Stimulation Of Irritant Receptors Research Articles

Should the clinical study on opioid-induced cough continue?

Since Bohrer et al. [1] reported in 1990 that administering fentanyl through a central venous catheter induces the cough reflex, it has become well-known that remifentanil and fentanyl used for inducing general anesthesia cause a cough in various types of clinical situations. This has led to many clinical studies [2-4] thus far, and the research paper of Yoo et al. [5] is also included in this group. The proposed mechanisms through which opioids induce a cough are as follows: (1) pulmonary chemoreflex resulting from stimulation of C-fiber receptors (J receptors) [1], (2) stimulation of irritant receptors (rapidly adapting receptors) from deformation of the tracheobrochial wall by tracheal smooth muscle constriction [6], (3) the release of histamine from lung mast cells [7], and (4) the sudden adduction of the vocal cords or supraglottic obstruction by soft tissue caused by opioid-induced muscle rigidity [8]. Based on these mechanisms, many efforts have been made to reduce the cough reflex induced by opioid agents, and it has been reported that terbutaline (a selective beta-2 agonist) [9], salbutamol [7], lidocaine [10], ephedrine [11], clonidine [12], ketamine [13], and dexamethasone [5] are effective in reducing fenanyl-induced cough (FIC) or remifentanil induced cough (RIC). However, Elcock [14] referred to the paper of Hung et al. [2] that was included in the 2010 volume of Anesthesia and raised the question whether fentanyl really induces a cough with such a high frequency (18-65%) in clinical settings. Also, he stated that his experience of using fentanyl clinically (administering 30 mg of propofol when administering 100 ug of fentanyl before inducing anesthesia) did not induce a cough, and that he was perplexed that research on fentanyl-induced cough continues, and that in actuality, it is not problematic except for pediatric patients. As a result, he asserted that it is meaningless to conduct studies on this phenomenon because, at least for adults, the commonly used dosage of fentanyl does not pose any actual problem. There are also recent reports that recommend not administering the medicine because FIC and RIC are temporary and the pre-treatment itself can cause problems [15]. Moreover, there are studies showing good results from adjusting the administration method of fentanyl and remifentanil so that their blood concentration levels increase gradually, because it is the sudden rise of their blood concentration levels that trigger the cough inducing mechanisms. There are also reports of reducing coughs by administering fentanyl slowly [16] or by administering a small amount in advance, so that there is not a sudden increase in concentration [2]. Also, there are studies that coughs are reduced by administering remifentanil in separate doses [17] and by limiting the peak plasma concentration when infusing remifentanil by TCI [18]. The paper of Ambesh et al. [3] that was published in the British Journal of Anesthesia in 2010 also reported significantly reduced cough (32% to 4%) induced by 2.5 ug/kg of fentanyl if a huffing maneuver was done before inducing anesthesia. Thus, fentanyl and remifentanil induced cough can be significantly reduced even without medicinal prevention. The continuous repetition of the same form of clinical study for more than 20 years seems meaningless even though I do not totally agree with Elcock's opinion. I have also published a paper [19] in 1996 reporting that administration of fentanyl to pediatric patients leads to high-dosage dependency and frequent coughs, and administering lidocaine in advance reduces coughs. In 2010 I published a paper about the impact of FIC on endotracheal intubation in pediatric patients [4]. Although many studies have been carried out over decades, the mechanism of FIC or of RIC has not yet been found. Therefore, I believe it is more useful shed light on why a sudden increase in blood concentration induces a cough, instead of conducting studies about reducing its clinical frequency.

Evaluation of Trigeminal Sensitivity to Ammonia in Asthmatics and Healthy Human Volunteers

Asthmatics often report the triggering or exacerbation of respiratory symptoms following exposure to airborne irritants, which in some cases may result from stimulation of irritant receptors in the upper airways inducing reflexive bronchoconstriction. Ammonia (NH3) is a common constituent of commercially available household products, and in high concentration has the potential to elicit sensory irritation in the eyes and upper respiratory tract of humans. The goal of the present study was to evaluate the irritation potential of ammonia in asthmatics and healthy volunteers and to determine whether differences in nasal or ocular irritant sensitivity to ammonia between these two groups could account for the exacerbation of symptoms reported by asthmatics following exposure to an irritant. Twenty-five healthy and 15 mild/moderate persistent asthmatic volunteers, with reported sensitivity to household cleaning products, were evaluated for their sensitivity to the ocular and nasal irritancy of NH3. Lung function was evaluated at baseline and multiple time points following exposure. Irritation thresholds did not differ between asthmatics and healthy controls, nor did ratings of odor intensity, annoyance, and irritancy following exposure to NH3 concentrations at and above the irritant threshold for longer periods of time (30 s). Importantly, no changes in lung function occurred following exposure to NH3 for any individuals in either group. Thus, despite heightened symptom reports to environmental irritants among asthmatics, the ocular and nasal trigeminal system of mild to moderate asthmatics does not appear to be more sensitive or more reactive than that of nonasthmatics, nor does short-duration exposure to ammonia at irritant levels induce changes in lung function. At least in brief exposures, the basis for some asthmatics to experience adverse responses to volatile compounds in everyday life may arise from factors other than trigeminally mediated reflexes.

Smoking cessation improves both direct and indirect airway hyperresponsiveness in COPD.

Smoking induces chronic obstructive pulmonary disease (COPD) and is associated with airway inflammation and airway hyperresponsiveness (AHR). It has not been studied in COPD whether direct (methacholine) and indirect (adenosine-5'-monophosphate (AMP)) stimuli are associated with airway inflammation and neither whether smoking cessation improves these features. The current authors cross-sectionally investigated the relationship of AHR to methacholine and AMP with lung function and inflammatory cells in the sputum of 33 smokers with COPD. In addition, changes in these parameters were prospectively assessed in 14 smokers who successfully quit smoking for 1 yr. The presence of AHR to both methacholine and AMP was associated with lower lung function, but not with sputum inflammation. AHR to methacholine and AMP improved significantly after a 1-yr smoking cessation, yet this was unrelated to changes in sputum cell counts. The numbers of neutrophils and epithelial cells significantly increased with smoking cessation. Both direct and indirect airway hyperresponsiveness are associated with lower lung function, but not with sputum inflammation in chronic obstructive pulmonary disease. Interestingly, 1-yr smoking cessation improved both direct and indirect airway hyperresponsiveness, yet without a significant association with changes in lung function or sputum inflammation. Thus, other factors are likely to induce these improvements, e.g. a reduction in stimulation of irritant receptors, airway wall changes or mucus hypersecretion.

2 Upper airway reflexes

The maintenance of a clear unobstructed upper airway and the rapid return of normal laryngeal reflexes after the end of general anaesthesia form two of the most fundamental principles of modern anaesthetic practice. Upper airway reflexes are of considerable importance to clinical anaesthetists. The sensitivity of the upper airway reflexes are important during induction of anaesthesia, when heightened upper airway reflexes may lead to the development of life threatening laryngospasm. Following anaesthesia the larynx plays a primary role in protecting the lungs from aspiration of foreign material. The irritant nature of inhalation anaesthetic agents varies, with halothane being one of the least irritant. Newer agents including isoflurane and desflurane have been found to be associated with a much higher incidence of airway irritation. The intravenous anaesthetic induction agents thiopentone and propofol seem to have different actions on the sensitivity of upper airway reflexes during induction of anaesthesia, the upper airway appearing to be less irritable following propofol. Laryngospasm is a common and potentially dangerous complication of general anaesthesia, the incidence is higher in young children particularly between the ages of 1 and 3 months. Upper respiratory tract infection increases the incidence of laryngospasm. This is thought to be due to the viral infection causing shedding of epithelial cells, leading to increased exposure of intraepithelial sensory receptors to inhaled irritants. Histologically, sensory nerve fibres are found in almost all areas of the laryngeal mucosa. A particularly high density of sensory free nerve endings are found in the posterior supraglottis. Stimulation of irritant receptors in the upper respiratory tract causes a reflex motor response, afferent signals travel in the vagus nerve and project centrally to the caudal and posterior parts of the nucleus tractus solitarius. The efferent response results in vocal cord closure, changes in respiratory rhythm and coughing, which together act to protect the lower airway from foreign material.

Reflex responses of laryngeal and pharyngeal submucosal glands in dogs

In dogs tracheal secretion is enhanced reflexly and by locally acting mediators such as substance P (SP). To evaluate the role of these mechanisms on submucosal gland secretion in the larynx (L) and pharynx (Ph), we compared the effects of mechanical stimulation of intrapulmonary irritant receptors and stimulation of pulmonary C-fiber receptors by capsaicin (20 micrograms/kg iv) with the response produced by intravenous SP. In six alpha-chloralose-anesthetized, paralyzed, and artificially ventilated dogs, submucosal gland secretion was monitored by analyzing the areas covered by hillocks of liquid and calculating the volume of secreted liquid (microliter) in the L and Ph. Mechanical stimulation of the carina increased both the number of hillocks and the volume of secreted liquid in the L. Excitation of pulmonary C-fiber receptors also increased the number of hillocks, and total volume of secreted liquid was elevated from 1.9 +/- 0.5 to 8.3 +/- 1.4 microliters (P less than 0.01). These responses were significantly reduced by prior cervical vagotomy and intravenous administration of atropine. Neither stimulation of irritant receptors nor stimulation of pulmonary C-fiber receptors caused discernible effects on Ph submucosal gland secretion. However, intravenous SP increased the number of Ph hillocks and elevated the volume of secreted Ph liquid from 1.0 +/- 0.6 to 10.2 +/- 1 microliters (P less than 0.01); similar responses to intravenous SP were observed in the L. Prior intravenous administration of atropine methylnitrate or bilateral vagotomy did not alter Ph or L secretory responses to intravenous SP.(ABSTRACT TRUNCATED AT 250 WORDS)

Mechanical stimulation of canine respiratory tract and nasal vascular and airway resistances

Mechanical irritation of the upper airways (nose and larynx) decreased nasal vascular and airway resistances in anaesthetized dogs; the responses were probably due to dilatation of the nasal resistance and venous outflow blood vessels via stimulation of irritant receptors. Mechanical irritation of the lower airways (bronchi) increased nasal vascular resistance but decreased nasal airway resistance; the responses were probably due to constriction of nasal resistance and venous sinusoidal blood vessels via stimulation of cough receptors.

A nonlinear pharmacologic model of the acute effects of ozone on the human lungs

A pharmacologic model describing the quantitative relationship between short-term exposure to ozone and pulmonary airway resistance is described. The model simulates the following processes: (1) removal of a fraction of inhaled ozone in the airways of the head; (2) ozone oxidation of membrane-bound fatty acids in the target tissue in the lower airways; (3) rupture of cell membranes, releasing inflammatory mediators into the intercellular space; (4) migration of inflammatory cells into the injured tissue, releasing additional mediators and thus amplifying the inflammatory effect of ozone in a positive feedback loop; (5) stimulation of irritant receptors by ozone directly and by inflammatory mediators leading to vagally mediated bronchoconstriction. Mathematically the model consists of a logistic equation determining losses in the head, and a set of four differential equations simulating the uptake of ozone in the target tissue and the ensuing inflammation and bronchoconstriction. The observed human response to ozone in chamber studies is nonlinear, and it was necessary to introduce a nonlinear feedback loop for inflammation in the model to replicate this. Despite limited data upon which to base the model, it successfully predicts the human response to ozone reported in a series of published short-term chamber studies and is superior to "effective dose" (the product of ozone concentration, minute ventilation, and exposure duration) used by other investigations to describe dose-response relationships. Nonlinear multicompartment pharmacologic models such as this one can exhibit very complex behavior making the estimation of model parameters difficult, but they hold promise because the physiologic processes under study are themselves complex nonlinear phenomena.

Hyperresponsiveness of Cough Receptors in Patients with Bronchial Asthma

The hyperresponsiveness of cough receptors was evaluated using the acetic acid inhalation test in healthy adults, patients with bronchial asthma, and children with or without cough. The concentration of acetic acid inducing cough was more than 20% in all 16 healthy adults and 18 children in the control group. There were two groups of asthmatic patients: Those in group 1 showed normal response to more than 20% acetic acid (n = 46), and those in group 2 showed a sensitive reaction to less than 10% (n = 11). Mean age was 9.0 +/- 4.2 years in group 1 and 15.1 +/- 7.6 years in group 2 (statistical significance, P less than .001). Six of 11 asthmatic patients in group 2 were classified as nonallergic asthmatics, whereas only five of 46 patients in group 1 were nonallergic (P less than .01). Bronchoconstriction was not induced in any case, in spite of the production of cough. It is suggested that the hyperresponsiveness of individual cough receptors without the stimulation of irritant receptors be evaluated.

Sodium cromoglycate, verapamil and nicardipine antagonism to leukotriene D4 bronchoconstriction.

1--The effects of nicardipine, verapamil and sodium cromoglycate (SCG) on the increase in pulmonary airway resistance(RAw) and decrease in pulmonary dynamic compliance (CDyn) induced by leukotriene D4 (LTD4) 0.5 micrograms kg-1 and acetylcholine (ACh) 3 micrograms kg-1 were investigated in anaesthetized guinea-pigs. The effects of these three agents on the contractile effects of LTD4 and ACh were tested on isolated tracheal preparations of the guinea-pig. 2--Nicardipine and verapamil (0.3 and 1 mg kg-1), as well as SCG (3 and 10 mg kg-1), partially but significantly inhibited the effects of LTD4 on RAw. Partial inhibition of the effect of LTD4 on CDyn was only observed with verapamil (0.3 and 1 mg kg-1). Nicardipine and verapamil had no effect on ACh-induced bronchoconstriction in vivo. 3--In concentrations higher than 10(-5) M, nicardipine and verapamil inhibited the contractile effects of LTD4 and ACh on guinea-pig isolated trachea. SCG had no effect on this preparation. 4--These results suggest that nicardipine, verapamil and SCG partially reduce the component of bronchoconstriction associated with stimulation of irritant receptors by LTD4. However, the site and mechanism of action of Ca2+-entry antagonists remain uncertain.