Inflammation has become the focus of many recent articles and publications and it has become a major area of interest to researchers. It is now thought to be the root cause of many diseases.

Gorman, Park, and Dell in their article, stated that inflammation is now thought to be the primary cause of most diseases. (Health: The Fires Within Inflammation is the body’s first defense against infection, but when it goes awry, it can lead to heart attacks, colon cancer, Alzheimer’s and a host of other diseases By Christine Gorman, Alice Park and Kristina Dell Monday, Feb. 23, 2004)

Rob Stein, in his Washington Post article noted, that Medical researchers are becoming increasingly convinced that inflammation, and is the most primitive part of the immune system, the body’s first defense against infection and injury. Study of inflammation may play a crucial role in some of the most devastating afflictions of modern humans, including heart disease, cancer, diabetes, and possibly Alzheimers. Inflammation is an exciting area of research, which could lead to the cause and therefore better treatment for pain and disease. (Body’s First Defense May Be Root of Diseases Cancer, Even Alzheimer’s, May Begin With Inflammation Rob Stein 2003)

Inflammation is a non-specific host response often involved in the elimination of injurious stimuli and injured tissues. There are five clinical features of inflammation: (I) rubor or redness, (II) tumor or swelling, (III) calor or heat, (IV) dolor or pain and (V) functio laesa or loss of function. (Blog Host Response to Injury no date)

Kapit, Macey, and Meisami write about pain saying, it has long been known that skin rubbing relieves the dull/hurtful pain sensation originating from that or a nearby area. Rubbing activates the large, fast-conducting tactile fibres (type A-alpha) while pain is conveyed by C fibres. In the dorsal horn, branches of touch fibres activate inhibitory interneurons, which in turn inhibit the synaptic transmission of pain signals. This is called the gate theory of afferent inhibition. (The Physiology Coloring Book Wynn Kapit, Robert I. Macey, Esmail Meisami 1987)

Kapit, Macey, and Meisami demonstrate the lymph capillaries have no basement membranes, and the junctions between their endothelial cells are often open, with no tight intercellular connections. This makes them very permeable to proteins as well as smaller molecules and water. When the tissue spaces fill with fluids, the increased pressure does not compress and close the lymph capillaries because they are held open by anchoring filaments attached at one end to the endothelial cells and to connective tissues at the other end. The edges of the endothelial cells overlap slightly so that they form “flap valves,” which allow fluid to enter the lymph capillary but not to leave it. Lymph flow is propelled through the periodic contractions of the smooth muscle embedded in the walls of the ducts. These contractions, which “milk” the lymph along, occur on the average some two to ten times per minute. (The Physiology Coloring Book Wynn Kapit, Robert I. Macey, Esmail Meisami 1987)

Guyton writes about inflammation as a complex of sequential changes in the tissue in response to injury. When tissue injury occurs, whatever it is caused by bacteria, trauma, chemicals, heat, or any other phenomenon, large quantities of histamine, bradykinin, serotonin, and other substances are liberated by the damaged tissue into the surrounding fluids. These especially the histamine, increase the local blood flow and also increase the permeability of the venous capillaries and venules, allowing large quantities of fluid and protein, including fibrinogen, to leak into the tissues. Local extracellular edema results, and the extracellular fluid and lymphatic fluid both clot because of the coagulating effect of tissue exudates on the leaking fibrinogen. Thus, brawny edema develops in the spaces surrounding the injured cells. (Human Physiology and Mechanisms of Disease Arthur C. Guyton 1982)

The skin is the most sensory-responsive organ in the body with five different nerve receptors, when delicate cells of the skin and connective tissue are damaged; the body sets to work to repair the damage. Sensory messages are carried along nerve receptors called nociceptor. Survival of the tissues depends on the preventative defense mechanisms aimed at minimizing the loss of blood and bacterial invasion during tissue injury.

Guyton further explains that certain chemical substances under the skin in human beings can cause the highest degrees of pain. Furthermore, extracts from damaged tissues also cause intense pain when injected beneath the normal skin. Among the substances in such extracts that are especially painful are bradykinin, histamine, prostaglandin, acids, excess of potassium ions, serotonin, and proteolytic enzymes. Obviously, many of these substances could cause direct damage to the pain nerve endings, especially the proteolytic enzymes. But some of the substances, such as bradykinin and some of the prostaglandins, can cause extreme stimulation of pain nerve fibres without necessarily damaging them. (Human Physiology and Mechanisms of Disease Arthur C. Guyton 1982)

Guyton explains that bradykinin causes very powerful vasodilatation and also increased capillary permeability. For instance, injection of 1 microgram of bradykinin into the brachial artery of a man increases the blood flow through the arm as much six-fold, and even smaller amounts injected locally into tissues can cause marked Edema because of the increase in capillary pore size. Histamine is released by essentially every tissue of the body whenever tissue becomes damaged. (Human Physiology and Mechanisms of Disease Arthur C. Guyton 1982)

Kapit, Macey, and Meisami explain how the sense of pain is served by free nerve endings located in the skin and certain visceral tissues. It is important to note that the pain receptors have a high threshold of stimulation, so they are usually activated when stimulus strength is very high [nociception]. Tissue damage results in the release of certain internal nociceptor substances such as serotonin histamine bradykinin ECT. In damaged tissue, these substances act on free nerve endings activating pain signals. (The Physiology Coloring Book Wynn Kapit, Robert I. Macey, Esmail Meisami 1987)

In their chapter on the sodium potassium pump Kapit et al writes on how proteins and many other smaller intracellular substances exert an osmotic pressure that is balanced by extracellular solutes, of which Na + and CI- are the most abundant. But both Na+ and CI- leak into cells. If nothing intervened, this leak would create a continuous osmotic gradient, drawing water into the cell, which would swell and burst. If the Na+ K+ pump is poisoned animal cells swell and eventually burst. (The Physiology Coloring Book Wynn Kapit, Robert I. Macey, Esmail Meisami 1987)

When cells rupture the chemical released, activate the sensory nerves causing the sympathetic nervous system to send messages back to the damaged tissues in order to constrict the arteriole smooth muscle thereby preventing blood loss. When it constricts due to continual inflammatory reflexes it causes poor blood flow and lack of pressure needed to flush out tissue by-products. The arteriole feeds the capillary bed where the cells live, eat breath, and give off waste.

In this abstract, Shah, defined myofascial trigger points (MFTPs) as hyperirritable nodules located within a taut band of skeletal muscle. MFTPs may be active (spontaneously painful and symptomatic) or latent (non-spontaneously painful). Painful MFTPs activate muscle nociceptors that, upon sustained noxious stimulation, initiate motor and sensory changes in the peripheral and central nervous systems. This process is called sensitization. In order to investigate the peripheral factors that influence the sensitization process, a microdialysis technique was developed to quantitatively measure the biochemical milieu of skeletal muscle. Biochemical differences were found between active and latent MFTPs, as well as in comparison with healthy muscle tissue. In this paper, we relate the findings of elevated levels of sensitizing substances within painful muscle to the current theoretical framework of muscle pain and MFTPs development. (Uncovering the biochemical milieu of myofascial trigger points using in vivo microdialysis: an application of muscle pain concepts to myofascial pain syndrome.
Shah JP1, Gilliams EA. 2008)

According to C.Z. Hong, the trigger point is usually activated by acute or chronic injury to a muscle, tendon, ligament, joint, disc, or nerve. Recent human and animal studies have suggested that the pathogenesis of either referred pain or local twitch response is related to integration in the spinal cord. It has been proposed that there are multiple sensitive loci in a trigger point region. A sensitive locus may contain one or more sensitized nociceptive nerve endings. (Pathophysiology of myofascial trigger point. Hong CZ1 1996)

Specialized peripheral sensory neurons known as nociceptors alert us to potentially damaging stimuli at the skin by detecting extremes in temperature and pressure and injury-related chemicals, and transducing these stimuli into long-ranging electrical signals that are relayed to higher brain centers. The activation of functionally distinct cutaneous nociceptor populations and the processing of information they convey provide a rich diversity of pain qualities. Current work in this field is providing researchers with a more thorough understanding of nociceptor cell biology at molecular and systems levels and insight that will allow the targeted design of novel pain therapeutics. (Nociceptors: the sensors of the pain pathway. Dubin AE1, Patapoutian A. 2010)

The American Dermatology Association reported that there are about 7,000 to 10,000 mast cells per mm3 in human skin. Many types of cells, such as activated T lymphocytes, monocytes, macrophages and skin resident cells like mast cells, could contribute to the production of cytokines according to Huygen FJ, Ramdhani N, van Toorenenbergen A, Klein J, Zijlstra FJ (2004) who measured mast cells that are involved in inflammatory reactions during in Complex Regional Pain Syndrome assessed by registration of pain and measurement of differences in temperature, volume and mobility between the involved and uninvolved extremity. There was a significant correlation between the intensity of pain and tryptase levels in the involved extremity. Huygen et al stated proinflammatory cytokines is direct evidence for an inflammatory process. (Mast cells are involved in inflammatory reactions during Complex Regional Pain Syndrome type 1.
Huygen FJ1, Ramdhani N, van Toorenenbergen A, Klein J, Zijlstra FJ 2004)

Cai C, Cao Z, Loughran PA, Kim S, Darwiche S, Korff S, Billiar TR. (2011) studied mast cells critical role in the systemic inflammatory response and resulting from trauma. Much of the morbidity after trauma results from excessive activation of the innate immune system. This is manifested as a systemic inflammatory response and associated end-organ damage. Although mast cells are known to be important in many immune responses, their role in the systemic response to severe trauma is unknown. Mast cell deficient mice exhibited greater hemodynamic stability than wild type mice. At baseline, the mast cell deficient mice exhibited no difference in any of the organ injury or inflammatory markers measured. As expected, wild type mice subjected to trauma exhibited end-organ as well as histologic evidence of tissue necrosis. In clear contrast, mast cell deficient mice exhibited almost no tissue damage. So mast cells appear to be a critical component of the initial host response to severe injury. (Cai, Cao Loughran, Kim, Darwiche, Korff, & Billiar, 2011)

Mast cells are well known as the producers of histamine and major effectors of type 1 hypersensitivity. They play however an important role in many other physiological and pathological processes. Lesser-known is their role in the processes such as a termination of pregnancy and initiation of delivery. The mast cells are considered as the modulators of endocrine signals on the local reactions in uterus. Many substances produced by the mast cells have the angiogenic effects known primarily for their role in tumour growth, but they influence also embryonal and postnatal growth or process of wound healing. Mast cells also participate in a number of compensatory reactions in the tissue response to the mechanical load, hypoxia, or inflammation (airway remodelling in asthma, remodelling of pulmonary vessels in chronic hypoxia, myocardial hypertrophy, liver cirrhosis, chronic pancreatitis). This review describes recent concepts of their role in labour, non-cancerous angiogenesis and remodelling of pulmonary vasculature during chronic hypoxia. (Mast cells–a new view of the old acquaintances. Article in Czech Maxová H1, Vízek M. 2010))

This study examines inflammation as the root cause of pain, the myofacial trigger points. They examined anatomy of nerve for sensory inputs for the root cause inflammations that excite nerve receptive pathways for the signal of cell death. Their goal was to use this knowledge to envision ways biosensors could be used to measure topical sites for surface pains. (Mast cells–a new view of the old acquaintances. Article in Czech Maxová H1, Vízek M. 2010)

Boeree states: when there is significant damage to tissue, several chemicals are released into the area around the nociceptors. This develops into what is called the “inflammatory soup.” In addition to all this, the nociceptors themselves release “substance P,” which causes mast cells to release histamine, which in turn stimulates the nociceptors! (Pain Dr. C. George Boeree 2002 & 2009)

Histamine is interesting in that, when it stimulates nociceptors, it is experienced as an itch rather than pain. We do not know why. We use antihistamines, of course, “to relieve the itch.” There are tissues that contain nociceptors that do not lead to pain. In the lungs, for example, there are “pain receptors” that cause you to cough, but do not cause you to feel pain. An acidic mixture that stimulates and sensitizes the nociceptors into a state called hyperalgesia, which is Greek for “super pain.” Some of the chemicals involved:

  • Prostaglandins are released by damaged cells
  • Potassium is released by damaged cells
  • Serotonin is released by the blood platelets
  • Bradykinin is released by blood plasma
  • Histamine is released by mast cells. (Pain Dr. C. George Boeree 2002 & 2009)

Dubin, Patapoutian, (2010) Injury to the skin induces protective physiological responses aimed at decreasing the likelihood of exacerbating the injury. After an injury induced by pungent chemicals (e.g., capsaicin, mustard oil) and burn, stimulation of the injured area produces enhanced pain to noxious stimuli. The released substances lead to arteriolar vasodilatation (“flare,”) and/or increased vascular permeability and plasma extravasation from venules (edema, via substance P). Liberated enzymes (e.g., kallikreins) and blood cells (e.g., platelets, mast cells) further contribute to the accumulation of inflammatory mediators and neurogenic inflammation. (Nociceptors: the sensors of the pain pathway.
Dubin AE1, Patapoutian A. 2010)