Neurologic Mechanisms in Psychoneuroimmunology.
Subject: Psychoneuroimmunology (Models)
Neurology (Research)
Central nervous system (Research)
Immunity (Psychological aspects)
Authors: Fox, Sherry
Shephard, Timothy J.
McCain, Nancy
Pub Date: 04/01/1999
Publication: Name: Journal of Neuroscience Nursing Publisher: American Association of Neuroscience Nurses Audience: Professional Format: Magazine/Journal Subject: Health care industry Copyright: COPYRIGHT 1999 American Association of Neuroscience Nurses ISSN: 0888-0395
Issue: Date: April, 1999 Source Volume: 31 Source Issue: 2
Geographic: Geographic Scope: United States Geographic Code: 1USA United States
Accession Number: 57563396
Full Text: Abstract: Synthesizing the neurologic mechanisms of psychoneuroimmunology (PNI) into a schematic model serves as a basis to enhance understanding of the complex interactions within the PNI framework. The examination of current research in physiology, neurotransmission, hormonal mechanisms, immunologic function and stress allows for the creation of a neurological model to depict hypothetical interactions of these systems. This model of neurological mechanisms in PNI can serve as the basis for integrating PNI in nursing practice. It is hoped that the model will serve as a bridge to understanding the neuroscience component of PNI and stimulate further research.


Psychoneuroimmunology (PNI) is the study of interactions among the central nervous system, endocrine system and the immune system. These interactions, in the form of autonomic and humoral communication, occur in a bi-directional manner. From an evolutionary standpoint, this bi-directional communication promotes the integration of immune responses into all activities of the organism for the purpose of maintaining homeostasis and ensuring survival.[2]

Current research in PNI has given much attention to the interrelationships between the endocrine system and peripheral immune interactions. However, the neurologic mechanisms that mediate these processes have received little attention.[2] Examination of such mechanisms is important in order to determine how these interactions affect health. Of particular interest to health care professionals is the potential link between psychological factors and the development of disease.

Many diseases, such as the neuromuscular diseases, have an immune component. Research demonstrating these links is limited, in part, by a lack of technology to adequately measure the complex chemical and neural interactions evoked in the presence of exogenous stressors. Research also has been limited due to the absence of an integrated theoretical model of how exogenous factors, such as psychological stressors, influence neuroimmune responses. The purpose of this article is to propose a model to assist clinicians and researchers in obtaining insight into the neurologic mechanisms involved in psychoneuroimmunology.

Current Research on Neurological Interactions in Chronic Psychological Stress

Perhaps of greatest interest and utility to health care professionals is the question of how chronic psychological stressors influence the immune response. Research exists to support the premise that psychological stress alters the immune system in such a way that disease develops or is exacerbated. However, more work is needed to examine how chronic psychological stressors lead to alterations in the immune system and how disease develops in otherwise healthy organisms.

Over the past few years, the effects of chronic stress on the immune system have been examined in human studies. Chronic stress models have been utilized in these studies including caregivers of patients with Alzheimer's disease and patients with chronic psychiatric disorders.[17,19] These studies demonstrated significant immunosuppression in all participants, with those most stressed showing the most immunosuppression. Importantly, these studies also demonstrated that immunosuppression persisted in these individuals long after the stressor was removed. The results suggest that the immune system does not always adapt and that perhaps some irreversible damage to the immune system occurs in the presence of chronic psychological stressors.[20]

The major thrust of the chronic psychological stress research is on neuroendocrine responses involving the hypothalamic-pituitary-adrenal (HPA) axis. Research on purely neural responses, mechanisms and pathways in chronic psychological stress is extremely limited. Many questions remain regarding the ways in which the neural system mounts a response to both endogenous and exogenous stressors, the communication pathways within the CNS and how different types of stressors or individual variables alter those pathways. The lack of research may be due to the technical difficulties in measuring neurotransmitters and the complex pathways of the neurological system. However, recent advances in technology and an increased interest in neural mechanisms have resulted in a few animal and human studies that have included the analysis of structural or neurotransmitter responses to chronic psychological stressors.

Animal models demonstrating the neurologic manifestations and measurements of chronic psychological stressors are limited. Only one current study was located, which demonstrated that the CA1 and CA3 hippocampal pyramidal neurons of tree shrews were morphologically changed by chronically induced psychological stressors such as repeated, inescapable foot shock.[11] Evidence that psychological stressors alter neuroimmune components is more available in acute stress animal models. These models demonstrate that neurotransmitters such as NE are elevated in the presence of acute stressors and that corticotropin releasing factor (CRF) is altered in various brain regions upon exposure to acute stressors such as other predatory animals.[11]

Human research on the effects of chronic psychological stressors on the neurologic components of the PNI response is also limited. One study demonstrated that persons undergoing chronic life stress who were challenged with acute stressors developed peak sympath-omedullary reactivity and decreases in natural killer (NK) cell function that extended beyond the termination of the stressor.[25] Marital conflict also has been used as a model of chronic psychological stress to demonstrate that neurotransmitters such as epinephrine and norepinephrine are elevated under such conditions.[16]

Introduction to Neurologic Mechanisms

In a recent review of the neuroanatomy of PNI, state-of-the-science research was summarized in the statement, "the brain as a whole participates in the modulation of peripheral immunity" (p. 202).[14] The empirical evidence as to how this complex event is orchestrated is yet to be clearly identified and the mechanisms by which psychological stressors affect neuroimmunodulation are complex and still poorly understood.

The stress response can be seen as the body's most important and fundamental process to ensure survival.[24] Built into an organism, whether it be man or animal, are complex systems that maximize the potential for survival. Fundamentally, the nervous system is no exception in systems that allow various levels of response depending on the threat presented. Stress response to cognitive stimuli may have evolved on the basis of a more primitive response that enabled adaptation to noncognitive stimuli. As evolutionary changes have occurred, cognitive and noncognitive processes have become less distinct, creating the complex neuroimmune pathways we are only beginning to understand.[24]

The concept of the evolutionary development of the neuroimmune response also facilitates a logical understanding of why some brain structures are involved in the neuroimmune response to stressors. Structures such as the hypothalamus, hippocampus, amygdala and other brainstem structures promote homeostasis within the organism. They arise during embryological phases of development and play a primary role in survival as higher levels of cognitive development occur. These structures underlie behaviors that promote survival, such as emotive reactions to threat and regulation of visceral activity.[7] Thus it is logical that these structures would be involved in promoting survival from an immune perspective.

Key Neurological Systems in PNI

With the understanding that the neurological processes of PNI are highly complex, interactive, evolutionary and logical, it is possible to examine the various functional structures involved in this response. In view of the fact that brain function is orchestrated by multiple parts of the brain, it is helpful to view the neurological mechanisms of PNI through a systems approach. Four key subsystems within the structural central/peripheral nervous system hypothetically play a role in the modulation of psychological stressors. These systems include the autonomic nervous system (ANS), limbic system, basal ganglia and extrathalamic cortical modulatory systems.[12,14]

The ANS functions by way of motor neurons and chemical messengers. Through the antagonism between the sympathetic and parasympathetic systems, the ANS regulates the activities of the viscera, involuntary smooth muscles, cardiac muscle and glands to maintain a stable internal environment within the body.

When man experiences stress, either endogenous or exogenous, the sympathetic nervous system (SNS) serves to mobilize energy to fight or flee from the stressor. Critical to the neuroimmune response to psychological stressors are SNS preganglionic fibers that directly innervate the adrenal medulla. These fibers are cholinergic and end directly on cells of the medulla to initiate secretion of epinephrine and norepinephrine and initiate the sympathetic nervous system response.

The limbic system, the second key system in the neuroimmunological response to stress, is a group of subcortical nuclei and fiber tracts that form a border around the brainstem. The system cannot be visualized as a gross anatomical structure. This highly complex system governs behavior and emotion.[7]

Several structures within the limbic system may be involved in PNI processes, including the hypothalamus, hippocampus and amygdala.[14] The hypothalamus regulates important physiological drives such as appetite, sexual arousal and thirst. It is the center for the ANS, particularly the sympathetic portion, and plays a role in the PNI response via hypophyseal activation. During a response to stress, cognitive recognition by higher centers of the CNS trigger the release of corticotropin releasing hormone (CRH) from the hypothalamus into the portal circulation between the hypothalamus and pituitary. Corticotropin releasing hormone acts on pituitary corticotrophs to elicit ACTH release into the circulation. Adrenocorticotropin hormone acts on the adrenal gland causing the production of glucocorticoid hormone. Many of the physiological effects of stress are mediated by the glucocorticoids.[5]

With respect to PNI, an important function of the hippocampus may be related to its involvement with recent memory and emotion. As proposed by Papez, the hippocampal formation and projections via the fornix to the cortex provide the main pathway by which impulses from the cortex can reach the hypothalamus. The central emotive process originates in the hippocampal formation and is transmitted to the thalamus and cingulate gyrus. The cingulate cortex is regarded as the receptive cortical region for emotional impulses.[7]

The amygdala plays a role as an integrator of autonomic and visceral functions through its connections with the hypothalamus and brainstem. It also is involved in complex cognitive functions that globally influence emotion and behavior. It has recently been suggested that the amygdala is involved in emotional learning and memory storage.[14]

The basal ganglia comprise the third major system involved in neurological modulation of the immune response.[14] The basal ganglia system has a significant role in modulating and processing information related to the limbic lobe, neocortical associational areas or prefrontal and temporal areas. Specifically, the ventral striatum and the nucleus accumbens have been identified as a part of the neuroimmune pathway.

Contained within the ventral striatum, the nucleus accumbens functionally links the basal ganglia with the limbic system. Information processing that would be required to perceive a psychological stressor occurs through a series of loop circuits that connect specific cortical areas and the basal ganglia. It is possible that these loops have a role in planning, programming and executing behavioral, autonomic and somatic motor responses related to emotion, affect and problem solving.[7]

In addition to the ANS, limbic system and basal ganglia, two specific extrathalamic cortical modulatory systems may also influence PNI interactions. The locus ceruleus and the raphe nuclei appear to have modulatory influences on the activity of the cerebral cortex. The locus ceruleus is an irregular collection of pigmented cells near the periventricular gray matter of the upper fourth ventricle. It contains large quantities of catecholamines, primarily norepinephrine. The most remarkable feature of the locus ceruleus is the extensive projections to all levels of the central nervous system (CNS). Functions of the locus ceruleus include facilitation and inhibition of sensory neurons and control of cortical activation.

A second extrathalamic cortical modulatory system within the brainstem is the raphe nuclei, located in the pons and the medulla. Serotonergic neurons are widely distributed in the raphe nuclei. Descending projections of the raphe nuclei are small and include projections to the locus ceruleus, while ascending connections of the raphe nuclei include the hippocampus.[7]

In summary, four major neurologic subsystems comprise the functional structures hypothetically involved in immune responses to psychological stressors. These systems include the ANS, limbic system, basal ganglia and two extrathalamic cortical modulatory systems, the raphe nuclei and locus ceruleus. These systems collectively are involved in the promotion of homeostasis and survival of the organism. With regard to PNI, the interaction of these systems remains speculative. The normal functioning and interactions of these systems is highly complex and beyond the scope of this paper, but may be more completely reviewed in other work such as Burt.[7]

Principal Neurotransmitters in PNI

An electrochemical process facilitates communication between the nervous and immune systems. This process is initiated through reception of stimuli by the CNS and afferent signal initiation by preganglionic neurotransmitters. The CNS initiates an electrical current from the nerve axon, which begins a chemical release in the postganglionic, presynaptic bulb. Neurotransmitters (NT) enable electrical-to-chemical conduction across the synaptic cleft. The neurotransmitter has an affinity for specific receptors in the postsynaptic bulb so that binding to the receptor enables the neurotransmitter to potentiate, inhibit, terminate or modulate a specific action.

There are usually multiple neurotransmitters at work in the neural synapse. An initial neurotransmitter will activate the fast ion channel receptor, while a second or third neurotransmitter will activate the second messenger system that modifies the effect of the initial transmitter. Fast ion channel receptors have short latency periods and duration of action. Second messenger receptors have much longer latency periods and a duration of minutes or longer.

Modulation is achieved by a process of protein phosphorylation, which can modify receptor affinity for a specific ligand, sensitivity to electrical current changes or reaction to enzymes. It is the second messenger system that can modify the postsynaptic potential of the neurotransmitter, enhancing the potential of the response, inhibiting further release of the NT or terminating the postsynaptic response. It is the second messenger system that will adapt the neural response to the condition of the organism. If over time, the acute requirements to maintain homeostasis become a chronic need, the second messenger system may modify the response of the neurotransmitter to maintain homeostatic needs. Because of the direct physical connection of the nervous system to the immune system, the second messenger receptor may play a role in modulating responses to health or disease states that will affect immunocompetence.

The seven general categories of neurotransmitters are presented in Table 1. The neurotransmitters listed are described in relation to psychoneuroimmunology.

Table 1 Categories of Neurotransmitters

Cholinergic Transmission

Acetylcholine is the primary neurotransmitter in neuromuscular junctions, peripheral ganglia of the autonomic nervous system and autonomic effector organs and in central nervous system synapses. It is synthesized within the axon terminal from choline and acetyl-coenzyme A, which is catalyzed by the enzyme choline acetyltransferase. Synthesis is primarily limited by the inhibition of available choline within the cell body.

Acetylcholine has two primary types of receptors, the nicotinic (nAChR) and the muscarinic (nAChR). The nicotinic receptor is the fast ion channel-gated receptor primarily found at the neuromuscular junction, spinal cord and superior colliculus. The nAChR responds to neurotransmitter stimulation by allowing rapid influx of sodium, producing an excitatory postsynaptic potential. The nAChR is the second messenger receptor principally found in autonomic ganglia, hippocampus, cerebral cortex ([m.sub.1]AChR) and the cerebellum ([m.sub.2]AChR). All muscarinic receptors are coupled to guanyl proteins that determine the specificity of their actions.


Dopamine, norepinephrine and epinephrine are found in a variety of central, autonomic and peripheral nervous system tissues. Dopamine is the immediate precursor of norepinephrine. Approximately 80% of all dopamine in the CNS is found in the motor fibers of the caudate and putamen of the basal ganglia. Dopamine is the primary neurotransmitter for specific pathways of the hypothalamus and the mesolimbic system projection fibers to the midbrain and forebrain. Little is known about changes in dopaminergic pathways or receptors with respect to chronic stress.[8]

Norepinephrine is the primary neurotransmitter for postganglionic sympathetic neurons and for projecting pathways from the locus ceruleus to the cerebral cortex, spinal cord and cerebellum. Epinephrine is synthesized from norepinephrine and can stimulate most catecholamine receptor sites. Epinephrine is the primary neurotransmitter for projection fibers from the raphe nuclei in the brainstem to the hypothalamus.

The receptor sites for catecholamines are complex and numerous. Unique characteristics of catecholamine receptors include the presence of autoreceptors that are sensitive to the specific neurotransmitter. By a negative feedback process, autoreceptors limit the release of additional neurotransmitter. The two-dopamine receptors are principally responsible for the activation or inhibition of adenyl cyclase, which facilitates second messenger kinases. Norepinephrine and epinephrine receptors are designated pharmacologically as alpha-adrenergic receptors ([Alpha]-AR) or beta-adrenergic receptors ([Beta]-AR). The [Alpha]-AR are associated with excitation responses and increase muscular and myocardial contractility as well as fight or flight responses. The [Beta]-AR are linked to inhibition or relaxation of sympathetic smooth muscle end organs. The [Beta]-AR are similar to the muscarinic receptors of the acetylcholine neurotransmitter.


Neurons specific to serotonin are localized within the raphe nuclei. However, the wide-ranging effects of altered serotonin levels are due in part to the neuronal projections to almost every part of the CNS, including the hippocampus, basal ganglia, hypothalamus, cerebral cortex and brainstem. Serotonin can function as neurotransmitter and as modulator of neurotransmitter potentials.

There are multiple receptor types for serotonin and most have an inhibitory function, although generalization is difficult. In the dorsal horn of the spinal cord, serotonin will inhibit somatosensory nerve impulses and produce an analgesic effect. In the ventral horn of the spinal column, serotonin facilitates motor activity related to homeostasis such as temperature, blood pressure, circadian rhythms and rapid-eye-movement sleep patterns. Serotonin also inhibits aggressive or impulsive behavior patterns. Most serotonin effects are mediated by seven known receptors; these are consistent with the mechanisms of second messenger receptor sites, ie, slow onset and long duration of action.

Inhibitory Amino Acids

Gamma aminobutyric acid (GABA) is principally found in the thalamus, basal ganglia and cerebral cortex, although it can be found in almost all areas of the CNS. It is synthesized primarily from glutamate, an intermediate of glucose metabolism and an excitatory amino acid. The catalytic enzyme that produces GABA from intermediate substrate is glutamic acid decarboxylase. Two types of receptors are associated with GABA, the ligand-gated, postsynaptic GABA receptors and the second messenger, presynaptic GABA receptors that inhibit dopamine, norepinephrine and serotonin release into the synaptic cleft.

Excitatory Amino Acids

Glutamate, the precatalytic substrate of GABA, is one of the primary excitatory neurotransmitters. Because glutamate cannot cross the blood-brain barrier it is synthesized in-situ. The primary mechanism of glutamate synthesis has not been identified, perhaps because it exists as metabolic product, substrate and neurotransmitter in so many areas. Three types of receptors for glutamate have been identified and are grouped according to their specific actions. The three receptor types are the N-methyl, D-aspartate (NMDA), quisqualic acid (QA) or kainic acid (KA).

The NMDA receptors are distinct from the rest in that they are both ligand and voltage-gated. Magnesium blocks the postsynaptic receptor site. Depolarization below threshold will cause magnesium to lose attraction for the receptor. Essentially, at resting membrane potential the receptor is not sensitive to the NT, but after depolarization there is sensitivity to NMDA and often one of the other receptors. This causes the excitatory postsynaptic potential to stimulate either QA or KA receptors, which in turn activate additional NMDA receptor sites, thereby enhancing the excitatory potential of the initial signal.

The NMDA receptors are also permeable to calcium influx when stimulated, which activates calcium/calmodulin protein kinases. The release of these enzymes can produce long-term alterations in the synapse. The extended temporal aspect of this mechanism is thought to link NMDA receptors to memory and learning.

Corticotropin-Releasing Factor (CRF)

Two widely held theories within the PNI literature are that (a) CRF plays an important role in initiating and integrating the entire response to stress within an organism, and (b) interactions between CRF and neuropeptides are responsible for adaptive responses to stress.[15] The response can be adaptive or maladaptive, with the distinction possibly residing in the temporal nature or other characteristics of the stressor. Acute stress responses facilitated by CRF will enhance cardiovascular and endocrine functions to provide the organism with the ability for a flight response to threat or other acute stressors. However, prolonged CNS responses to CRF actions may result in deleterious effects such as hypertension.


Cytokines and their receptors may also play a role in neuroimmune responses to psychological stressors, although their specific actions are still unclear. Cytokines are ubiquitously distributed in the brain, including all areas of the limbic system. Glial cells, brain endothelial cells and neurons serve as major cellular sources of cytokines. Three major cytokines may be released with neural responses to stress: interleukin (IL)-1, IL-6 and tumor necrosis factor (TNF).[14,26]

The mechanisms by which cytokines stimulate neural processes in stress can be examined through two major neurocommunication pathways. Cytokine stimulation of the brain via an afferent humoral route has recently been noted to alter the electrical resistance of cerebral endothelial cells in rats, which then allows entry of the cytokines into the brain.[9] Hypothetically, these soluble mediators enter the brain through the circumventricular organs, specifically the median eminence and the organum vasculosum laminae terminalis, located in the hypothalamus. Cytokine stimulation of the immune system via efferent routes is less clear. However, recent research indicates that IL-1 can activate the HPA axis at many levels, such as the hypothalamus, pituitary and adrenal glands. However, most research supports the need for hypothalamic CRF in order for this activation to occur.[8,14]

Neurologic Model for PNI Transmission

The exact mechanisms by which chronic psychological stressors trigger the immune system and whether these responses result in disease are not yet known. Current knowledge of the normal functioning of neural structures and chemical messengers involved in the PNI response, combined with the available research, were used to develop the hypothetical schematic model presented in Figure 1.


The reaction of the nervous system to stress is quite likely a multilayered response. Perhaps as a function of evolutionary development, the organism functions in such a way that homeostasis and survival can be maintained through numerous back-up systems. These layers of response may occur within milliseconds of each other and are initiated as the stimulus is picked up by any of the five major senses.

Incoming stimuli may be perceived within the CNS as a stressor by three levels of response: instinct, conditioning or higher levels of cognitive analysis. At the instinctual level the amgydala picks up the stimulus, perceives it as a stressor and then triggers the extrathalamic modulatory systems, including the locus ceruleus and the raphe nuclei, to enhance the selectivity and magnitude of the cortical neural response to primary afferent information.

The brain is now more vigilant to incoming stimuli. The amygdala signals the hypothalamic-pituitary system to begin the neuroendocrine response to stress. The hypothalamus, which under normal circumstances has an ANS-controlled diurnal release of corticosteroids, then becomes driven by signals from the hippocampal formation.[7]

Stimuli produced by stressful thoughts and emotions reach the periventricular nucleus (PVN) of the hypothalamus via axons from the amygdala-hippocampal formation. Within minutes of the stressor, CRF appears in the PVN and is subsequently secreted into capillaries to reach the anterior pituitary gland. Within the anterior pituitary the CRF acts to induce proopiomelanocortin (POMC), which cleaves to form adrenocorticotrophic hormone (ACTH). ACTH then activates the production of corticosteroids from the adrenal gland, resulting in a systemic endocrine response to the stressor.[4]

In addition to stimulating the pituitary, PVN axons also extensively ramify to the autonomic nervous system, specifically the locus ceruleus (LC), which has CRF receptors. As a second response to stress, norepinephrine is synthesized and secreted from the LC, resulting in further autonomic stimulation and, ultimately, the release of norepinephrine from peripheral sympathetic nerve terminals and epinephrine from the adrenal medulla.[4]

Now the entire body is on "full alert" to the perceived stressor(s). As the cortical neurons are more attuned to the stressor, previously conditioned responses are retrieved from the memory via the hippocampal-amygdala connection to create an additional level of responsiveness. Further triggering of the hypothalamus continues from the amygdala, probably via the basal ganglia. This triggering is manifest by the nucleus accumbens in the form of a loop circuit, which is theoretically important in the planning, programming and execution of behavioral responses to the incoming stressor.[7]

There also may be a third layer of response in which the stressor is analyzed by higher-level cognitive processing. Through a series of higher-level analyses the organism can perceive a stimuli to be a stressor in the absence of instinctual or conditioned responses. This scenario would likely still involve interactions between higher-level cortical centers and the amygdala-hippocampal complex.

There are multiple paths of neurotransmission within the stress response model depicted in Figure 1. When an external stimulus is perceived by the senses of the sentient being, two basic responses can be described. The first response is the protective survival mechanism. A stimulus that elicits an immediate survival response causes glutamate release, possibly within the amygdala. This excitatory amino acid stimulates the locus ceruleus in the brainstem, which then releases NE into pathways to the cerebral cortex. NE will then cross the post-synaptic cleft within the CNS and stimulate an [Alpha]-AR or [Beta]-AR site. The alpha-receptor will continue the EPI surge associated with the fight or flight response, whereas [Beta]-AR stimulation will diminish the response as a result of input from the limbic system and hippocampus. If the stress stimulus is continued, the cerebral cortex will release acetylcholine or serotonin into the hypothalamic and PVN pathways. The cascade then progresses to the release of CRF into anterior pituitary paths, and stimulation of POMC, ACTH, NE and EPI.

In a second situation, wherein the perception of stress stimuli is less acute, glutamate release may stimulate the HPA pathway through the cortex with additional input from the limbic system. In this situation, catecholamine and second messenger systems may more accurately modulate the specificity of the response. It is postulated that there will be increased NE release with anger and motor activity whereas, anticipation, fear and anxiety will produce increased EPI levels.[13] In the PNI model, the chronicity and type of stressor may influence the impact on the immune system. For example, in a chronic physical stress model there may be a decrease in the alpha-2 adrenergic autoreceptors that are responsible for blocking further release of transmitter, resulting in elevated NE levels and taxation of the organism. The presence of catecholamines in response to chronic stressors will have deleterious effects on the immunocompetence of the organism.[21,22]

Inhibitory neurotransmitters such as GABA and serotonin also play a role in the chronic stress model. Based on the hypothetical model, limbic system-influenced release of serotonin or GABA will inhibit the release of catecholamines from the brainstem or cortex, thereby reducing the potentially immunosuppressive effects of sustained catecholamine discharge. Hypothetically, if the limbic system influences, and is influenced by, positive or negative emotions, these inhibitory pathways have important implications for PNI-based models of health and disease.

As illustrated by the thin connecting lines in Figure 1, GABA and serotonin play inhibitory roles in modulating the stress response within the CNS. Noting that both excitatory and inhibitory pathways exist between the same neurological structures, it becomes clear that the agonist/antagonist relationships of homeostasis are facilitated through the balancing of neurotransmitters within specific structures. From this model it may be hypothesized that with chronic stress, the inhibitory mechanisms in the modulation of the stress processes are unable to maintain homeostasis, precipitating immunosuppression. Negative effects of elevated excitatory neurotransmitters, either through increased release or decreased uptake, include decreased NK cell activity, premature release of lymphocytes into the circulation and decreased lymphocyte response to mitogens. This leads to a diminished ability of the body to mount an immune response to invading pathogens.

In addition to the modulating effects of GABA and serotonin, the release of endogenous opioids, b-endorphins, enkephalins and dynorphins will down-regulate the excitatory mechanisms that negatively affect the immune system. For example, the release of b-endorphin is initiated concomitantly with elevation of CRF levels. It is not known whether the mechanism of action of endogenous opiates is through direct inhibition of neural pathways or through elevation of mood, thereby facilitating limbic system control of stress responses. The model depicts the inhibitory pathways of GABA between the brainstem, amygdala, hippocampus and hypothalamus/PVN. This could be the mechanism by which the instinctual response is terminated and the conditioned or learned response assumes control of the stress response through the hippocampus. Much of the learned response is mediated through the glutamate receptors and most likely via second messenger receptors.

In summary, the neurotransmission of the stress response is highly complex and poorly understood at present. In the hypothetical model presented as herein, the interplay between excitatory and inhibitory neurotransmitters and receptors maintains homeostasis. With the experience of chronic stress, elevated levels of catecholamines released through the HPA axis have negative consequences for the immune system. Modulation of the excitatory mechanisms is facilitated through inhibitory amino acids, feedback mechanisms and second messenger transmitter receptors. Further investigation of the effects of positive or negative mental states on neurotransmitter levels in specific brain structures or pharmacological blockade of specific receptor sites may lead to the ability to influence immunocompetence in situations of chronic physical or psychological stress.

Implications for Future Research

It is clear from a review of the literature that much work is left to be done on the neural mechanisms involved in processing psychological stressors and the impact of those stressors on neuroimmune mechanisms. Very little PNI research has been conducted on neuroimmune interrelationships and pathways and most research to date focuses on the neuroendocrine mechanisms of PNI. However, there is an expanding group of studies specific to or inclusive of neurological mechanisms in PNI.

The research currently underway involves localization of synaptic activity using neurochemical techniques and the identification of pathways connecting the CNS with the immune system by using antibodies or antagonists to block the effects of hypothalamic peptides responsible for endocrine responses.[2] If clinically useful information applicable to predictive models of disease is to be developed, these types of studies must expand to include comparisons of acute and chronic psychological stressors and their neurochemical and neurostructural correlates.

In addition to the above methods, current and evolving technology also may provide several means by which to better understand the neuroimmune consequences of chronic psychological stressors. Functional magnetic resonance imaging (fMRI), electroencephalography (EEG) and microdialysis are tools that may provide clues to the interrelationships among neural structures and processes in the context of PNI. Spectroscopy and positron emission tomography (PET) are relatively recent technological developments that can detect chemical markers in brain tissue. Spectroscopy allows whole brain visualization to test hypotheses regarding the potential effects of psychological stressors on specific regions of the brain. PET could be used to trace neurotransmitter activity in stressful situations. EEG is an easily accessed technological method that provides an integrated signal reflecting the macro-organization of brain activity. In scenarios involving varying levels of psychological stress, EEG could be used to provide information regarding the spatial and temporal distribution of neural firing corresponding to those variables.[2] Finally, microdialysis is an experimental technology used to directly measure neurotransmitters and other neurochemical activity within the brain tissue.[2] Microdialysis may be useful in quantifying neurotransmitter and cytokine levels in PNI-based research.

Implications for Nursing Practice

In beginning a discussion of the application of this proposed model to practice, the clinician must expand beyond the neural model alone to incorporate the entire PNI framework, including the neurological, psychological, endocrine and immune systems and their multidimensional integrated functions. As noted earlier, the ways in which the neurologic system processes and responds to psychological stress are complex and highly integrated throughout the organism. One cannot apply the model without expanding to a holistic use of the integrated PNI framework.

Using the PNI framework as the lens to view application of the model, several activities present themselves as avenues for clinicians to begin using the information derived from the proposed model. First and foremost, clinicians must begin to familiarize themselves with the rapidly emerging field of PNI. This field of interdisciplinary study, which first began emerging in 1980, provides insight into the complex, inherently integrated relationships between the integrity of the immune system and the resultant impact on health. The neurologic system clearly plays a role in immune integrity and vice versa. Clinicians in neuroscience nursing must familiarize themselves with the PNI literature and begin examining the applications to neurologic disease. For example, exploration of the autoimmune basis of some neurologic diseases and the impact of life stressors in the presence of chronic neurologic disease may provide knowledge to assist clinicians in developing interventions for disease management and health promotion.

Certainly one immediate implication of this model would be to integrate stress assessment components into the history and physical data of neurologic patients. This would require that the clinician direct questions to the patient to obtain information about potential or existing stressors and coping strategies. The assessment would also require a holistic approach with the clinician looking beyond the neurologic system to examine the sequela that may have occurred as a result of the interrelationships between the neuroendocrine and immune systems.

In addition to working with the individual patient to assess links between stress and neurologic disease, clinicians should also consider the implications for populations of patients and begin to formulate research questions that need to be explored. For example, are there common stressors that result in progression or exacerbations of immune-based neurologic disease? What are these stressors? What physiologic effects do they have on the immune system? Can the exacerbations be prevented and immune functioning modulated by modifying stressors or coping strategies? What are the modifiers of stress in specific patient populations? The list of questions is endless, and the opportunities for nurses to use the PNI framework to improve patient care are equally so.


Psychoneuroimmunology is a highly complex field of study that requires integration of several physiologic systems of the human organism. The as yet undefined nature of the interplay between the psychological and physiologic mechanisms that influence the wellness of human beings may have significant implications for the design of healthcare systems in the future, as well as health maintenance programs in the community.

The physiologic mechanisms involving neuroendocrine and immunologic systems have been explored more extensively than that of the primary neuroanatomy and neurotransmitter functions hypothesized to be involved in the entire field of inquiry. This paper has presented the neurologic mechanisms hypothesized to be involved in PNI processes and developed a model for the interactions of neural structures and electrochemical messenger systems. It is proposed that the model can serve as a basis for further hypothesis formulation and testing of the complex biologic systems at work within a PNI framework.

In addition to further investigation, the theoretical concepts of PNI can be utilized and explored in daily practice. Professional nurses should incorporate assessment of acute and chronic stress into their evaluation of patient health and illness. Nurses should observe for patterns of stress and illness within their patient populations and investigate mechanisms for intervening on the patient's behalf. Finally, professional nurses should increase their knowledge of PNI and investigate means to advance the field to the benefit of their patients and practice.


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Questions or comments about this article may be directed to: Sherry L. Fox, RN, MS, CNRN, CNS, 4349 Collingswood Drive, Chesterfield, Virginia 23832. She is a Neuroscience Clinical Nurse Specialist at the Medical College of Virginia Hospitals.

Timothy J. Shephard, RN, MSN, CCRN, CNRN, CNS, is a Neurovascular Case Manager at Medical College of Virginia Hospitals. Nancy McCain, RN, DSN, is an Associate Professor at Virginia Commonwealth University.3
Category                 Major Neurotransmitters

Cholinergic              Acetylcholine
Catecholamines           Dopamine, Norepinephrine, Epinephrine
Indole Amines            Serotonin (5-HT)
Inhibitory Amino Acids   GABA
Excitatory Amino Acids   Glutamate
Neuroactive Peptides     Somatostatin, Corticotropin Releasing
                         Factor (CRF)
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