The Hypothalamic-Pituitary-Adrenal (HPA) axis is a complex set of direct influences and feedback interactions between and among the hypothalamus (a hollow, funnel-shaped part of the brain), the pituitary gland (a pea-shaped structure located below the hypothalamus), and the adrenal (or suprarenal) glands (small, conical organs on top of the kidneys). The interactions among these organs constitute the HPA axis, a major part of the neuroendocrine system that affects reactions to stress and is related to many body processes, including digestion, immune system activity, mood, emotions, sexuality, energy storage and energy expenditure. Elements of the HPA axis are present in a wide variety of species, from the most ancient organisms to humans. The HPA axis is the common mechanism for interactions among glands, hormones, and parts of the midbrain that mediate the general adaptation syndrome (GAS). It produces Adrenocorticotropic Hormone (ACTH), cortisol, epinephrine, norepinephrine, and vasopressin (Anti-Diuretic Hormone, or ADH). The HPA axis plays an important role in allostasis, but it cannot explain tissue repair, and therefore cannot explain allostasis completely.
The Immune System in vertebrates consists of specialized cells and tissues that interact in an elaborate and dynamic network. It adapts over time to recognize specific pathogens quickly and efficiently. It attacks foreign substances and bacteria by phagocytosis and by releasing “antibody” proteins that bind to foreign proteins and bacteria. The antibodies activate immune cells and complement cascade blood enzymes, causing them to destroy the bacteria and foreign substances or rid them from the body. Normally it can distinguish “self” so that it does not attack host cells and tissues, but it is often assumed to cause “autoimmune disease” when it becomes confused and attacks host tissues. Examples of diseases that are supposedly caused by such “autoimmune” activity include diabetes and rheumatoid diseases such as rheumatoid arthritis, Sjogren’s Disease, and Systemic Lupus Erythematosis. Stress theory indicates that the actual cause of these illnesses is SRM dysfunction that causes amyloidosis. The immune system is activated by thrombin, so that increased immune activity automatically occurs in the presence of increased SRM activity, and this has caused the confusion as to the actual cause of these illnesses.
Stressoris an internal or external factor that makes demands on an individual and tends to disrupt homeostasis. Stressors include physical trauma, disease, social events and situations, and the demands of exercise and competition.
Stress is the body’s reaction to a stressor, real or imagined. Acute stressors affect an organism in the short term; chronic stressors over the long term. Examples of stress include fever, hormone release, inflammation, hypertension, and tachycardia.
Eustressis enhanced mental or physical function in response to stressors.
Distress is physical or mental deterioration in response to stressors.
General Adaptation Syndrome (GAS) is a sequence of reactions that occurs in response to stressors that is universal in vertebrates.
Alarm is the first stage of the GAS. When the stressor is identified or realized, the body’s stress response is a state of alarm. During this stage the HPA axis is activated and hormones such as adrenalin, glucagon, and cortisol are produced in order to bring about the fight-or-flight response.
Resistance is the second stage of the GAS. The body attempts to adapt to the continuing presence of environmental stressors, but its resources are gradually depleted.
Exhaustion is the third and final stage of the GAS model. At this point, of the body’s resources are depleted and the body is unable to maintain normal function. The initial autonomic nervous system symptoms may reappear (sweating, increased heart rate, etc.). If stage three is extended, long-term damage may result as the capacity of the immune system and glands, especially the adrenal gland, become exhausted. There is functional deterioration of previously working structures and systems. This can manifest itself in obvious illnesses such as ulcers, depression, diabetes, digestive disturbances, cardiovascular problems and mental illnesses.
Allostasis is the process that enables an organism to maintain homeostasis in the presence of environmental adversity through adaptation or change. Allostasis is known to involve the autonomic nervous system, the HPA axis, and cardiovascular, metabolic, and immune effects that are assumed to protect the body by responding to internal and external stimuli.
Allostatic Load is physiological “wear and tear” on the body that results from ongoing adaptive efforts to maintain stability (homeostasis) in response to stressful environmental factors. The activity of the SRM explains how this happens.
The Coagulation Cascade clarifies the sequence of interactions of blood enzyme Factors V, VII, VIII,IX and X with fibrinogen and other blood substances that generates insoluble fibrin that is essential for both “red clot” formation and capillary hemostasis. Though the coagulation cascade identifies the sequence of enzymatic interactions, it does not explain how insoluble fibrin actually induces How insoluble fibrin induces hemostasis remains as mysterious today as when Virchow’s described his Triad in 1856 (clot formation is preceded by stasis of blood flow, increased blood coagulability, and tissue disruption). Hemostasis is traditionally discussed in terms of clot formation, even though capillary hemostasis is arguably more important than clot formation in conserving blood loss. Meanwhile, evidence has accumulated that coagulation cascade enzymes are involved with tissue repair as well as coagulation, though the nature of the relationship remains obscure.
Tissue Factor is a glycoprotein produced by the vascular endothelium and secreted into extravascular tissues. It activates Factor VII, and thereby acts as a “trigger” for coagulation cascade enzyme activity.
Von Willebrand’s Factor is a gigantic molecular hormone produced by the vascular endothelium and released into blood circulation in accord with nervous activity. It binds to hepatic Factor VIIIC to enable the enzymatic activities of VIIIC. The two molecules circulate together in a gigantic protein complex known as Factor VIII.
Tissue repair theory postulates that a single physiologic mechanism controls the orderly and predictable sequence of events that proceeds during the tissue repair process. Tissue repair begins with clot formation that is followed by inflammation, chemotaxis, cell proliferation, angiogenesis, apoptosis and resolution. The mechanism that controls this sequence has yet to be found.
Capillary gate theory postulates the presence of a sub-microscopic, molecular-level mechanism called the “capillary gate” that regulates capillary flow and capillary hemostasis. Its activity would indirectly explain vascular resistance (viscosity) blood pressure, cardiac output, organ regulation, and numerous pharmaceutical effects. The idea of a capillary gate is intuitively attractive, because the control of blood flow would be most efficient and effective at the capillary level, where vessel diameters, flow rates, flow pressures and turbulent flow resistance are all minimal, and surface area far exceeds that of all other vessels combined. Capillary hemostasis implies the existence of such a mechanism, for capillaries lack muscular elements and cannot contract. However, no mechanism has been found that can explain the capillary gate. In the absence of identified mechanisms that explain capillary gate theory, hemodynamic physiology is generally attributed to muscular “vasoconstriction,” “vasodilation” and arteriolar “stiffness”, but these concepts are unsatisfactory in several respects. Smooth muscle contraction in arteries and arterioles is energy intensive, short-lived, and followed by obligatory relaxation, so that it cannot explain sustained elevations in vascular flow resistance.
Anesthesia and Analgesia are terms that are imprecisely defined and thus frequently confused with each other. The traditional definitions are as follows:
Anesthesia is 1. Total or partial loss of sensation, especially tactile sensibility, induced by disease, injury, acupuncture, or an anesthetic, such as chloroform or nitrous oxide. 2. Local or general insensibility to pain with or without loss of consciousness, induced by an anesthetic. 3. A drug, administered for medical or surgical purposes that induces partial or total loss of sensation and may be topical, local, regional, or general, depending on the method of administration and area of the body affected.
Analgesia is the absence of the sense of pain without loss of consciousness.
The confusion of anesthesia with analgesia largely derives from the “Golden Age of Ether” that lasted about 100 years following the discovery that anesthetic inhalation agents could sharply increase surgical survival. Compared to modern inhalation anesthetic agents, ether is absorbed slowly into the blood, so that patients anesthetized with ether commonly lose the ability to perceive pain before they lose consciousness. This conveyed the deceptive impression that anesthetic inhalation agents have analgesic properties. However, true analgesic agents such as lidocaine, marcaine and opioids have the ability to inhibit both pain and nociception, while anesthetic inhalation agents and other hypnotic agent can only inhibit the perception of nociception as pain. An example of the confusion is that drugs such as lidocaine and bupivacaine that inhibit peripheral nerve function are called “local anesthetics” even though the term “local analgesic” would be more appropriate, because these agents control both nociception and pain but have minimal effect on conscious awareness.
Stress Theory provides the following improved definitions:
Nociception is the neural processes of encoding and processing noxious stimuli. It is the afferent activity produced in the peripheral and central nervous system by stimuli that have the potential to damage tissue. This activity is initiated by nociceptors (also called pain receptors) that can detect mechanical, thermal or chemical changes above a set threshold. Once stimulated, nociceptors transmit signals along peripheral nerves to the spinal cord, and trigger a variety of autonomic responses. Conscious awareness generated by corticofugal structures in the brain interprets nociception as pain.
Pain is the perception of nociception by conscious awareness generated by corticofugal brain structures.
Anesthesia is the abolition of pain by hypnotic agents that inhibit conscious awareness
Analgesia is the abolition of both nociception and pain with minimal effect on conscious awareness by true analgesic agents that inhibit peripheral nociceptors, peripheral pain pathways, or spinal cord pathways.