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Neural Biological Mechanisms

Richard A. Feely, D.O., FAAO, FCA, FAAMA

The goal of this article is to provide the clinician with information and knowledge of known biological mechanisms involved in somatic dysfunction.

The reader will have the ability to describe:

  • The neural endocrine-immune network and its relationship to somatic dysfunction
  • How somatic dysfunction is endocrine-controlled and maintained
  • Some of the known mechanisms of how somatic dysfunction is altered biomechanically, biochemically, and bioenergetically

The human body is a complex interdependent relationship of structure, function, and mind. The body possesses complex homeostatic mechanisms that maintain equilibrium for self-regulation and self-healing. These homeostatic mechanisms represent an integrated network of messenger molecules produced by cells in neural, endocrine, and immune systems. Their signal coding and messenger molecules communicate through receptor complexes located on cell membranes. The critical role of the nervous system, especially the lymphatic, forebrain, and hypothalamus, influences the output of the endocrine and immune systems.

Traditionally, the Immune and Nervous Systems

Traditionally, the immune and nervous systems were considered separate and independent, each with its own cell types, cell functions, and intercellular regulators. Altered function in each system was related to the disease considered specific to that system. We now recognize not only the interdependence and interlocking molecular organization but also their extensive integration with the endocrine system. The conceptual separations between the neural endocrine immune system concerning structure, function, and communication have been discarded. In their stead is a combination of multiple dimensional network contributing to the functional unity of the body.

Today, we recognize this multifactorial nature is a result of the following interactions of genetic, endocrine, nervous, immune, and behavioral-emotional systems. This complex bi-directional interaction occurs within the neural-endocrine-immune network. This network forms the prime defense against disease and is responsible for the resistance of infectious disease as well as cancer. The sensory information from external and internal sources is tightly integrated with cognitive and emotional processes which influence their neural endocrine immune network through the hypothalamic-pituitary-adrenal axis.


The basis for communication in the neural-endocrine-immune system is the numerous messenger molecules that are released in the extracellular fluid. These signal codes are small peptides, glycoproteins, amines, and steroids. They express their activity through autocrine (self-stimulating), paracrine (stimulates local tissue), synaptic, and hormonal activity.

The Endocrine System

The endocrine system is described as using blood-borne messengers operating over long distances by humoral transport. The neural system is described as using chemical transmitters released into the neural synaptic cleft, separating the pre and post-synaptic specialized nerve cells. These common cellular mechanisms are bi-directional in communication. Their similar molecular structure of many of the messengers and the receptors are combined to transcend the traditional borders that separate the neural, endocrine, and immune systems over the years.

Monitoring the concentration of many of these extracellular messengers. The central nervous system, particularly the limbic system and hypothalamus, directly modulates the activity of the autonomic nervous system and the endocrine systems. See The Network. Both of these systems have extensive communication with the immune systems, thereby regulating it under neural modulation as well. This combined action is multi-dimensional and creates a compensatory reserve that enables the body to mount an adaptive response to stressful conditions regardless of their origin whether somatic, visceral, or psychogenic.


Somatic, visceral, and emotional stimuli act as drivers capable of influencing the activity via the hypothalamus, the spinal cord, pituitary, to the autonomic nervous system, endocrine system, and immune system, causing the general adaptive response. Noxious somatic stimuli initiate protective reflexes providing the central nervous system with warning signs. They influence the release of extracellular messengers from the endocrine immune access system just described.

When activated by noxious stimuli such as rises from somatic dysfunction, small capillary primary afferent fibers called alpha-gam lambda and C-fibers, a-C-fibers or collectively referred to as (B afferent system) from peripheral nociceptor endings, release neural peptides such as substance P into the surrounding tissue thereby initiating neurogenic inflammation.

The B afferent fibers systems represent a small subset of small capillary primary afferent fibers with high threshold for activation that are present in both somatic and visceral tissue. Central processes of these fibers stimulate cells in the dorsal horn of the spinal cord. Within the dorsal horn, the cells responding to the nociceptive input initiate signals carried to the motor nuclei of the ventral horn to alter the tonal muscles innervated by that particular spinal segment and through the anterior lateral tract of the spinal cord which communicates with the brain stem and the hypothalamus.

A significant result of the nociceptive input is increased activity in the hypothalamic-pituitary-adrenal axis culminating in increased output of norepinephrine from the sympathetic nervous system. This reflex can be blocked by selectively eliminating the small capillary primary afferent fibers. Capsaicin reduces the level of substance P in the peripheral nervous system by destroying the small caliber primary afferent fibers. This diminishes the hypothalamic response and reduces the pituitary adrenal and autonomic responses to somatic stressors. The neural-endocrine-immune network is affected by the output of the signals from somatic dysfunction by initiating a compensatory shift in extracellular messengers that then alters the function of the immune system.

Collins and Strauss found that modulation of the sympathetic nervous system plays an integral part in somatic pain and is a principal mechanism of acupuncture's action. The control of somatic sympathetic vasomotor activity before and after the placement of acupuncture needles resulted in pain relief by reducing sympathetic vasomotor activity.

Nakamura, et al. found that afferent pathways of diskogenic low back pain are transmitted mainly by sympathetic afferent fibers in the L2 nerve root and after needle injection, pain dissipated.


The visceral factors in the cervical, thoracic, abdominal, and pelvic areas, as well as peripheral blood vessels, communicate with the brain stem and spinal cord through an extensive complement of afferent fibers also considered part of the B afferent system. The visceral afferent fibers reach their target organs by coursing in the same nerves as the efferent autonomic fibers. They follow the routes of the vascular system. The visceral sensory fibers, typically small caliber and having little or no myelin, have cell bodies located in the thoraco-lumbar dorsal root ganglia and in ganglia of several cranial nerves. These central processes, neurons, terminate in the superficial and deep regions of the dorsal horn of the spinal cord.

Spinal trigeminal nucleus and solitary nucleus of the vagus. The thoraco-abdominal and pelvic organs have extensive sensory innervations. These afferent fibers travel to the central nervous system with efferent autonomic fibers. These sensory fibers traveling in the parasympathetic nerves such as the vagus carry non-noxious information for reflex control of the organ. Those traveling with the sympathetic nerves such as the greater splanchnic carry noxious information packets.

The neurons of the deeper portions of the dorsal horn receive extensive convergence of information from the small caliber sensory axons arising in both visceral and somatic sources.

A similar convergence of somatic and visceral input is seen in the solitary nucleus of the vagus. Neurons responsive to both visceral and somatic nociceptive stimuli are located in the spinal cord, brain stem, hypothalamus, and thalamus. These dual response neurons provide an explanation for the phenomenon of referred pain between visceral and somatic sources.


The emotional factors of the human effecting the neural endocrine immune network arise largely from the limbic forebrain system and hypothalamus. The major components of the limbic forebrain include large portions of associated neocortex, which include the prefrontal area, the cingulate cortex, the insular cortex, and the inferior medial aspect of the temporal lobe. Hippocampal formation and the amygdala receive extensive connections from the frontal parietal and cingulate associational areas of the neocortex and in turn project to the hypothalamus from the fornix and striaterminalis, influencing the hypophyseotropic and hypothalamic nuclei.

This limbic forebrain areas exert considerable influence over the pituitary gland as well as the autonomic nervous system affecting growth hormone, ACTH, prolactin, and somatostatin. The limbic system also increases the sympathetic output from the spinal cord. These alterations in the neural-endocrine activity affect the metabolic processes of the body, shifting peripheral tissue to a catabolic form of metabolism, leading to marked changes in the function of the immune system, including stress-induced suppression of immune function. These conditions characterize the general adaptive response in life.

Highly stressful circumstances in life significantly alter the status of the immune system. This can include the death of a loved one, caring for a family member with chronic progressive disease, summer vacation, change in lifestyle, divorce, new job, etc.

The regulation of the neural-endocrine-immune network increases susceptibility to various disease states. Overproduction or underproduction of extracellular messages in response to either external or internal stimuli or as a secondary response to other disease-dysfunctional processes result in dysfunction of many aspects of the network. The aging process also alters the regulation of the network and is associated with various disease-dysfunctional states.

Lundberg showed that psychosocial factors significantly associated with back pain and shoulder problems were related to psychophysiological stress levels, i.e., high psychophysiological stress levels and low work satisfaction.

He also found that mental and physical stress was found to increase physiological stress levels and muscular tension and that mental stress is of importance for the development of musculoskeletal symptoms and pain. In addition, mental stress is not only induced by high demands but also by demands that are too low which happens in many repetitive and monotonous work situations. Interestingly enough, women are more prone than men to have somatic complaints with repetition and monotonous work.

The Network


  • Catecholamines: Dopamine, Norepinephrine
  • Cholines: Acetylcholine
  • Indolamines: Serotonin
  • Peptides: Substance P, Neuropeptide Y, Calcitonin gene-related, Polypeptide, Enkaphalins, Endorphins, Neurotensin, Cholecystokinin, Angiotensin II, Vasoactive intestinal polypeptide, Bombesin, Adrenocorticotropin, Somatostatin, Corticotropin
  • Amino Acids: Glutamate, Aspartate, GABA, Glycine
  • Dynorphin, Histamine
  • Purines: Adenosine


  • Thymocytes: Lymphoid Cells of the thymus
  • T-Cells: Lymphoid cells that mature in the thymus & express the T-cell receptor (TCR)
  • Helper T-Cells: Lymphoid cells responding to cell surface antigens by secreting cytokines
  • Cytotoxic T-Cells: Lymphoid cells responding to the cell surface antigens by lysing cell producing the antigen
  • B-Cells: Lymphoid cells that, when activated, are capable of producing immunoglobulins
  • Natural Killer Cells: Lymphoid cells capable of killing tumor cells and virus/infected cells
  • Neutrophils: Major Lymphoid cell of the acute inflammatory response and effector cells of humoral immunity
  • Basophils: Effector cells of IgE-mediated immunity that secrete histamine granules in response to IgE activation
  • Eosinophils: Lymphoid cells containing lysosomal granules that can destroy parasites


  • Fibroblast: Connective tissue cell capable of secreting and maintaining the collagenous fiber matrix
  • Endothelial Cell: Squamous cell lining of the inner aspect of the vascular system
  • Mesangial Cells: Specialized mesenchymal cells found in the renal glomerulus
  • Chromaffin Cell: Neural peptides secreting cell found in the adrenal medulla
  • Enterochromaffin Cell: Neural peptides secreting cell found in the lining of the gastrointestinal system
  • Hepatocyte Liver Cell: Liver cell capable of secreting the acute phase proteins
  • Endometrial Cell: Epithelial cell lining the inner surface of the uterus
  • Astrocyte: Neuroglial cell found in the central nervous system involved in forming the blood-brain barrier
  • Oligodendrocyte: Neuroglial cell forming myelin sheath around axons in the central nervous system
  • Osteoblast: Specialized mesenchymal cells capable of secreting the osteomatrix for the formation of bones
  • Osteophyte: Connective tissue cell found in bone representing a mature form of osteoblast
  • Reticular Cell: Endodermal cell creating a three-dimensional network for lymphocytes in the thymus, spleen, and lymph nodes


  • Interleukins 1-7
  • Interferons alpha, beta, and gamma
  • Tumor necrosis factor, beta
  • Colony-stimulating factors:
    • Granulocyte-stimulating factor
    • Macrophage-stimulating factor
    • Granulocyte macrophage-stimulating factor
    • Interleukin III
    • Leukemia inhibiting factor or neuroleukin
  • Transforming factor, beta


  • Pituitary
    • Adrenal Corticotrophin-ACTH
    • Thyrotrophin-TSH
    • Growth hormone releasing factor-GRH
    • Somatostatin-SS-SS
    • Prolactin
  • Adrenal Medullary Hormones
    • Epinephrine
    • Norepinephrine
  • Adrenal Cortical Hormones
    • Cortisol
    • Corticosterone
    • Aldosterone
  • Thyroid Hormones
    • Thyroxine
    • Triiodothyronine
  • Growth Hormones
    • Somatotropin
    • Somatomammotropin
    • Somatomedin
  • Thymus
    • Thymulin
    • Thymosin
    • Thymopoietin
    • Thalmic factor X
  • Others
    • Estrogen
    • Testosterone
    • Insulin


  • Beal, Myron, D.O., FAAO, 1995-96 Yearbook, Osteopathic Vision, American Academy of Osteopathy, 1996.
  • A.A. Buerger, Ph.D., Philip E. Greenman, D.O., Empirical Approaches to the Validation of Spinal Manipulation, 1985, published by Charles C. Thomas.
  • D. Thomas Collins, S. Strauss, “Somatic Sympathetic Vasomotor Changes Documented by Medical Thermographic Imaging During Acupuncture Analgesia“, Clinical Rheumatology, 1992, 55-59.
  • Richard G. Gillette, Ronald C. Kramis, William J. Roberts, ” Sympathetic activation of cat spinal neurons responsive to noxious stimulation of deep tissues in the low back“, Pain , 1994, 56, 31-42.
  • Ulf Lundberg, ” Methods and application of stress research“, Technology and Health Care, 1995, 3-9.
  • Shin-Ichiro Nakamura, Kazuhisa Takahasi, Yuzuru Takahashi, Masatsune Yamagata, Hideshige Moriya, ” The Afferent Pathways of Discogenic Low Back Pain“, Bone and Joint Surgery, 1996, July; 78/B, 606-612.
  • Robert C. Ward, Foundations for Osteopathic Medicine, American Osteopathic Association, 1997; Williams & Wilkins
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