More than 400 articles were identified; 200 reporting incidence or possible mechanisms for the side effects or both were selected Data extraction and synthesis All pertinent information, including incidence and mechanisms of ACE inhibitor-induced cough and angioedema, was reviewed and collated Conclusions Cough occurs in 5% to 20% of patients treated with ACE inhibitors, recurring with reintroduction of the same or another ACE inhibitor It is more common in women The mechanism may involve accumulation of prostaglandins, kinins (such as bradykinin), or substance P (neurotransmitter present in respiratory tract C-fibers); both bradykinin and substance P are degraded by ACE A 4-day trial of withdrawal of the ACE inhibitor or temporary substitution of another class of antihypertensive agent inexpensively and easily ascertains if the ACE inhibitor caused the cough Change to another ACE inhibitor or additive therapy with nonsteroidal anti-inflammatory drugs is not recommended Prompt recognition of ACE inhibitor-related cough can prevent unnecessary diagnostic testing and treatment Angioedema occurs in 01% to 02% of patients receiving ACE inhibitors The onset usually occurs within hours or, at most, 1 week after starting therapy The mechanism may involve autoantibodies, bradykinin, or complement-system components Treatment involves first protecting the airway, followed by epinephrine, antihistamines, and corticosteroids if needed Therapy is then resumed with an alternate class of antihypertensive agent

Cough and angioneurotic edema associated with angiotensin-converting enzyme inhibitor therapy. A review of the literature and pathophysiology.

1. Hoe 140 (D-Arg-[Hyp3, Thi5, D-Tic7, Oic8]bradykinin) is a new bradykinin (BK)-antagonist. It was tested in several in vitro assays and compared with D-Arg-[Hyp2,Thi5,8,D-Phe7]BK. 2. In receptor binding studies in guinea-pig ileum preparations, Hoe 140 showed an IC50 of 1.07 x 10(-9) mol l-1 and a KI value of 7.98 x 10(-10) mol l-1. 3. In isolated organ preparations Hoe 140 and D-Arg-[Hyp2,Thi5,8, D-Phe7]BK inhibited bradykinin-induced contractions concentration dependently, with IC50-values in the guinea-pig ileum preparation of 1.1 x 10(-8) mol l-1 and 3 x 10(-5) mol l-1, respectively. pA2 values in this tissue were 8.42 and 6.18, respectively. In the rat uterus preparation the IC50 value was 4.9 x 10(-9) mol l-1 for Hoe 140. D-Arg-[Hyp2, Thi5,8, D-Phe7]BK showed an IC50 of 4.0 x 10(-6) mol l-1. The IC50 values in the guinea-pig isolated pulmonary artery were 5.4 x 10(-9) mol l-1 and 6.4 x 10(-6) mol l-1, respectively. In the rabbit aorta no inhibitory effects on Des-Arg9-BK induced contractions were observed. 4. In cultured bovine endothelial cells, Hoe 140 antagonized (IC50 = 10(-8) mol l-1) bradykinin-induced endothelium-derived relaxing factor (EDRF) release and the bradykinin-induced increase in cytosolic free calcium (IC50 = 10(-9) mol l-1). 5. Hoe 140 (10 -7mol I1) totally suppressed the bradykinin-induced (10 8 to 10- mol I') prostacyclin (PGI2) release from cultured endothelial cells of bovine aorta. D-Arg-[Hyp2, Thi5'8, D-Phe7]BK (10- 7 mol I1- ) showed a weaker antagonism. 6. Taken together these results show that Hoe 140 is a highly potent bradykinin antagonist. It was two to three orders of magnitude more potent than D-Arg-[Hyp2, Thi5 8, D-Phe7]BK.

Hoe 140 a new potent and long acting bradykinin-antagonist: in vivo studies

We have attempted in this review to give an account of an afferent vagal input from the lower respiratory tract that has still to be explored fully, and to present experimental evidence that this fine fibre afferent system plays a significant role in the neural control of respiratory function in both normal and pathological circumstances.

Afferent vagal C fibre innervation of the lungs and airways and its functional significance

Bradykinin is released in the lungs in asthma and pulmonary anaphylaxis. It has negligible direct bronchoconstrictor effects in humans or dogs, but inhaled as aerosol it causes cough and reflex bro...

Bradykinin stimulates afferent vagal C-fibers in intrapulmonary airways of dogs

1. We have examined the effect of bradykinin on impulse traffic in sympathetic afferent fibres from the heart, great vessels and pleura, and have attempted to identify cardiac nociceptors that on the basis of their functional characteristics might have a role in the initiation of cardiac pain. 2. In anaesthetized cats, we recorded afferent impulses from ‘single-fibre’ slips of the left 2nd--5th thoracic rami communicantes and associated chain, and selected fibres arising from endings in the heart, great vessels, pericardium and pleura. We applied bradykinin solution (0 . 1--1 . 0 microgram/ml.) locally to the site of the ending; we also injected bradykinin (0 . 3--1 . 0 microgram/kg) into the left atrium. 3. Afferent endings excited by bradykinin (159 of 191 tested) were of two types. The larger group (140) were primarily mechanoreceptors with A delta of C fibres (mean conduction velocity, 7 . 5 +/- 0 . 6 m/sec). They were very sensitive to light touch. Those located in the heart, great vessels or overlying pleura had a cardiac rhythm of discharge and were stimulated by an increase in blood pressure or cardiac volume. 4. Bradykinin increased mechanoreceptor firing from 0 . 7 +/- to 5 . 0 +/- 0 . 3 (mean +/- S.E. of mean) impulses/sec. Some endings appeared to be stimulated directly by bradykinin, others sensitized by it so that they responded more vigorously to the pulsatile mechanical stimulation associated with the cardiac cycle. 5. The smaller group of eighteen endings, of which ten were in the left ventricle, were primarily chemosensitive. Most had C fibres, a few had A delta fibres (mean conduction velocity, 2 . 3 +/- 0 . 7 m/sec). They were insensitive to light touch. With one exception they never fired with a cardiac rhythm, and even large increases in aortic or left ventricular pressure had little effect on impulse frequency. 6. Chemosensitive endings were stimulated by bradykinin, impulse activity increasing from 0 . 6 to 15 . 6 +/- 1 . 3 impulses/sec and remaining above the control level for 1-3 min. The evoked discharge, which was either continuous or occurred in irregular bursts, was not secondary to mechanical changes in the heart and great vessels. 7. Tachyphylaxis occurred when the interval between successive applications of bradykinin was 20 min or less. It was a feature of the response of both mechanosensitive and chemosensitive endings. 8. Because of their responsiveness to changes in pressure and their sensitivity to light touch, the mechanosensitive endings appear to be unlikely to subserve a primarily nociceptive function, although they may be responsible for evoking some of the components of the pseudoaffective response. By contrast, the chemosensitive endings appear well fitted to act as cardiac nociceptors.

https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1113/jphysiol.1980.sp013412

Search for a cardiac nociceptor: stimulation by bradykinin of sympathetic afferent nerve endings in the heart of the cat.

A great deal is known about afferent endings in the atrial walls of the heart. Histological studies have yielded descriptions of their appearance and distribution, and electrophysiological investigations have enabled their impulse activity to be extensively described (reviewed by Paintal, 1963). Less is known about receptors in the ventricles. A variety of afferent endings have been demonstrated histologically in the ventricular wall (see Discussion) but without any clearly defined pattern of distribution such as Nonidez (1937) found in the atrium. The impulse activity of ventricular fibres has been described in detail in cats (Paintal, 1955) and in frogs (Kolatat, Kramer & Miihl, 1957) but there has so far been no detailed account of these fibres in the dog. This is surprising in view of the many attempts made in this animal to evoke reflex effects by distending the ventricle (e.g. Salisbury, Cross & Rieben, 1960). The present paper describes experiments in which impulses were recorded in dogs from ventricular fibres with a cardiac rhythm of discharge, similar to those described by Paintal (1955) in the cat. In addition, other fibres were encountered with an irregular type of discharge and whose afferent endings were near the epicardial surface of the ventricles. Some further observations were also made on the distribution and nerve connexions of receptors in the atria.

https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1113/jphysiol.1964.sp007490

Cardiac receptors in the dog, with particular reference to two types of afferent ending in the ventricular wall.

This paper describes experiments in which impulses have been recorded from afferent vagal fibres whose endings were located in the lung. These fibres differed from the pulmonary stretch fibres described by Adrian (1933) and subsequent workers in that their spontaneous activity was sparse and irregular and showed no respiratory modulation at normal ventilation volumes. The fibres were stimulated, however, by inflating the lungs with larger volumes. The fibres appeared to be of small diameter, having a mean conduction velocity of 16 m/sec and a blocking temperature of 1-6° C. These slowly conducting fibres were identified in the following way. Capsaicin, a decylenic acid amide of vanillylamine, injected intravenously produces bradyeardia, systemic hypotension and apnoea (Toh, Lee & Kiang, 1955; Porsz6asz, Such & Porszasz-Gibiszer, 1957). Porsztasz et al. (1957) suggested that this triad of effects was evoked reflexly by stimulation of baroreceptors in the extrapulmonary parts of the pulmonary artery. Subsequently, Coleridge, Coleridge & Kidd (1964) found that although pulmonary arterial baroreceptors undoubtedly played a part in mediating the reflex effects, some other afferent endings within the vascular bed of the lung itself were probably involved. A search was therefore made for intrapulmonary receptors which were stimulated by capsaicin. The afferent fibres described in the present paper were encountered in the course of this work. They were the only pulmonary fibres consistently stimulated by capsaicin, the drug having little or no effect on the activity of pulmonary stretch fibres of the type described by Adrian (1933).

https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1113/jphysiol.1965.sp007660

Hazel M. Coleridge

Papers

Afferent vagal C fibre innervation of the lungs and airways and its functional significance

Bradykinin stimulates afferent vagal C-fibers in intrapulmonary airways of dogs

Search for a cardiac nociceptor: stimulation by bradykinin of sympathetic afferent nerve endings in the heart of the cat.

Cardiac receptors in the dog, with particular reference to two types of afferent ending in the ventricular wall.

Pulmonary afferent fibres of small diameter stimulated by capsaicin and by hyperinflation of the lungs.