Towards an Understanding of the Neurophysiology of the Human Cough Reflex
Lead Research Organisation:
University of Manchester
Department Name: Medical and Human Sciences
Abstract
Coughing is essential to protect our lungs from harm. However, many people have a troublesome cough that interferes with their life by causing problems like incontinence, embarrassment or depression. Any cough lasting more than 8 weeks is known as a chronic cough.
Unfortunately, existing cough medications are often ineffective. To develop new treatments we need to understand more about the changes that occur in the human body that can lead to chronic cough.
Cough and pain are similar in many ways. Just as the brain has control over the amount of pain we feel by releasing morphine-like substances, the brain may also control coughing. This study will investigate whether the brain is no longer effective at controlling coughing in people with chronic cough. I aim to show that:
(i) The brain releases morphine-like substances which control coughing in healthy people, but not for people with chronic cough.
(ii) The brain is less effective at controlling coughing in women, explaining why more women develop a chronic cough.
Unfortunately, existing cough medications are often ineffective. To develop new treatments we need to understand more about the changes that occur in the human body that can lead to chronic cough.
Cough and pain are similar in many ways. Just as the brain has control over the amount of pain we feel by releasing morphine-like substances, the brain may also control coughing. This study will investigate whether the brain is no longer effective at controlling coughing in people with chronic cough. I aim to show that:
(i) The brain releases morphine-like substances which control coughing in healthy people, but not for people with chronic cough.
(ii) The brain is less effective at controlling coughing in women, explaining why more women develop a chronic cough.
Technical Summary
Background: Cough is a major unmet need, and is the most common reason for which patients seek medical attention. It has a huge impact on the UK economy (£1 billion/year). Chronic cough (cough lasting more than 8 weeks) affects 14-23 % of the adult non-smoking population and can substantially reduce quality of life. Existing cough treatments are ineffective.
Current understanding of the neurophysiology of the cough reflex is largely based on animal studies for which there are many limitations. An improved understanding of the mechanisms leading to excessive coughing in humans would identify targets for drug development.
I propose there are similarities between cough and pain. Both are protective in health, but can become mal-adaptive in disease. In chronic pain states, pathological changes include a decline in descending inhibitory pathways. One such inhibitory mechanism (Diffuse Noxious Inhibitory Controls or DNICs) can be activated by applying pain to one part of the body (conditioning stimulus) thereby reducing pain felt elsewhere (test stimulus). These are opiate mediated and are less effective in females.
Aim: To investigate whether inhibitory mechanisms are defective in chronic cough in humans.
Objectives: To demonstrate that:
(i) Opiate-sensitive inhibitory mechanisms control coughing in healthy subjects, but are impaired in chronic cough patients.
(ii) Inhibitory mechanisms are less effective in females.
Methods:
(A) I will develop a method for measuring cough inhibition. Capsaicin reproducibly elicits coughing when inhaled at increasing doubling concentrations. I will explore the relationship between concentration of capsaicin inhaled and number of coughs elicited to determine plateau cough response (coughmax). Coughmax will be compared in male and female healthy volunteers, asthmatics and chronic cough patients.
(B) Descending inhibitory control mechanisms will be investigated in chronic cough subjects and healthy controls. The effect of a painful/non-painful somatic conditioning stimulus (Diffuse Noxious Inhibitory Controls, DNIC) on coughmax will be compared.
(C) Inhibitory mechanisms activated by application of a painful stimulus will be blocked by injection of an opiate receptor antagonist, naloxone, and the effect compared in chronic cough patients and healthy controls.
Conclusion: This study will establish the role of Diffuse Noxious Inhibitory Controls (DNICs) in chronic cough and identify new targets for pharmacological intervention
Current understanding of the neurophysiology of the cough reflex is largely based on animal studies for which there are many limitations. An improved understanding of the mechanisms leading to excessive coughing in humans would identify targets for drug development.
I propose there are similarities between cough and pain. Both are protective in health, but can become mal-adaptive in disease. In chronic pain states, pathological changes include a decline in descending inhibitory pathways. One such inhibitory mechanism (Diffuse Noxious Inhibitory Controls or DNICs) can be activated by applying pain to one part of the body (conditioning stimulus) thereby reducing pain felt elsewhere (test stimulus). These are opiate mediated and are less effective in females.
Aim: To investigate whether inhibitory mechanisms are defective in chronic cough in humans.
Objectives: To demonstrate that:
(i) Opiate-sensitive inhibitory mechanisms control coughing in healthy subjects, but are impaired in chronic cough patients.
(ii) Inhibitory mechanisms are less effective in females.
Methods:
(A) I will develop a method for measuring cough inhibition. Capsaicin reproducibly elicits coughing when inhaled at increasing doubling concentrations. I will explore the relationship between concentration of capsaicin inhaled and number of coughs elicited to determine plateau cough response (coughmax). Coughmax will be compared in male and female healthy volunteers, asthmatics and chronic cough patients.
(B) Descending inhibitory control mechanisms will be investigated in chronic cough subjects and healthy controls. The effect of a painful/non-painful somatic conditioning stimulus (Diffuse Noxious Inhibitory Controls, DNIC) on coughmax will be compared.
(C) Inhibitory mechanisms activated by application of a painful stimulus will be blocked by injection of an opiate receptor antagonist, naloxone, and the effect compared in chronic cough patients and healthy controls.
Conclusion: This study will establish the role of Diffuse Noxious Inhibitory Controls (DNICs) in chronic cough and identify new targets for pharmacological intervention
