Inhibitory control of the cough reflex by galanin receptors in the caudal nucleus tractus solitarii of the rabbit

Abstract

The caudal nucleus tractus solitarii (NTS) is the main central station of cough-related afferents and a strategic site for the modulation of the cough reflex. The similarities between the characteristics of central processing of nociceptive and cough-related inputs led us to hypothesize that galanin, a neuropeptide implicated in the control of pain, could also be involved in the regulation of the cough reflex at the level of the NTS, where galanin receptors have been found. We investigated the effects of galanin and galnon, a nonpeptide agonist at galanin receptors, on cough responses to mechanical and chemical (citric acid) stimulation of the tracheobronchial tree. Drugs were microinjected (30 -50 nl) into the caudal NTS of pentobarbital sodium-anesthetized, spontaneously breathing rabbits. Galnon antitussive effects on cough responses to the mechanical stimulation of the airway mucosa via a custom-built device were also investigated. Bilateral microinjections of 1 mM galanin markedly decreased cough number, peak abdominal activity, and increased cough-related total cycle duration. Bilateral microinjections of 1 mM galnon induced mild depressant effects on cough, whereas bilateral microinjections of 10 mM galnon caused marked antitussive effects consistent with those produced by galanin. Galnon effects were confirmed by using the cough-inducing device. The results indicate that galanin receptors play a role in the inhibitory control of the cough reflex at the level of the caudal NTS and provide hints for the development of novel antitussive strategies. airway defensive reflexes; galanin; galanin receptors; galnon; nucleus tractus solitarii COUGH IS A VERY IMPORTANT airway protective reflex and is one of the most common reason why patients seek medical attention. Cough is purposeful and useful under many circumstances, but in case of persistent or chronic cough (e.g., 15) is without an apparent aim and benefit and can results in a wide range of physical and psychological complications including urinary incontinence, insomnia, depression, and anxiety. The efficacy of antitussive drugs is far from clear from the available evidence and, in addition, limited by important side effects. Therefore, further research to find better antitussive approaches is necessary (for reviews see Refs. 4 and 15). Studies undertaken to provide insights into the neural mechanisms subserving the cough reflex may also provide useful suggestions for novel antitussive therapeutic strategies. The cough reflex involves several brain stem structures that also underlie respiratory rhythm generation (e.g., 7,9,10,19,24,27,[47][48][49]55).In particular, the nucleus tractus solitarii (NTS), especially in its caudal aspects, is the main central terminus of cough-related afferents (14, 39 -41, 43, 53 also for further references) and, in addition, a possible strategic site of synaptic plasticity, where cough-related sensory inputs can be modulated (e.g., 10,14,34,39,40,43).In recent years, we and other researchers have focused our attention on the s...

The cough reflex is upregulated by lisinopril microinjected into the caudal nucleus tractus solitarii of the rabbit

“…In all instances, no appreciable changes in the pattern of breathing and cough responses were observed. In accordance with the results of our previous studies on the NTS region (Mutolo et al, 2007(Mutolo et al, , 2008(Mutolo et al, , 2012(Mutolo et al, , 2014, control injections of equal volumes of the vehicle solution at the responsive sites (5 trials performed in 5 different preparations before drug administration) were ineffective.…”

“…All efforts were made to minimize both the number of animals used and their suffering. Experimental procedures and details about the methods employed have previously been described Mutolo et al, 2007Mutolo et al, , 2008Mutolo et al, , 2009Mutolo et al, , 2010Mutolo et al, , 2012Mutolo et al, , 2013Mutolo et al, , 2014.…”

“…Mechanical stimulation was delivered by a custom-built device recently described and validated (Mutolo et al, 2014) using a 0.5 mm diameter nylon fiber with a smoothed tip inserted through a lateral port of the tracheal cannula. The device allowed to set the number of forth and back movements or cycles (1-3 cycles), shaft velocity (10-20 mm/s), and shaft displacement (10-20 mm).…”

“…The inspiratory (T I ) and expiratory (T E ) times, as well as the total duration of the respiratory cycle (T T ) were measured on recordings of raw phrenic nerve activity (Mutolo et al, 2014;Poliacek et al, 2011). The respiratory frequency was subsequently calculated (breaths/min).…”

“…In four additional preparations, bilateral control microinjections of 1 mM lisinopril were performed at different medullary locations sufficiently far from the responsive sites Lipski et al, 1988;Mutolo et al, 2007Mutolo et al, , 2008Mutolo et al, , 2009Mutolo et al, , 2012Mutolo et al, , 2014Nicholson, 1985;Sykova and Nicholson, 2008). Four microinjections of 1 mM lisinopril were executed into each of the following neural structures (for comparison, see Meessen and Olszewski, 1949;Shek et al, 1986): the nucleus cuneatus medialis, the nucleus tractus spinalis nervi trigemini and the region located >0.8 mm caudal to the responsive NTS sites.…”