Cells of the Central and Peripheral Nervous Systems

The central nervous system (CNS) includes the brain and spinal cord. The peripheral nervous system includes the cranial and spinal nerves and their receptors and is divided into the somatic and autonomic nervous systems. The somatic nervous system contains sensory neurons for the control of skin, muscles, and joints. The autonomic nervous system, which consists of the sympathetic, parasympathetic, and enteric subdivisions, is responsible for involuntary innervation of various organ systems.

The CNS is derived from two primary cell types: neurons and neuroglial (or glial) cells. The neuron is the basic functional cell of the CNS and consists of a cell body (perikaryon) and specialized cytoplasmic processes, dendrites, and a single axon (Figure 28-1). A single axon emerges from the cell body at the axon hillock. The axon may branch to form collateral nerves at a point distal to the neuron cell body. Axon diameters range from 0.2 to 20 µm. Most of the axons in the brain are only a few millimeters long, although the axons that run from the spinal cord may be as long as 1 meter. Stimulation of the dendrites produces antegrade impulse conduction (toward the neuron cell body) with subsequent conduction away from the neuron cell body by way of the axon.

Neuron cell bodies vary in size and shape and are classified as unipolar, bipolar, pseudounipolar, or multipolar. Unipolar neurons are found only in lower invertebrates. Bipolar neurons are found in the retina, ear, and olfactory mucosa. Pseudounipolar neurons have one cytoplasmic process that exits the cell and divides into two branches, one serving as the dendrite, the other as the axon. Pseudounipolar neurons are present in the dorsal root ganglia and cranial ganglion cells, enabling sensory impulses to travel from the dendrite directly to the axon without passing through the cell body. Multipolar neurons have multiple dendritic processes but only one axon and constitute the majority of the CNS neurons.

The gray matter of the CNS is composed of neuron cell bodies in the CNS, and the white matter is composed of myelinated axons. Regions of concentrated cell bodies within the peripheral nervous system form the cranial, spinal, and autonomic ganglia.

Neurons may be classified according to their specific function: motor neurons, sensory neurons, or interneurons. Motor neurons are multipolar and innervate and control effector tissues such as muscles and glands. Sensory neurons are pseudounipolar and receive exteroceptive, interoceptive, or proprioceptive input. Interneurons are pseudounipolar and connect adjacent neurons.

The neuron is bound by a bilaminar lipoprotein membrane derived from phospholipid molecules arranged with their fatty acid chains facing one another, producing an inner hydrophobic membrane. The membrane surface in contact with the extracellular fluid contains polar hydrophilic groups of phospholipid molecules. The neuronal membrane contains integral membrane proteins, which form ionic pumps, ion channels, enzymes (e.g., adenylate cyclase), receptor proteins, and structural proteins.

The neuron contains a number of common cellular organelles including a well-developed nucleus, mitochondria (distributed throughout the cell body), and cytoplasmic processes. Ribosomes, endoplasmic reticulum, lysosomes, and Golgi complexes are also found. Neurotubules and neurofilaments extend through the cytoplasm from the dendrites to the axon terminal; they provide structural support and a pathway for intracellular transport of neurotransmitters.

The second major cell type found within the CNS is the neuroglial, or glial cell (Table 28-1). Four types of glial cells are found within the CNS: astrocytes, oligodendrocytes, microglial cells, and ependymal cells. Most neoplasms of the CNS arise from glial cells (astrocytes). Glial cells are smaller, outnumber neuronal cells, and lack dendritic and axonal processes. Although they do not participate in neuronal signaling, glial cells are essential for neuronal function. The role of neuroglia includes the maintenance of a proper ionic environment, the modulation of nerve cell electrical conduction, control of reuptake of neurotransmitters, and repair after neuronal injury.

The astrocyte is the predominant glial cell. Astrocytes provide structural neuronal support, group and pair neurons and nerve terminals, regulate the metabolic environment, and are active in repair after neuronal injury.

Two distinct types of astrocytes exist: fibrous astrocytes, found in the white matter, and protoplasmic astrocytes, concentrated in the gray matter. Astrocytes have multiple processes that radiate from the cell, producing a star-shaped appearance. Some of these processes (astrocytic feet) terminate on the surfaces of blood vessels within the CNS (perivascular feet). The contact of the cerebral endothelium by astrocytes has been proposed to be essential in the development of the blood-brain barrier.¹

Oligodendrocytes have fewer branches than astrocytes (oligo, “few”; dendro, “branches”). Oligodendrocytes form the myelin sheath of axons in the brain and spinal cord and are capable of myelinating more than one axon. However, oligodendrocytes are incapable of division and fail to regenerate after injury.

The velocity of nerve impulse conduction in an unmyelinated axon increases with the square root of the diameter of the axon. Accordingly, a doubling of impulse conduction requires that the axon be doubled in size. One could only imagine the size of the peripheral nervous system without the presence of myelin. Myelin is essential to increase the velocity of impulse conduction and minimize the size of the axon.

Myelin is formed in the vertebral peripheral nervous system by modified glial cells termed Schwann cells.² Unlike the oligodendrocyte, the Schwann cell myelinates only one axon, surrounding the axon and forming successive layers of plasma membrane. The resultant thickness is variable in different axons. The junction between adjacent Schwann cells is devoid of myelin at 1-mm intervals along the length of the axon. This nonmyelinated portion of the axon, the node of Ranvier, is the site of electrical impulse propagation. Impulses in myelinated axons travel from one node of Ranvier to another (saltatory conduction), bypassing the area between the nodes and increasing the velocity of conduction (see Figure 28-1). Wallerian degeneration results in the distal degeneration of the axon after peripheral nerve injury. Proximal axon degeneration also may occur. Within 1 week of the initial injury, Schwann cells proliferate to form a tube into the area of degeneration, forming a scaffold to direct axon regeneration. Myelin regeneration precedes axon regeneration, with the myelin eventually reaching its previous thickness.

Microglial cells are the smallest neuroglial cells and are scattered throughout the CNS. They are transported throughout the CNS to sites of neuronal injury or degeneration, where they proliferate and develop into large macrophages that phagocytize neuronal debris.

Ependymal cells line the roof of the third and fourth ventricles of the brain and the central spinal canal. Ependymal cells form the cuboidal epithelium (choroid plexus), which secretes cerebrospinal fluid (CSF).

Blood-Brain Barrier

The injection of an intravenous dye causes most of the body tissues and internal organs to be stained; yet the brain and spinal cord remain unblemished. This finding led to the discovery of the blood-brain barrier, which effectively isolates the brain and spinal cord extracellular compartment from the intravascular compartment.³

The endothelial cells of the CNS form tight junctions between adjacent cells, preventing the transport of polar substances from the intravascular to the cerebral extracellular fluid compartment. CNS endothelial cells lack transport mechanisms, so little intracellular transport takes place. A number of midline brain structures receive neurosecretory products from the blood and therefore lack a blood-brain barrier. These structures, the circumventricular organs, include the area postrema, pituitary gland, pineal gland, choroid plexus, and portions of the hypothalamus.⁴

The blood-brain barrier is incompletely developed in the newborn. The high vascular content of bile pigments in jaundiced newborns may enter the basal ganglia, producing kernicterus. Blood-brain barrier disruption can be caused by traumatic head injury, subarachnoid or intracerebral hemorrhage, or cerebral ischemia. The development of mass lesions also may produce blood-brain barrier disruption. Osmotically active substances may penetrate the brain or spinal cord after blood-brain barrier disruption. Intentional intracarotid injection of a hyperosmolar solution shrinks the endothelial cells, opens tight junctions, and disrupts the blood-brain barrier. This technique allows the delivery of chemotherapeutic drugs through the blood-brain barrier for the treatment of neural malignancy.5,6

Cerebral Structures

The cerebral hemispheres are the most intricately developed and largest regions of the brain (Figure 28-2). They contain the cerebral cortex, hippocampal formation, amygdala, and basal ganglia. The cerebral cortex consists of the outer 3-mm layer of the cerebral hemispheres. The surface of the cerebral cortex is convoluted, increasing the surface area of the cerebral hemispheres. Elevated convolutions called gyri are separated by shallow grooves called sulci and by deeper grooves called fissures.

The medial longitudinal fissure divides the cerebral hemispheres into right and left halves. The lateral fissure of Sylvius and the central sulcus of Rolando divide each hemisphere into four lobes, which are named for the cranial bones that overlie each area. The frontal lobe, essential for motor control, and the parietal lobe, essential for the senses of pain and touch, are separated by the central sulcus. The cerebral cortex is divided into nearly 50 structurally distinct areas called Brodmann’s areas (Figure 28-3). Voluntary muscle activity is controlled by the motor cortex located in the precentral gyrus, or Brodmann area 4. Brodmann’s areas 1, 2, and 3 make up primary somtosensory area 1, also referred to as the somatosensory cortex. This area contains a high degree of localization for various body parts, whereas areas 5 and 7 function as the somatosensory association area (Figure 28-4). The sensations of touch, pain, and limb position, as well as the sensory perception of grasped objects, are controlled by the somatic sensory cortex located in the postcentral gyrus of the parietal lobe. The temporal lobe, which contains the auditory cortex, is separated from the frontal and parietal lobes by the sylvian fissure. The occipital lobe lies posterior to the parietooccipital sulcus. Here the visual cortex lies within the walls of the calcarine fissure on the medial brain surface.

The corpus callosum lies deep in the longitudinal fissure and contains commissural fibers that interconnect the cerebral hemispheres. These fibers arise from neurons in one hemisphere and synapse with neurons in the corresponding area of the adjacent hemisphere. The remaining major structures of the cerebral hemispheres include the basal ganglia, the amygdala, and the hippocampal formation. The basal ganglia are involved in the control of movement. The amygdala functions in the regulation of emotional behavior, response to pain, and appetite and is essential in forming the response to stressors. The hippocampal formation is essential for memory formation and learning.

The diencephalon is located in the midline between the two cerebral hemispheres and contains two important structures—the thalamus and the hypothalamus. The oval-shaped thalamus integrates and transmits sensory information to various cortical areas of the cerebral hemispheres via separate thalamic nuclei. The hypothalamus is composed of several nuclei, including the mammillary bodies. The hypothalamus is the master neurohumoral organ.

The midbrain, pons, and medulla form the brainstem. The brainstem contains the reticular activating system, which functions to maintain consciousness, arousal, and alertness. The pons is anterior to the cerebellum, separated by the fourth ventricle, connecting the medulla oblongata and the midbrain (Figure 28-5). The pons contains ascending and descending fiber tracts and the nuclei of the trigeminal nerve (cranial nerve V) and the facial nerve (cranial nerve VII). The medulla extends from the pons to the foramen magnum, where it becomes continuous with the spinal cord (see Figure 28-5). In addition to ascending and descending fiber tracts, the medulla contains respiratory and cardiovascular control centers and the vestibulocochlear nerve (cranial nerve VIII), the glossopharyngeal nerve (cranial nerve IX), the vagus nerve (cranial nerve X), the spinal accessory nerve (cranial nerve XI), and the hypoglossal nerve (cranial nerve XII) nuclei.⁷

The cerebellum is convoluted in appearance and lies below the occipital lobe of the cerebral cortex and posterior to the pons and medulla. Structurally it resembles the cerebral cortex, containing an outer layer of gray matter and an inner core of white matter with several nuclei embedded within. The cerebellum can be divided into three functional areas. The flocculonodular lobe (archeocerebellum) is active in the maintenance of equilibrium, and the paleocerebellum (anterior lobe and part of vermis) regulates muscle tone. The neocerebellum (posterior lobe plus most of the vermis) is the largest subdivision of the cerebellum and is essential in coordinating voluntary muscle activity. The cerebellum integrates information received from other areas of the CNS and the peripheral nervous system. Information from the cerebellum is transmitted to the cerebral cortex and to lower motor neurons involved in the maintenance of muscle tone, equilibrium, and voluntary muscle activity.⁷

Meninges

The brain and spinal cord are enveloped by three meningeal layers: the dura mater, the arachnoid mater, and the pia mater (Figure 28-6). The dura mater, the thickest of the meningeal layers, overlies the cerebral hemispheres and brainstem and is functionally separated into an outer periosteal layer (adherent to the inner cranium) and an inner meningeal layer. The dura mater forms a fold, the falx cerebri, that functionally separates the cerebral hemispheres. A similar fold, the tentorium cerebelli, separates the occipital lobe and the cerebellum. The dura mater of the spinal cord is continuous with the meningeal layer of the cranial dura mater and the perineurium of the peripheral nerves. Innervation of the dura mater is provided by the first three cervical roots and the trigeminal nerve. During awake craniotomy, the patient may complain of pain “behind the eye” when traction is applied to the dura.

The arachnoid mater is a thin, avascular membrane joining the dura mater. The subdural space, a potential space between the dura mater and the arachnoid mater, is of clinical importance. The unintentional injection of local anesthetic during spinal anesthesia into the subdural space produces patchy, asymmetric block. In addition, injury to a blood vessel in the subdural space can create bleeding (subdural hematoma), requiring surgical intervention.

The pia mater is a thin avascular membrane adherent to the brain and spinal cord. The subarachnoid space lies between the arachnoid mater and the pia mater. In the spinal cord, the subarachnoid space extends to the S2 to S3 level and is filled with CSF. In addition, the vasculature that overlies the CNS is located within the subarachnoid space. Injury to the vascular structures may produce subarachnoid hemorrhage and hematoma.

The epidural space is located outside the dura but inside the spinal canal. The epidural space contains a venous plexus and epidural fat that provides protection of the neural structures. The distance from the skin to the epidural space may be as little as 3 cm or as large as 8 cm.

Cerebrospinal Fluid

CSF is contained within the ventricles of the brain, the cisterns surrounding the brain, and the subarachnoid space of the brain and spinal cord (see Figure 28-6). The total volume of cranial and spinal CSF in the adult is approximately 150 mL. The specific gravity is 1.002 to 1.009, and the pH is 7.32. CSF bathes the brain and spinal cord, cushioning these delicate structures, and controls and maintains the extracellular milieu for neurons and glial cells.

CSF is secreted by the ependymal cells of the choroid plexus within the ventricular system at a rate of approximately 30 mL/hr. Although CSF is isotonic with plasma, it is not a plasma filtrate. CSF concentrations of potassium, calcium, bicarbonate, and glucose are lower than their respective plasma concentrations, and concentrations of sodium, chloride, and magnesium are higher. The entire CSF volume is replaced every 3 to 4 hours. Normal CSF pressure is between 5 and 15 mmHg. CSF flows from the lateral ventricles of the cerebral hemispheres through the foramen of Monro into the third ventricle, through the aqueduct of Sylvius in the midbrain, into the fourth ventricle. CSF enters the subarachnoid space through the medial foramen of Magendie and the paired lateral foramina of Luschka, openings in the roof of the fourth ventricle.

The cisterna magna, located between the medulla and the cerebellum, is formed from the separation of the arachnoid mater from the pia mater and is filled with CSF. Two additional cisterns exist, the cisterna pontis and the cisterna basalis. CSF drains into the venous blood via the superior sagittal sinus and is absorbed by arachnoid granulations.

Spinal Cord

The spinal cord extends from the medulla at the foramen magnum to the filum terminale, a threadlike connective tissue structure that attaches to the first segment of the coccyx. Thirty-one pairs of spinal nerves carry motor and sensory information: 8 cervical, 12 thoracic, 5 lumbar, 5 sacral, and 1 coccygeal. The first pair of cervical nerves exits the spinal cord between the base of the skull and the first cervical vertebra (atlas), and the remaining 30 pairs exit between adjacent vertebrae. All of the exiting spinal nerves are covered with pia mater. Because the spinal cord is approximately 25 cm shorter than the vertebral canal in adults, the lumbar and sacral nerves have relatively long roots (the cauda equina). The spinal cord fills the canal in utero, but the canal elongates at a greater rate than does the neural tissue as the child ages, forming the cauda equina.

The spinal cord is divided into dorsal, lateral, and ventral regions by the entering dorsal sensory root fibers and the outgoing ventral motor root fibers. Neuron cell bodies and unmyelinated fibers lie in the H-shaped central gray region of the cord, surrounded by fiber tracts that form the white matter. Although it does not have a uniform appearance, this general arrangement continues throughout the entire spinal cord.

The spinal gray matter is divided into the ventral and dorsal gray commissures. The ventral projections of gray matter are called the gray horns or columns; the posterior projections are called the posterior gray horns or columns. Intermediolateral gray horns or columns are found between T1 and L2. The gray matter has been subdivided into 10 (I through X) laminae of Rexed. Rexed laminae I through VI are located in the dorsal (posterior) horn and contain cell bodies that receive sensory information from the periphery. Projections from the laminae form afferent tracts. A large number of interneurons are found in laminae V, VI, and X. Laminae VII, VIII, and IX make up the ventral (anterior) horn and contain motor neurons and interneurons involved in motor functions. The gray matter is enlarged in two areas of the spinal cord, C5 to C7 and L3 to S2. The cervical enlargement contains neuron cell bodies that innervate the upper extremities; the lumbosacral enlargement contains neuron cell bodies that innervate the lower extremities.

The tracts or fascicles that make up the white matter are highly organized, similar to the organization of the cerebral cortex and other areas of the brain. The dorsal white matter is composed almost exclusively of ascending sensory fiber tracts. The lateral and ventral white matter contain descending motor tracts. Commonly, fiber tracts at some level in the spinal cord or brain decussate, or cross over to the other side. As in the brain, spinal cord fiber tracts can be projection tracts connecting the spinal cord and brain, or they can be association (intersegmental, fasciculi proprii) tracts that originate and terminate entirely within the spinal cord. The association tracts play an important role in spinal reflexes.7–10

Shortly after leaving the spinal cord, the meningeal coverings of the peripheral nerves merge with the connective tissue layers that cover the peripheral nerve. The outermost covering of the peripheral nerve is called the epineurium. The bundles or fascicles of axons in each nerve are covered by the perineurium, and each axon in a fascicle is surrounded by the endoneurium.

Peripheral nerves may be classified according to their diameter. Generally, the larger the diameter, the faster the conduction velocity; therefore A alpha fibers, the fibers with the largest diameters, have the fastest conduction velocity, and C fibers, which have the smallest diameter, have the slowest conduction velocity. Between the two extremes lie A beta, A gamma, A delta, and B fibers, in decreasing order of size and conduction velocity. The degree of myelination affects the conduction velocity of the nerves.

Sympathetic Nervous System

Preganglionic neurons of the SNS originate in the intermediolateral gray horn of the spinal cord between the first thoracic (T1) and second or third lumbar vertebra (L2 or L3). The myelinated preganglionic axons (i.e., preganglionic fibers of the preganglionic neurons) exit the spinal cord via the anterior (ventral) nerve root. These processes leave the spinal cord by way of a small trunk, the white rami communicans. A series of paired paravertebral ganglia is ranged bilaterally along the spinal cord (Figure 28-8). All of the paired segmental paravertebral ganglia are connected, forming the sympathetic trunks. These ganglia may contain the cell body of the second efferent neuron (postganglionic neuron). The preganglionic fibers of the preganglionic neuron enter the white rami communicans and may synapse with the second efferent neuron located within the ganglion. The postganglionic fiber of the postganglionic neuron may either exit the gray ramus to enter a spinal nerve or may extend through a connection between the paravertebral ganglion and one of the three (celiac, superior, or inferior) mesenteric ganglia. The postganglionic fibers then synapse with the smooth muscle of the digestive tract and other abdominal organs. SNS preganglionic axons secrete acetylcholine at their ganglionic synapses, and postganglionic fibers secrete norepinephrine.

Usually one paravertebral ganglion is present for each spinal nerve, except in the cervical area, where they fuse to form two or three ganglia. On entering the sympathetic chain, the preganglionic fiber may synapse at the entry level or travel up or down the ganglionic chain before forming a synapse. Some preganglionic axons pass through the sympathetic chain without synapsing and after leaving the chain form a distinct nerve (e.g., splanchnic nerve) before synapsing in prevertebral ganglia, such as the superior or inferior mesenteric ganglia. Some preganglionic axons in the sympathetic trunk synapse with several postganglionic neurons located in several chain ganglia. This arrangement explains the manner in which a central SNS discharge spreads over several segments. After synapsing in the sympathetic chain, the postganglionic axons, which are unmyelinated, enter the spinal nerve through the gray ramus communicans and travel to the periphery.

The cervical ganglia are divided into superior, medial, and inferior cervical ganglia. The inferior cervical ganglion fuses with the first thoracic ganglion to form the stellate ganglion. Stimulation of SNS fibers from the superior cervical ganglion produces contraction of the radial muscle of the iris (mydriasis), relaxation of the ciliary muscle of the eye, and constriction of the blood vessels of the head. Destruction of the superior cervical ganglion, central SNS damage, or injury to other cervical paravertebral ganglia produces Horner syndrome, clinically distinguished by miosis, anhydrosis (absence of sweating), and ptosis on the affected side. Ptosis is incomplete because the primary innervation to the levator palpebrae superioris muscle of the eyelid is through the oculomotor nerve, and only a few SNS fibers innervate this muscle.

Postganglionic fibers from the upper thoracic chain ganglia (stellate to T4 to T5) innervate the heart and lungs. β-Receptor stimulation produces an increased heart rate (positive chronotropic effect), an increase in conduction (positive dromotropic effect), and an increase in myocardial contractility (positive inotropic effect). Myocardial α-receptor stimulation produces coronary vasoconstriction. The resultant pulmonary effects also depend on the receptor type that is stimulated; bronchial dilation follows β₂-receptor stimulation, and mild bronchoconstriction follows α-receptor stimulation.

The SNS fibers supplying abdominal and pelvic viscera (T5 through L3) pass through the chain ganglia forming the greater and lesser splanchnic nerves, which subsequently terminate in preterminal ganglia. Postganglionic fibers from the prevertebral ganglia, such as the superior and inferior mesenteric ganglia, travel to the abdominal and pelvic viscera. Stimulation of these SNS fibers activates liver glycogenolysis and gluconeogenesis, decreases secretions from pancreatic acinar cells and β-cells, initiates lipolysis, decreases the tone and motility of the gastrointestinal tract, contracts gastrointestinal sphincters, relaxes urinary smooth muscle, and increases renin secretion from the kidney.

Parasympathetic Nervous System

The efferent neurons of the parasympathetic subdivision are located in the gray matter of the midbrain and medulla. The preganglionic fibers exit the brain via cranial nerves II, VII, IX, and X. The remainder of the cell bodies of the first efferent neurons arise from the lateral horn of the sacral portion of the spinal cord (S2 through S5). Acetylcholine is secreted by both parasympathetic preganglionic and postganglionic fibers (see Figure 28-8).

The second efferent neuron (postganglionic neuron) of the parasympathetic subdivision may be located in a small ganglion adjacent to the innervated organ or within the organ itself. Preganglionic axons travel with the vagus to ganglia located near the organ they innervate. The postganglionic axons innervate the bronchioles, heart, coronary arteries, stomach, and large intestine up to the left colic flexure. PNS postganglionic fibers to the descending colon and the genitourinary systems are supplied by parasympathetic fibers from sacral segments of the spinal cord. Most of the parasympathetic preganglionic fibers originate at the S3 and S4 segments. Shortly after exiting the spinal cord with the spinal nerves, the preganglionic fibers form the pelvic nerves (nervi erigentes), which synapse in ganglia in close proximity to the innervated organ.

Synaptic Transmission

After depolarization, the flow of information is transmitted to adjacent neurons at specialized membrane sites called synapses (see Figure 28-1). Synapses are present on dendrites and axons. Synapses may be present on axon terminals of specific neurons in contact with endocrine glands (e.g., salivary glands) or skeletal muscle. The neuron sending the information is the presynaptic neuron, and the receiving neuron is the postsynaptic neuron. Separating the presynaptic and postsynaptic neurons is a small intracellular space (the synaptic cleft). The majority of synaptic transmission occurs in the direction from the presynaptic to the postsynaptic neuron, but retrograde nerve impulse conduction is known to occur and modulates the strength of synaptic connections.

Synaptic transmission may be electrically or chemically mediated. Electrically mediated synapses are large compared with chemically mediated synapses. Electrical synapses have direct cytoplasmic continuity and no synaptic delay. Electrical synapses are excitatory in nature and are located in the CNS, peripherally in smooth muscle, and in cardiac muscle. Synaptic delays (delayed synaptic transmission) occur in chemically mediated transmission because of the transit time of the chemical mediator (specific neurotransmitter) from the presynaptic terminal to the postsynaptic membrane.

The majority of CNS neurons have chemically mediated synapses. The presynaptic neuron releases a neurotransmitter, a low-molecular-weight compound that diffuses across the synaptic cleft and binds to specific receptors on the postsynaptic membrane. Depolarization stimulates the uptake of calcium by the nerve terminal, fusing intracellular vesicles that contain the neurotransmitter to the presynaptic membrane. The neurotransmitters are subsequently released into the synaptic cleft. The neurotransmitter diffuses across the synaptic cleft, interacting with a specific postsynaptic receptor. Neurotransmitters that increase the permeability of the axolemma to sodium ions are excitatory (e.g., acetylcholine, glutamate); neuroinhibitory neurotransmitters (e.g., γ-aminobutyric acid [GABA], glycine) hyperpolarize the membrane by increasing the permeability to chloride ions. The neurotransmitter serotonin excites some neurons and inhibits others. The attachment of the neurotransmitter to the postsynaptic receptor can produce either an immediate (fraction of millisecond) or a delayed (from a few milliseconds up to seconds) effect on the postsynaptic membrane. The delayed transmission involves second messengers, such as cyclic adenosine monophosphate and cyclic guanosine monophosphate, which are activated when the neurotransmitter attaches to the postsynaptic membrane.

Acetylcholine

Acetylcholine is an excitatory neurotransmitter with a widespread distribution. It is the predominant neurotransmitter within the CNS, at the neuromuscular junction, within all autonomic nervous system preganglionic fibers and postganglionic parasympathetic fibers, and within postganglionic sympathetic fibers innervating sweat glands. Acetylcholine is synthesized in the presynaptic nerve terminal from acetic acid, coenzyme A, and choline in the presence of the enzymes acetyl kinase and choline acetylase. This enzyme is also referred to as choline acetyl transferase. Acetylcholine is packaged in vesicles and stored in the presynaptic terminal. Calcium uptake into the presynaptic terminal is required for acetylcholine release, and magnesium (Mg²⁺) and manganese (Mn²⁺) block the uptake of Ca²⁺ and the subsequent release of acetylcholine. Acetylcholine interacts with the postsynaptic receptor for a few milliseconds before being hydrolyzed by acetylcholinesterase to acetic acid and choline. Both the acetic acid and the choline are taken up by the presynaptic nerve terminal and recycled.

Cholinergic receptors are classified as either nicotinic or muscarinic. Nicotinic receptors are found in autonomic ganglia and at the neuromuscular junction. Muscarinic receptors are found on smooth muscle, cardiac muscle, and sweat glands. Acetylcholine is the neurotransmitter at cranial nerve nuclei and ventral horn motor neurons of the spinal cord, including various collateral nerves to Renshaw cells (interneurons). Acetylcholine may be interactive in neuronal circuits involved with pain reception. Acetylcholine also may act as a sensory transmitter in thermal receptors and taste bud endings.

Biogenic Amines

The biogenic amines include epinephrine, norepinephrine, dopamine, serotonin, and histamine. The catecholamines epinephrine, norepinephrine, and dopamine are synthesized in a series of hydroxylation, decarboxylation, and methylation reactions from the amino acids phenylalanine and tyrosine. The adrenal medulla secretes both epinephrine (75%) and norepinephrine (25%). Postganglionic adrenergic neurons secrete norepinephrine; norepinephrine and dopamine are probably neurotransmitters within the CNS. Amacrine cells of the retina and some neurons of the intrinsic nervous system of the intestine secrete dopamine. As with acetylcholine, the release of norepinephrine, epinephrine, and dopamine is calcium dependent. One notable difference from acetylcholine is that norepinephrine and dopamine act by means of second messengers (slow synaptic transmission), whereas most of the actions of acetylcholine are directly on ion channels (fast synaptic transmission). The duration of effect of catecholamines is regulated by presynaptic reuptake. Enzymatic breakdown of catecholamines by monoamine oxidase and catechol-O-methyltransferase within the liver is primarily responsible for terminating their effects.

Dopamine is an inhibitory neurotransmitter and the predominant biogenic amine within the CNS. Dopamine is concentrated within the basal ganglia. Dopamine’s inhibitory effects occur through action on adenylate cyclase, which is dopamine sensitive.

Norepinephrine is concentrated in the reticular activating system and the hypothalamus. Norepinephrine acts as an inhibitory neurotransmitter, inhibiting impulses to the cerebral cortex.

Serotonin is an inhibitory neurotransmitter that influences behavior and mood. Histamine is also an inhibitory neurotransmitter concentrated within the hypothalamus and the reticular activating system. Histamine requires the second messenger cyclic adenosine monophosphate to mediate its inhibitory effects.

Amino Acids

Glutamate is the primary excitatory transmitter found within the cerebral cortex, the hippocampus, and the substantia gelatinosa of the spinal cord.¹² Glutamate plays a formidable role in learning and memory (perhaps interactive in memory formation during awareness during anesthesia) and the appreciation of pain. Glutamate also has been implicated in excitotoxic neuronal injury after ischemic or traumatic brain injury.

Glutamate is formed from the deamination of glutamine supplied by the Krebs cycle. Glutamate may activate either an inotropic or a metabotropic amino acid receptor. N-methyl-d-aspartate (NMDA) receptors are ligand-gated inotropic receptors that produce a conformational change in the receptor, opening a sodium channel, which results in the depolarization of the postsynaptic membrane. The metabotropic receptor is an integral transmembrane receptor that regulates intracellular second messenger systems.¹³

GABA is the major inhibitory neurotransmitter found in the CNS. It is concentrated in the basal ganglia, cerebral cortex, cerebellum, and spinal cord. Activation of the GABA receptor opens neuronal membrane chloride channels, producing hyperpolarization (the hyperpolarized neuron is resistant to excitation). GABA is important in antagonizing the excitatory effects of amino acid neurotransmitters.¹⁴

Glycine is the primary inhibitory neurotransmitter in the spinal cord. In the past, glycine irrigation was employed during transurethral resection of the prostate. Postoperative visual impairment after the intravascular absorption of glycine suggests that glycine may act as an inhibitory neurotransmitter within the retina.

Neuropeptides

Neuropeptides are either excitatory or inhibitory. Common neuropeptides include the opioids, substance P, and many pituitary and pancreatic islet hormones.

Substance P is an excitatory neurotransmitter found in the striatum and substantia nigra of the basal ganglia, hypothalamus, brainstem (raphe nuclei), and dorsal root ganglia of the spinal cord. Substance P is released by pain-fiber terminals that synapse with the substantia gelatinosa of the spinal cord.

The opioid neuropeptides include β-endorphin, enkephalins, dynorphins, and endomorphins. They act at opiate receptors distributed throughout the brain and spinal cord. Three classes of opiate receptors have been identified—delta, kappa, and mu. Dynorphin is a potent agonist at kappa receptors, and the enkephalins are agonists at delta and mu receptors. Opiate alkaloids like morphine interact with mu receptors. Morphine-like agents block slow pain pathways, raise the pain threshold, and modify the response to pain. Other effects, such as miosis and respiratory depression, result from the actions of these agents on opiate receptors located in the parts of the brain that control these functions.2,10,15