Noxious cold stimulation: pro–con perspectives on the hypothermic effect on experimentally evoked cough

To the Editor:

We read with great interest in the recent article by Hilton et al. [1] published in the European Respiratory Journal, about the effect of pain conditioning on experimentally evoked cough; the hypothesis and protocol are well thought out. The study showed that noxious cold-water-induced pain significantly reduced capsaicin-evoked cough; however, it was less effective in refractory chronic cough (RCC) patients than healthy volunteers. The results indicated that endogenous inhibitory control mechanisms, especially those activated by noxious stimuli-inducing pain (conditioned pain modulation, CPM), can modulate cough response evoked by capsaicin. Impairment of such mechanisms may contribute to persistent coughing in RCC patients.

To our knowledge, at present the effect of cold stimulation on cough remains controversial. The results reported by Hilton et al. [1] are inconsistent with the latest study conducted by Dong et al. [2]. The latter study reported that exposure of the whole body and trunk-limbs to cold environments significantly increased the cough response to cinnamaldehyde in guinea pigs with chronic cough via the activation of the TRPA1 signalling pathway in skin. This effect was abolished by pretreating the skin with TRPA1 antagonist. The results reported by Dong et al. [2] suggested that cold stimulation could aggravate cough by activating the cold receptors. However, Hilton et al. [1] may not have considered the potential effect of cold stimulation on cough receptors. Therefore, the role of impaired endogenous inhibitory control mechanisms on cough was possibly amplified in RCC patients. To eliminate the effect of cold stimulation on cough receptors, it is suggested to apply other conditioning stimuli (such as ischaemic pressure acting on a site of the body) to induce CPM effects [3].

Besides, the varying factors responsible for the different phenomenon observed in the two studies are worth considering. Firstly, the tussigenic agents applied were different. Capsaicin specifically acting on TRPV1 was utilised by Hilton et al. [1], while cinnamaldehyde, a TRPA1 agonist, was applied by Dong et al. [2]. TRPV1 is a heat-activated ion channel and TRPA1 is sensitive to cold [4]. Therefore, exposure to the cold environment mainly activated TRPA1, but not TRPV1. Secondly, cold stimulation acting on different body sites might contribute to the inconsistent effects due to the activated afferent nerves that innervate different parts of the body. A similar phenomenon has been reported, that heat stimuli delivered to different body sites induced a variety of pain intensity [5]. Moreover, the temperature set in the two studies was 10°C and 0°C, respectively. A previous study showed that immersing one hand into 46.5°C and 12°C water induced a significant decrease in pain scores, but no reduction in pain perception with exposure to 15°C, 18°C, 33°C and 44°C [6]. Thereby, it is speculated whether there is a threshold to differentiate between the activation and inhibition effect of temperature on coughing. Furthermore, anatomical structures and functions of the nervous system probably present some essential differences between human and guinea pigs. The cough reflex in human beings could be adjusted by consciousness through the higher brain, but this effect in animals remains to be determined further, and whether the thermoregulatory centre in the hypothalamus could regulate cough sensitivity is also unknown.

Yoshihara et al. [7] reported that repeated cold water skin stimulation inhibited capsaicin-induced cough in guinea pigs, which is similar to the results of Hilton et al. [1]. Additionally, the authors found that the reduction of coughing was associated with a reduction in the substance P (SP) which is contained in sensory nerves of the airway. In contrast, the levels of SP in bronchoalveolar lavage fluid were increased in guinea pigs and positively correlated to cough, when exposed to the cold environment in the study conducted by Dong et al. [2]. The reasons resulting in such differences remain unclear, but it is notable that the tussigenic agents and the exposure temperature were different. Neurogenic inflammation may play a crucial role in cold stimulation-mediated cough.

Moreover, we are concerned whether the ED50 dose of capsaicin inhaled at 15-s intervals within 1 min will generate rapidly adaptive response to capsaicin, as previous studies demonstrated that repeated inhalation of capsaicin in the short term to induce cough could result in tachyphylaxis [8]. In addition, if a greater reduction of coughing during cold water immersion is found in healthy volunteers than RCC patients, it will be more reasonable to speculate that endogenous inhibitory control mechanisms are impaired in RCC patients. However, the data reflecting the change of coughing during cold water immersion in healthy controls and RCC patients were not provided by Hilton et al. [1]. Previously, functional magnetic resonance imaging studies indicated that multiple brain regions in the patients with chronic cough, including the nucleus cuneiformis and periaqueductal gray, might be closely related to dysfunctional inhibitory control [9]. However, this mechanism still needs further exploration.

Generally, the study provides a novel insight into elucidating the mechanisms of RCC. The cold stimulation effect on the body may have bidirectional influences on cough response, based on inhibition of TRPV1 or excitation of TRPA1 in differential exposure temperature and areas. However, whether cold stimulation effect on the body decreases or increases cough response should be studied further.

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