How Environmental and Physiological Changes Trigger Pain

THE CARCO STRESS MODEL: Carbon Monoxide Exposure → Peroxynitrite Formation in Capillaries → Fibrin Amyloid Formation → Microvascular Obstruction → Reduced Mitochondrial Oxygen Availability → Aerobic Energy Production Failure → Systemic Dysfunctions

Pain in this model does not begin with the environmental trigger itself. It begins with an already compromised microcirculation in which fibrin-amyloid structures can restrict small-vessel blood flow. The trigger then further reduces oxygen availability, interferes with removal of metabolic products, or changes the physical conditions around the tissue. These changes alter the chemical and ionic environment around sensory nerve endings and can activate or sensitize nociceptors — the pain-sensing nerve endings.

1. Reduced Microvascular Blood Flow

Small blood vessels deliver oxygen and nutrients to tissue and remove carbon dioxide, hydrogen ions, and other metabolic products. When microvascular blood flow is reduced, tissue receives less oxygen and nutrients while metabolic waste products are cleared more slowly.

Reduced microvascular blood flow → reduced oxygen and nutrient availability + impaired removal of metabolic products → disturbed cellular energy production and ion regulation → increased H⁺ concentration and other changes in the local tissue environment → activation or sensitization of nociceptors → pain.

Studies of chronic pain conditions have reported reduced nutritive or capillary blood flow, microvascular abnormalities, tissue oxygenation abnormalities, and metabolic changes, including in CRPS and fibromyalgia (1).

2. Increased Blood Viscosity

Blood viscosity describes how easily blood flows. When blood becomes more viscous, it encounters greater resistance, particularly in small vessels.

Increased blood viscosity → greater resistance to blood flow → reduced microvascular perfusion → reduced tissue oxygen availability + slower removal of CO₂, H⁺ and other metabolic products → altered tissue chemistry → activation or sensitization of nociceptors → pain.

Experimental research also indicates that viscosity can influence endothelial signaling and capillary recruitment, meaning that changes in blood viscosity can directly affect microvascular blood-flow regulation (2).

3. Dry Indoor Air and Fluid Loss

Dry indoor air means that the air contains relatively little water vapour. This is particularly common during winter. Cold outdoor air contains little absolute moisture, and when that air is brought indoors and heated by radiators, its relative humidity can fall substantially.

Water is continuously lost from the body through the skin and respiratory tract. At very low humidity, this invisible water loss increases. A controlled human study found that low relative humidity increased insensible water loss, and that the combination of low humidity and low atmospheric pressure produced an even greater loss of body fluid (3).

Dry indoor air → increased water loss through skin and respiration → reduced body-fluid volume → more concentrated blood and potentially increased blood viscosity → greater resistance to microvascular flow → reduced tissue perfusion → reduced oxygen availability + slower removal of H⁺ and other metabolic products → increased H⁺ concentration and altered ionic environment around sensory nerve endings → nociceptor activation or sensitization → pain.

This provides a physiological pathway by which very dry indoor air could worsen pain in tissue that already has restricted microvascular reserve.

4. Cold Temperature

Cold can reduce tissue blood flow through vasoconstriction. Cooling also changes the physical properties of blood: blood becomes more viscous and red blood cells can become less deformable.

Cold → vasoconstriction + increased blood viscosity + reduced red-cell deformability → reduced microvascular blood flow → reduced tissue oxygen availability → impaired metabolic-product clearance → increased H⁺ and other chemical changes in the tissue → activation or sensitization of nociceptors → pain.

Experimental measurements have demonstrated increased blood viscosity and reduced erythrocyte deformability when temperature falls (4).

5. Low Atmospheric Pressure

Low atmospheric pressure is a separate environmental factor from dry air and cold. A fall in atmospheric pressure can alter the physical pressure environment surrounding the body and, when the pressure reduction is sufficiently large, reduce the oxygen pressure available for breathing.

Low atmospheric pressure → altered pressure environment + reduced ambient oxygen pressure at sufficiently low atmospheric pressure → reduced tissue oxygen availability in a system with limited reserve → greater dependence on glycolytic metabolism and disturbed cellular ion regulation → increased H⁺ concentration and altered extracellular ionic conditions → activation or sensitization of acid-sensitive and other nociceptors → pain.

Low pressure can also interact with fluid balance. In controlled human experiments, low pressure increased body-fluid loss and blood viscosity, while the combination of low pressure and low humidity produced the greatest fluid loss (3).

Thus, in a tissue already affected by restricted microvascular flow, low atmospheric pressure can add another reduction in the available physiological reserve rather than acting through one single mechanism.

6. Changes in Tissue Pressure

When oxygen availability and cellular energy production become inadequate, ATP-dependent systems that regulate ions and cell volume can become less effective. Sodium, potassium, calcium and hydrogen-ion gradients require active cellular regulation.

Disturbed ion and fluid regulation → water moves into cells → cellular swelling → increased pressure within the tissue → compression of small vessels → further reduction in microvascular blood flow → further reduction in oxygen availability.

This can create a reinforcing cycle in which impaired perfusion contributes to tissue swelling, while the resulting tissue pressure further restricts perfusion.

7. Reduced Oxygen Availability Activates Pain Receptors

Reduced oxygen availability becomes a pain mechanism when it changes the chemical environment surrounding sensory nerve endings. Carbon monoxide is one example of an exposure that can further reduce oxygen availability by impairing oxygen transport and cellular oxygen use. 

Insufficient oxygen relative to metabolic demand → reduced aerobic ATP production → increased dependence on glycolysis + impaired ion regulation → increased H⁺ concentration and altered extracellular ions → activation or sensitization of nociceptors → pain signals transmitted through sensory nerves.

Acid-sensitive ion channels such as ASICs can respond directly to increased extracellular hydrogen-ion concentration and reduced tissue pH. Other chemical signals released by metabolically stressed tissue can also increase nociceptor activity (5).

8. Disturbed Calcium Regulation Can Maintain Muscle Pain

Calcium must be actively transported after muscle contraction so that the contractile machinery can relax. This process requires ATP.

Reduced oxygen availability → reduced aerobic ATP production → impaired calcium removal → prolonged intracellular calcium elevation → prolonged muscle activation and impaired relaxation → continuing stimulation of sensory nerve endings → muscle aching, burning, tightness or pain.

The resulting sensation does not require structural muscle damage. A muscle can become painful because its normal contraction–relaxation cycle is not being completed efficiently.

9. Hydrogen Ions and Tissue Acidity

Hydrogen ions are one of the most direct chemical links between metabolic disturbance and pain.

Reduced oxygen availability + continued metabolic demand → increased glycolytic activity and H⁺ production → reduced local tissue pH → activation or sensitization of acid-sensitive nociceptors → pain.

At the same time, reduced microvascular flow slows removal of H⁺ from the tissue. The result is not simply more acid being produced, but acid remaining in the local tissue environment for longer.

The important pain-related mechanism is therefore the change in local hydrogen-ion concentration and pH, rather than lactate itself. Lactate may accompany increased glycolytic activity, but the acid-sensitive sensory response is linked to the chemical environment, particularly H⁺ and pH (5).

10. Why Environmental Triggers Can Produce Disproportionate Pain

The same environmental conditions do not necessarily produce pain when microvascular blood flow and tissue oxygen availability are normal. In this model, the crucial difference is whether the microcirculation can maintain adequate blood flow, oxygen availability, and removal of metabolic products when an additional environmental stress occurs. 

If fibrin-amyloid structures are already restricting microvascular flow, tissue may have reduced oxygen availability and limited capacity to compensate for additional physiological stress.

The sequence is therefore:

Carbon Monoxide exposure → Fibrin Amyloid structures →  Microvascular obstruction → reduced tissue oxygen availability → reduced cellular energy production → disturbed calcium and ion regulation → increased H⁺ and altered tissue chemistry → nociceptor activation or sensitization → pain.

An environmental trigger can then push this system further:

Dry indoor air → increased water loss through the skin and respiratory tract → fluid loss → increased blood concentration/viscosity → reduced microvascular flow → reduced oxygen availability → increased reliance on anaerobic glycolysis → increased lactate/H⁺ production + impaired clearance → decreased tissue pH (increased acidity) → nociceptor activation → pain.

Cold → vasoconstriction + increased blood viscosity → reduced microvascular flow → reduced oxygen availability → increased reliance on anaerobic glycolysis → increased lactate/H⁺ production + impaired clearance → decreased tissue pH (increased acidity) → nociceptor activation → pain.

Low atmospheric pressure → reduced ambient oxygen pressure + possible fluid-loss effects → further reduction in tissue oxygen availability → increased reliance on anaerobic glycolysis → increased lactate/H⁺ production + impaired clearance → decreased tissue pH (increased acidity) → nociceptor activation → pain.

Increased tissue pressure → compression of small vessels → reduced microvascular flow → reduced oxygen availability → increased reliance on anaerobic glycolysis → increased lactate/H⁺ production + impaired clearance → decreased tissue pH (increased acidity) → altered cellular ion regulation → nociceptor activation → pain.

This is why the trigger and the pain mechanism should be treated as two connected but separate parts: the trigger changes the physiological conditions, while the resulting changes in tissue chemistry, ions, oxygen availability and cellular function activate or sensitize the pain-sensing nerves.

Sources