Brainstem opioid peptidergic neurons regulate cough reflexes in mice

Cough is a vital defensive reflex for expelling harmful substances from the airway.The sensory afferents for the cough reflex have been intensively studied.However,the brain mechanisms underlying the cough reflex remain poorly understood.Here,we developed a paradigm to quantitatively measure cough-like reflexes in mice.Using this paradigm,we found that prodynorphin-expressing(Pdyn+)neurons in the nucleus of the solitary tract(NTS)are critical for capsaicin-induced cough-like reflexes.These neurons receive cough-related neural signals from Trpv1+vagal sensory neurons.The activation of Pdyn+NTS neurons triggered respiratory responses resembling cough-like reflexes.Among the divergent projections of Pdyn+NTS neurons,a glutamatergic pathway projecting to the caudal ventral respiratory group(cVRG),the canonical cough center,was necessary and sufficient for capsaicin-induced cough-like reflexes.These results reveal that Pdyn+NTS neurons,as a key neuronal population at the entry point of the vagus nerve to the brainstem,initiate cough-like reflexes in mice.

Neural Mechanisms Underlying the Coughing Reflex

Breathing is an intrinsic natural behavior and physiological process that maintains life.The rhythmic exchange of gases regulates the delicate balance of chemical constituents within an organism throughout its lifespan.However,chronic airway diseases,including asthma and chronic obstructive pulmonary disease,affect millions of people worldwide.Pathological airway conditions can disrupt respiration,causing asphyxia,cardiac arrest,and potential death.The innervation of the respiratory tract and the action of the immune system confer robust airway surveillance and protection against environmental irritants and pathogens.However,aberrant activation of the immune system or sensitization of the nervous system can contribute to the development of autoimmune airway disorders.Transient receptor potential ion channels and voltage-gated Na+channels play critical roles in sensing noxious stimuli within the respiratory tract and interacting with the immune system to generate neurogenic inflammation and airway hypersensitivity.Although recent studies have revealed the involvement of nociceptor neurons in airway diseases,the further neural circuitry underlying airway protection remains elusive.Unraveling the mechanism underpinning neural circuit regulation in the airway may provide precise therapeutic strategies and valuable insights into the management of airway diseases.