Central SP/NK-1 signalling mediate cold-aggravated cough hypersensitivity in guinea pigs

Research question Cold exposure commonly worsens chronic cough, but mechanisms linking peripheral cold sensing to central cough hypersensitivity remain unclear. We examined whether cutaneous transient receptor potential ankyrin 1 (TRPA1) signalling contributes to cold-aggravated cough hypersensitivity via synaptic sensitisation and substance p (SP)/neurokinin-1 (NK-1) signalling in the paraventricular nucleus (PVN) and nucleus tractus solitarius (NTS). Materials and methods Cough hypersensitivity was induced in conscious guinea pigs by repeated citric acid inhalation. Trunk–limb cooling was applied with head and airways at room temperature. Cough reactivity to inhaled cinnamaldehyde was assessed. We inhibited cutaneous TRPA1 with HC-030031 and blocked NTS NK-1 receptors via stereotaxic microinjection. Neuronal activation, SP/NK-1 and airway TRPA1 expression, BALF SP levels, and NTS synaptic transmission were examined. Results Cold exposure increased cough reactivity in citric acid-sensitised guinea pigs and upregulated c-fos, SP, and NK-1 in PVN and NTS. Cutaneous HC-030031 pretreatment attenuated cold-induced neuronal and neuropeptide activation. NTS NK-1 receptor blockade reduced cold-aggravated cough responses, lowered BALF SP and airway TRPA1 upregulation, and dampened NTS central sensitisation. Patch-clamp recordings showed enhanced excitatory synaptic drive to NTS neurons after cold exposure, reversed by NK-1 antagonism; action potential firing was unchanged. Answer to the question Cold exposure is associated with aggravated cough hypersensitivity and altered cutaneous TRPA1 signalling, PVN activation, and SP/NK-1-mediated synaptic transmission in the NTS. Our data point to a peripheral-to-central pathway whereby cutaneous cold sensing may modulate brainstem cough processing. Cutaneous TRPA1 and NTS NK-1 signalling are candidate targets for further investigation in cold-aggravated cough.