What is the Role of Type III/IV Muscle Afferents in Airway Resistance and Thermoregulatory Responses to Exercise?

February 27, 2026 updated by: Northern Arizona University

Type III/IV Muscle Afferents in Airway and Thermoregulatory Responses

Exercise places serious demands on the body. These demands are fundamentally caused by increases in oxygen demand and the consequent increase in body temperature. These demands are met by several physiological responses, including increases in heart rate, blood pressure, breathing and blood flow. These responses must be proportional to the increase in demand and some signal must relay information from the muscle to the brain. Group III/IV afferents do just this. They relay information about the muscle (movement, temperature, acidity, etc.) up to the brain so that appropriate responses are mounted. There is strong evidence in animals that group III/IV afferents play a key role in making breathing easier (decreasing airway resistance) and initiating sweating and blood flow responses. There has been no research on the role of group III/IV afferents on these fundamental exercise responses in humans. The investigators propose to isolate the role of group III/IV afferents on regulate airway resistance, sweating and blood flow responses to exercise in humans.

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

Detailed Description

Group III/IV afferents are nerves that relay information from the muscles to the central nervous system. This afferent activity acts as negative feedback to minimize the overall strain placed on muscles . Without this negative feedback, locomotor muscles become damaged during intense exercise. It is well-established that group III/IV afferents are required for normal breathing and blood pressure responses to physical activity. In certain disease states, such as chronic obstructive pulmonary disease, heart failure and hypertension, group III/IV afferents become dysfunctional and lead to exercise intolerance. This is a major issue in these patient groups where regular exercise is advocated to slow or halt disease progression. Understanding how these reflexes contribute to basic cardiorespiratory responses to exercise is thus warranted.

At the onset of exercise, there is a near instantaneous decrease in airway resistance that permits high rates of breathing ; these high rates of breathing are essential to ensure appropriate oxygen transport to working muscles. The decrease in airway resistance is facilitated by a rapid withdrawal of parasympathetic tone to the smooth muscle lining the airways, allowing them to open up and remain rigid. Evidence in cats and dogs indicate that group III/IV afferents reflexively contribute to this response, thereby coupling airway dilation to muscle work. Airway resistance can be quantified by measuring the work required by breathing muscles to pull air into and push air out of the lungs. If the magnitude of airway dilation changes due to the suppression of group III/IV afferents, the investigators would observe a compensatory increase in how much work is required to overcome resistance. This has not been investigated directly in humans.

Alongside the fundamental cardiorespiratory responses to exercise, humans mount powerful thermoregulatory responses that dissipate heat generated from muscle work. The primary thermoregulatory responses in humans are eccrine sweating and skin vasodilation; both of which are activated as body temperature rises. Exercise augments thermoregulatory responses to heating, and sweating is initiated within 1-2 seconds of initiating exercise despite body temperature remaining stable. Thus, there is clearly a link between muscular work and thermoregulation. Reduced preparations in cats have shown that group III/IV afferent activity is elevated during external muscle heating, and human sweating responses are more closely coupled to muscle temperature than to core or skin temperature. To date, no study in humans has tried to isolate the role of group III/IV afferents on thermoregulatory responses to exercise.

These group III/IV afferents can be studied in exercising humans by suppressing their activity using intrathecal (spinal) opioids. Simply, a subject exercises on two different occasions, one with intact muscle reflex feedback, and the other with the feedback suppressed; differences in exercise responses are isolated to the role of group III/IV afferents. The investigators aim to use this model to quantify the contribution of group III/IV afferent reflexes to airway resistance, sweating and skin vasodilation.

Study Type

Interventional

Enrollment (Estimated)

15

Phase

  • Early Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • United States
    • Arizona
      • Flagstaff, Arizona, United States, 86011
        • Northern Arizona University
        • Contact:
        • Sub-Investigator:
          • RILEY CONNOR, MS
        • Principal Investigator:
          • TRAVIS D GIBBONS, PhD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult

Accepts Healthy Volunteers

Yes

Description

Inclusion Criteria:

  • regularly physically active as determined via questionnaires (Par-Q & You)
  • maximal aerobic power 30 mL/min/kg (female), 40 mL/kg/min (male)

Exclusion Criteria:

  • current smokers
  • acute bronchial asthma
  • diabetics
  • chronic back pain
  • peripheral neuropathy
  • chronic obstructive airway or status asthmaticus
  • obese (body mass index > 30 kg/m2)
  • convulsive disorders
  • requiring daily medications that may affect responses to exercise (e.g. anti-hypertensive, anti-arrhythmogenics, blood thinners)
  • history of drug abuse
  • history of disease/dysfunction that could cause complication with exercise (e.g. cardiovascular, respiratory, neurological, musculoskeletal)
  • irregular or absent menstrual cycle
  • pregnant or suspected pregnancy
  • adverse response to physical exercise
  • current or history of esophageal or gastric disease, or frequent heart burn (>2x per week)
  • Lidocaine allergy

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Placebo Comparator: Placebo-control
Exercise with saline injection
Drug: EXERCISE TRAINING WITH OR WITHOUT MEDICATION
Cycling exercise with group III/IV afferent feedback blocked via drug
Experimental: Group III/IV afferent blockade
Feedback from group III/IV afferents is blocked
Drug: EXERCISE TRAINING WITH OR WITHOUT MEDICATION
Cycling exercise with group III/IV afferent feedback blocked via drug

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Airway resistance
Time Frame: 2 weeks
Calculated based of work of breathing and ventilation flow rate
2 weeks
Sweat rate
Time Frame: 2 weeks
Local eccrine sweat rates at 3 different sites
2 weeks
Skin blood flow
Time Frame: 2 weeks
Skin blood flux measured at different skin sites
2 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Northern Arizona University

Investigators

  • Principal Investigator: TRAVIS D GIBBONS, PhD, Northern Arizona University

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

April 1, 2026

Primary Completion (Estimated)

December 31, 2026

Study Completion (Estimated)

April 1, 2027

Study Registration Dates

First Submitted

December 24, 2025

First Submitted That Met QC Criteria

February 27, 2026

First Posted (Actual)

March 5, 2026

Study Record Updates

Last Update Posted (Actual)

March 5, 2026

Last Update Submitted That Met QC Criteria

February 27, 2026

Last Verified

December 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2357749

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

IPD Plan Description

I am concerned for privacy protection of our participants.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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