A human being can be considered as an open, living adaptive system that aims to adapt to the environment and survival. Like every system, it includes nested subsystems, that function as component parts. A system is defined by a set of components constituting a whole within which each component interacts with or is related to at least one other component. All these components serve a common objective. Some (sub)systems of the human body are the nervous, endocrine, and immune system, and they function interdependently. In the following, I will explain how these systems work, in what way these specific systems function interdependently, and why this is different for each individual.

An adaptive system usually has three key characteristics, namely:

1. Irritability: the system responds to a perturbation (e.g., a stressor) by moving away from an equilibrium to meet the challenge and return toward equilibrium afterwards.
2. Connectivity: connectivity patterns produce self-regulating feedback.
3. Plasticity: this reflects an often non-linear, selectively adaptation in response to alterations in the environment. A key aspect of non-linearity is that small perturbations can produce large system changes.

Some other characteristics of adaptive systems are self-organization and self-regulation.

A stressor might be considered as the cause of a perturbation and is defined as any event that induces a stress response and may be either a physical or social event, an invading microorganism or a signal of tissue trauma. Therefore, musculoskeletal injury (e.g., low back pain, ankle sprain or tendinopathy) or systemic disease (e.g., diabetes mellitus, rheumatoid arthritis or fibromyalgia) can be considered a stressor. A normal stress response consists of an alarm reaction, resistance, and recovery. The impact of a stressor is the extent of the response it induces and involves cognitive mediation. Cognitive mediation is involved because it is a function of both the predictability and controllability of the stressor. When a stressor persists for a longer period or when repeated stressors occur in fast sequence, the body cannot manage them. The result is a disturbance of the equilibrium in the body that may not be restored.

Any injurious event (a type of physical stressor) provokes autonomic and immune processes as well as sensory signaling. These processes interact and comprise a defensive biological response to injury. Tissue injury disrupts local tissue environment, triggers inflammation, constricts blood vessels, and stimulates immune response. More specifically, sympathetic responses at the injury restrict blood flow, subsequently keeping healing factors within the injured tissue. Next, a period of vasodilation produces an inflammatory response. C-fibers interact with injured tissue, by secreting pro-inflammatory peptides and signal injury. An acute phase reaction is generated and protects against microbial invasion. They sensitize the injured area to protect and promote tissue healing. As you may have noticed, characteristics of the nervous system (interaction of C-fibers), endocrine (vasodilation), and immune (pro-inflammatory peptides and protection against microbial invasion) systems are present during the acute phase of tissue healing.

Chronic injuries fail to repair themselves in a well-organized and timely fashion and remain perpetually. The healing process is incomplete and disorganized. A well-known example is chronic pain after commonplace or sometimes less commonplace injuries. Normal healing processes may be disrupted by emotional arousal. Emotional arousal increases sympathetic activity systemically through autonomic and endocrine mechanisms, resulting in reduction of blood flow. Diverse injuries may fail to heal, persisting as a focus of chronically disorganized, inflamed processes that respond maladaptive to systemic changes at the nervous, endocrine, and immune levels. Some chronic pain states reflect chronic injuries, but the key concept is persistence of chronic disorganization, it relates poorly or not at all to a focus of injury and incurs a constellation of related miseries like fatigue, sleep disturbance, and impaired physical and mental function. In many chronic patients, the local tissue environment appears to repair itself, but sensory processes remain abnormal, resulting in chronic pain. The first hypothesis for this type of chronic pain is the failure of the central nervous system processes to “reset” sensitizing adjustments after completion of complete tissue healing of the injury. A second hypothesis is that incomplete tissue healing may involve altered relationships between local tissue and higher order systems or related subsystems. This may be the case as a result of the impact of an injury extends beyond its local tissue environment to its interactions with higher order systems or these related subsystems.

To explain chronic injuries, we need to understand the cross-communication and interdependence of related subsystems like the nervous, endocrine, and immune system and consider it as a single overarching system that responds to tissue injury. Therefore, it is useful to summarize the individual contribution of each system. Next, the cross-communication and interdependence of these subsystems will be summarized. Consequently, the contribution of the whole system to the multidimensional subjective experience of pain can be considered. Therefore, the next paragraphs will summarize the response of the individual systems to tissue injury.

The nervous system is the primary agent for detecting and defending against threats in the external environment. The nociceptive C-fiber responds to tissue injury and participates actively in the injured tissue by releasing peptides that contribute to the dynamic process of inflammation. By the release of these peptides, a chemical “soup” of pro-algesic mediators is created. Nociceptor activation initiates neurogenic inflammatory processes that amplify responses to subsequent stimuli (noxious or innocuous). Sympathetic nerve terminals contribute to this sensitization by releasing specific neurotransmitters.

The endocrine system responds in two phases, a defensive arousal (fast response) and recovery (slow response). In the defensive arousal, any stimulus that threatens the biological (injury), psychological (cognitive stress) or psychosocial (work overload) integrity results in the release of neurotransmitters (catecholamines) into the blood stream. These substances increase the heart rate and breathing, tighten muscles, constrict blood vessels in parts of the body and initiate vasodilation in other parts of the body, such as brain, lung, and heart. Before this defensive arousal ends, the recovery phase already starts, to protect against an arousal overshoot. If the defensive state is too long or too strong, it can deplete neurotransmitters and dysregulate system functions. After the recovery phase stopped the defensive arousal when it is safe, it brings the body back to normalcy.

The immune system is the primary agent for the defense of the internal environment. It detects tissue injury in at least three ways: i) blood-borne immune messengers from tissue injury; ii) by nociceptor-induced sympathetic activation and subsequent stimulation of immune tissue; iii) by sympatho-adrenal-medullary axis and hypothalamic-pituitary-adrenal axis endocrine signaling. Immune messaging begins at the injured tissue and produces and releases pro-inflammatory cytokines. Other immune tissues and cells are activated and have a complex systemic impact. Immune and nervous system interact at the injured tissue. Sympathetic outflow following injury can directly modulate many aspects of immune activity and provide feedback. This is because all lymphoid organs have sympathetic nervous system innervation. Pro-inflammatory cytokines act on the vagus and glossopharyngeal nerves, hypothalamus, and other locations to trigger a cascade of unpleasant, activity-limiting symptoms.

From the above information, it is obvious that injuries activate processes in the nervous, endocrine, and immune system. These processes operate in an interdependent and integrated manner and their highly orchestrated agency in defending against threat employs self-regulation and self-direction. These systems communicate with each other by neurotransmitters, peptides, cytokines, and hormones and the effect of these substances is not always straightforward, because it also depends upon system context (e.g., prior experiences, psychosocial or psychological influences). At systems level, they deliver positive and negative feedback that makes continuous coordination possible and consequently move away or towards an equilibrium. The ‘chemical’ products of one subsystem provide messenger substances that provide feedback for another subsystem. When endogenous messenger substances disappear, occur in excess or become confounded by exogenous products (e.g., medications), feedback delivery may fail. Consequently, dysregulation of normal processes occurs.

As mentioned above, the individual patient can be considered a system as well and it exists within a larger system that influences the individual patient. The psychosocial system is such a system and contains a potential source of stressors and can result in a failure of injured tissue induced acute stress responses to resolve properly and consequently lead to chronic disorders.

This framework proposes that pain becomes chronic and disabling as a result of regulatory problems developing over time within the nervous-endocrine-immune system. Prolonged dysregulation can cause irreversible organ pathology and can generate noxious signaling. Dysregulation may present in at least four ways in chronic pain patients:

1. Biorhythm disturbance: disturbance of circadian rhythm.
2. Feedback dysfunction: a subsystem regulated by negative feedback breaks down in one way or another, for example through depletion of a key neurotransmitter or peptide.
3. Disturbed inter-subsystem coordination: the essential connectivity for cross-subsystem coordination may fail or break down. Dysfunction in one subsystem is likely to lead to dysfunction in the others.
4. Incomplete recovery: if a system fails to readjust to the normal level after the stress has passed. These setpoints are often straightforward to define and may be used to determine recovery.

Individual differences in stress response/recovery stem from inheritable (genetic and epigenetic mechanisms) and non-inheritable (environmental) factors. Generally, the influences interact to determine an individual’s unique vulnerability for developing chronic pain. A severe stressor, a cascade of stressors or continued self-generated stress-inducing thoughts can cause dysregulation in one or another subsystem. Genetic and epigenetic factors interact with environmental factors (e.g., psychosocial) to determine which organ system is most vulnerable. This contributes to the complexity of the development of chronic pain.

Michel GCAM Mertens

Graduate and research assistant Rehabilitation Sciences and Physiotherapy, research group MOVANT, University of Antwerp.

2022Pain in Motion

References and further reading:

This blog provides a simplified summary of the framework proposed by Chapman et al. For a more detailed explanation and extensive review of this Supersystem, you can read the full text:

Chapman CR, Tuckett RP, Song CW. Pain and Stress in a Systems Perspective: Reciprocal Neural, Endocrine, and Immune Interactions. The Journal of Pain. 2008;9(2):122-45.

Image by PublicDomainPictures from Pixabay

​