Peripheral Neuropathies

Peripheral Nerve

The main function of the peripheral nerve is to rapidly conduct electrical signals between the central nervous system and end organs. The neuronal cell body is the main functional component that maintains the neuron and produces important structural proteins and neurotransmitters that are necessary for nerve function. The peripheral nerve axon is the major component of the neuron that, through a cascade of physiologic reactions, conducts the electrical signals between different sites. The anatomic structure of the peripheral nerve consists of more than simply the axon and its surrounding myelin; supportive connective tissue structures, intracellular structural proteins, and accompanying vasculature are necessary to maintain the structure and function of the nerve.

A single nerve, such as the median or ulnar nerve, is composed of thousands of axons that are grouped into several distinct nerve fascicles (see Plate 6-1 , top left). Each of the fascicles is held together by the epineurium , the connective tissue sheath that maintains the structure of the entire nerve. Longitudinal vessels, arterioles and venules , course along the surface of the epineurium ; these provide the necessary vascular supply to the nerve. Compromise of this vascular supply—by compression, ischemia, or inflammation—can result in infarction of an entire nerve or individual fascicles, producing acute or subacute nerve dysfunction. Clinical examples of nerve injury resulting from vascular compromise include those that occur with peripheral nerve vasculitis. The group of axons within a single nerve fascicle is surrounded by additional connective tissue called the perineurium . Within the perineurium are also small vessels providing vascular supply to the individual fascicles and axons. Each fascicle is composed of a number of individual nerve fibers, the main functional component of a nerve.

The epineurium and perineurium have important roles in maintaining the structure of the nerve, but also in providing a safety mechanism protecting the nerve from physical stresses that may injure the axons. Not only do they provide the framework for the nerves to remain adjacent and in close proximity to each other, but they protect the nerves from physical stress or injury (see Plate 6-1 , top right). Physical compromise of a nerve can occur by direct external compression, such as from repetitive physical compression of superficial nerves (e.g., habitual leg crossing compressing the fibular nerve at the fibular head, habitual leaning on the elbow compressing the ulnar nerve as it courses superficially behind the medial epicondyle, or long-distance bicycle riding compressing the ulnar nerve at the wrist). Although the connective tissue structures provide some degree of protection, with severe or repetitive compression, damage to the myelin sheaths and eventually the axons can occur.

In addition, the supportive structures and the spiral configuration of the nerve fiber bundles within each fascicle help to protect the nerve from traction injuries, in which the nerve may be suddenly extended longitudinally. This type of injury often occurs with sudden, direct blunt trauma to the limb or neck region in the case of the nerves in the brachial plexus, such as with trauma after high-speed collisions. Although the spiral configuration protects the nerves from relatively minor traction injuries, it does not prevent injury from more severe injuries (e.g., nerve root avulsion from the spinal cord).

There are two main anatomic types of individual nerves: those that are myelinated and those that are unmyelinated (see Plate 6-1 , bottom). Myelinated fibers consist of an axon surrounded by multiple Schwann cells that are present longitudinally along the course of the axon. The cytoplasm of the Schwann cells wrap around a 0.5- to 1.0-mm longitudinal segment of the axon in a spiral formation, producing lamellae . The plasma membrane of the Schwann cells that encircle the axon is composed of lipids (including cholesterol, cerebrosides, sulfatides, proteolipids, sphingomyelin, glycolipids, and glycoproteins) and proteins, and the concentric layers of the membrane that wrap around the axons form the “myelin.” The function of the myelin is to form “insulation” around segments of the nerve. Between the segments of myelin are small unmyelinated regions called nodes of Ranvier , the sites at which there is a high concentration of sodium and potassium channels. As a result, the action potentials that are generated along the nerve are rapidly transmitted from node to node, producing a very rapid “saltatory” conduction.

In contrast to myelinated fibers, unmyelinated fibers consist of an axon that is embedded within several Schwann cells, and a single Schwann cell surrounds a number of unmyelinated axons. In these fibers, rather than each axon having multiple Schwann cells wrap their cytoplasm around the axon, many axons are embedded in fewer Schwann cells. Although there is a small amount of protective myelin, there are no nodes of Ranvier, and sodium channels are equally dispersed along the entire course of the axon, resulting in slower action potential propagation along the nerve.

Both types of nerve fibers contain the other basic structures of a neuron: dendrites, a cell body, the axon, and the nerve terminals. Within the axon are a number of other proteins that provide axonal structure and assist in transporting proteins and waste back and forth from the cell body to the nerve terminals. The largest of these proteins are microtubules , which transport products from the axon to the nerve terminal, that is, anterograde transport, and from the nerve terminal to the cell body, that is, retrograde transport . Other proteins, such as intermediate filaments, help to maintain the structure of the axon.

The structures of the nerve can be identified microscopically. At different magnifications, the definition and various individual components of the nerves can be identified. The upper image (see Plate 6-2 ) shows a light micrograph transverse section of a peripheral nerve at a magnification of 200× (Masson trichrome stain). In this image, four individual nerve fascicles are seen. The epineurium (Ep) is the connective tissue that envelops and supports the individual fascicles. Each fascicle is surrounded by a dark-appearing band of connective tissue, the perineurium (Pe) , which also provides tensile support of the axons. The individual axons within the perineurium and the connective tissue surrounding the axons (endoneurium) are difficult to identify at this magnification.

In the middle light micrograph image (see Plate 6-2 ), a transverse section of a single nerve fascicle is seen on the light micrography at medium magnification (280×, hematoxylin and eosin [H&E] stain). In this image, the darker-stained perineurium (Pe) can be seen forming a surrounding protective support for the axons within. Inside the perineurium are multiple nerve fibers that are sectioned transversely or obliquely. Many of the fibers are surrounded by myelin sheaths, although the myelin is difficult to see well as a result of the lipid content. Surrounding the individual axons are nuclei of fibroblasts, Schwann cells, and capillary endothelia cells.

The bottom electron micrograph image (see Plate 6-2 ), is a transverse section of a single individual axon as visualized on electron microscopy at very high magnification (30,000×). The axon is surrounded by perineurial c ells (Pe) and collagen fibrils (CF) that constitute the supportive endoneurium. The Schwann cell surrounding the axon is composed of cytoplasm (SC) that wraps around the axon in lamellae forming the myelin sheath (MS); this appears as a thin “onion” covering wrapping around the axon. The thin external basal lamina of the myelin can also be identified. Within the myelin is the axon. Individual organelles, including mitochondria (Mi), neurofilaments, and microtubules can also be seen.

Peripheral nerves and their respective muscle fiber integrity and sensory pathway function are assessed through electrodiagnostic testing (electromyography [EMG]), including motor and sensory nerve conduction studies and needle electromyography. Injury or dysfunction at any motor unit site may lead to limited motor unit function. EMG abnormalities help to identify the site and physiologic basis of the motor unit dysfunction. The peripheral nerves are most commonly affected by genetically determined abnormalities, such as Charcot-Marie-Tooth disease (CMT1a), that are often autosomal dominant. Metabolic-derived conditions, including diabetes mellitus and chronic renal disorders and often occult malignancies producing a paraneoplastic process, as well as various toxins, including medications and certain environmental risks such as arsenic, can also affect peripheral nerve function.

Individual peripheral nerves may be affected by local factors, such as thickening of the transverse carpal ligament producing a carpal tunnel syndrome (CTS) or crossing one's knees, thus entrapping the common peroneal nerve at the fibular head. With sufficient loss of motor units in a muscle, or with inability of an impulse to conduct along the motor unit, muscle strength diminishes. Primary or conjoint sensory dysfunction is studied with EMG, noting sensory nerve action potentials (SNAPs) absence secondary to an axonal process or prolonged conduction across the transverse carpal ligament typical of the carpal tunnel syndrome.

Cell Types of Nervous System

Resting Membrane Potential

Rapid transmission of electrical signals along neurons relies on the generation and propagation of electrical charges along the membrane. A complex and constantly occurring series of processes along the axon membrane are necessary for the development of the action potential. The axon membrane potential electrical gradient at rest provides the foundation for the changes that occur during action potential generation. Several structures along the axonal plasma membrane are responsible for the generation of the resting membrane potential—the sodium (Na ⁺ ), potassium (K ⁺ ), and chloride (C1 ⁻ ) channels and the adenosine triphosphate (ATP)-dependent Na ⁺ -K ⁺ pump.

The transmembrane ion concentrations at rest is dependent upon the passive diffusion of ions from the site of higher concentration to the site of lower concentration through ion channels, as well as the active adenosine triphosphatase (ATPase)-dependent transport of ions against a concentration gradient. At rest, the concentrations of sodium, chloride, and calcium ions are higher extracellularly, whereas the concentrations of potassium ions and impermeable protein anions are higher intracellularly. As a result, sodium and chloride are forced to move from the extracellular to intracellular space and potassium in the opposite direction. With the diffusion of ions across the cell membrane, a separation of charges develops because the nondiffusible negatively charged intracellular ions have a charge opposite that of the diffusible ions. As a result, an electrical potential difference develops between the intracellular and extracellular axon membrane. This electrical potential difference produces an electrical pressure that opposes the physical movement of the ion. The net ionic movement continues until the electrical pressure equals the diffusion pressure, and there is no net movement of ions. The resulting electrical potential across the membrane is called the equilibrium potential .

The equilibrium potential of each ion (E _ion ) is the voltage difference across the membrane that exactly offsets the diffusion pressure of an ion to move down its concentration gradient. This potential is different for each ion and can be defined by the Nernst equation, which defines the equilibrium potential, E _m , inside the cell for any ion in terms of its concentration extracellularly [Xe] and intracellularly [Xi].

In the resting state, the approximate equilibrium potentials of the major ions are

The contribution of a given ion to the actual resting transmembrane voltage depends not only on the ion's concentration gradient but also the permeability of the membrane to that ion as a result of the opening or closing of the ion channel. Increased permeability (i.e., opening of the channel) to a particular ion brings the membrane potential toward the equilibrium potential of that ion. If a membrane is permeable to multiple ions that are present in differing concentrations on either side of the membrane, the resultant membrane potential is a function of the concentrations of each of the ions and of their relative permeabilities. The Goldman equation combines these factors for the major ions (Na ⁺ , K ⁺ , and Cl ⁻ ) that influence the membrane potential and is used to calculate the resting membrane potential.

An electrical circuit model using Ohm's law (E = IR) can be used to demonstrate the contribution of each ion to the resting membrane potential. The movement of ions across the membrane is expressed as an ion current. By Ohm's law, this current depends on the driving force of the ion (the difference between the membrane potential and the equilibrium potential of that ion) and conductance of the ion (g). Using this model, the conductance (g) (or the reciprocal of the resistance) for a particular ion is dependent on the ion channel permeability of each ion. The concentration ratios of the different ions are represented by their respective equilibrium potentials ( E _Na , E _K , E _Cl ); their ionic permeabilities are represented by their respective conductances. Therefore, at rest, the conductance of the potassium ions is high, whereas sodium conductance is low and chloride conductance is moderate. As a result, the flow of potassium ions is the predominant contributor to the membrane potential at rest. The resting membrane potential (RMP) is the sum of the conductances of all the open channels permeable to each ion.

Ion Channel Mechanics and Action Potential Generation

The role of the neuron is to generate and rapidly transmit electrical signals over relatively long distances. This function relies on the membrane potential and its effect on the gating of the sodium channels, which play a critical role in action potential generation and propagation.

At rest, the resting membrane potential, or the absolute difference in electrical potential between the inside and the outside of the inactive neuron, results predominantly from the membrane permeability to potassium as a result of the open state of the potassium leak channels. This resting membrane potential is approximately −70 mV. If an electrical circuit diagram is used to demonstrate the transmembrane potential at rest, with conductance and resistance of Na ⁺ , K ⁺ , and Cl ⁻ shown in parallel, the contribution of conductance of K ⁺ and Cl ⁻ are responsible for the overall current flow and membrane potential.

When a negatively charged stimulus (physiologic or external) is applied to the extracellular axon membrane, there is a decrease in the value of the resting membrane potential as the charge difference between the extracellular and intracellular membranes decreases (called depolarization). If the membrane is depolarized only a small degree, only a few sodium channels are activated, and a local potential is generated. If this charge difference reaches the excitation threshold for opening of many voltage-gated sodium channels (approximately −50 to −55 mV) the conductance of sodium rapidly becomes greater than that of K ⁺ , and Na ⁺ ions rapidly move from the extracellular to intracellular space, resulting in a movement of the transmembrane potential difference toward the equilibrium potential of sodium (+60 mV). This depolarization locally reverses the polarity of the membrane, the inside becoming positive with respect to the outside.

This rapid change in conductance results in the action potential . Action potentials are “all-or-none,” allowing for rapid transmission of information over long distances along the nerve. The change in sodium conductance is transient and lasts only a few milliseconds. As the sodium channels become inactive and the potassium channels re-open, the sodium conductance decreases and potassium conductance increases, resulting in an increase in flow of potassium out of the cell and repolarization of the membrane.

The rate of return of the membrane potential to the baseline slows after sodium conductance has returned to baseline, producing a small residual on the negative component of the action potential, which is called the negative afterpotential . This afterpotential is positive when the membrane potential is recorded with a microelectrode within the cell, but it is negative when recorded with an extracellular electrode. The increase in potassium conductance persists and results in a hyperpolarization after the spike component of the action potential—the after-hyperpolarization—which is due to continued efflux of potassium ions, with a greater than resting difference in potential between the inside and the outside of the cell. The after-hyperpolarization is positive when measured with extracellular electrodes and therefore is called a positive afterpotential .

The changes in Na ⁺ and K ⁺ channel activation and inactivation overlap to a degree. As a result, the membrane potential is a function of the ratios of the conductances of the Na ⁺ , K ⁺ , and Cl ⁻ ions. These can be demonstrated in an electrical circuit diagram, demonstrating current flow relative to the conductances (ion channel permeability) of Na ⁺ , K ⁺ , and Cl ⁻ in the resting states and after a threshold-reaching stimulus.

Neurophysiology and Peripheral Nerve Demyelination

Several different pathologic changes within the nerves may occur as a result of disease. Nerve injury occurs in three stages of severity—neurapraxia, axonotmesis, and neurotmesis. In neurapraxia, there is a block of conduction of the action potential across the region of nerve injury. This is a relatively common clinical lesion that occurs when external pressure is applied against a single nerve resting against a bony surface. An example of focal neurapraxia is the wristdrop that develops from subacute pressure against the radial nerve passing through the spiral groove within the midhumerus. Some diffuse peripheral nerve disorders, such as the autoimmune Guillain-Barré syndrome, are also characterized by neurapraxia, but here there are multiple areas of asymmetric focal demyelination. In both settings, the axon and supporting structures may remain intact structurally; however, action potential conduction across the abnormal demyelinated axon is slowed or blocked. Conduction of action potentials and the structural integrity of the proximal and distal portions of the region of neurapraxia are maintained. Focal demyelination is the predominant pathologic alteration of this stage. A similar physiologic response may also develop when there is alteration of the cell membrane or channels, such as with local anesthetic.

On neurophysiologic testing with motor nerve conduction studies (NCS), the pattern of changes in the recorded responses differs when focal neurapraxia occurs to the same degree and at the same site along multiple axons within a nerve compared with differing degrees of focal demyelination among different axons within the nerve. In disorders where uniform demyelination occurs at a focal site along a nerve ( conduction block ), stimulation of the nerve distal to the site will elicit a normal compound muscle action potential (CMAP) response, whereas stimulation proximal to the site will elicit a CMAP that is of lower amplitude and area but of similar morphology. (A) In contrast, when multifocal demyelination occurs among the axons within the nerve, the degree of slowing or block varies among different axons. As a result, stimulation distal to the areas of demyelination will result in a normal CMAP response, but stimulation at a proximal site will elicit a response that is of lower amplitude and area as well as increased in duration ( temporally dispersed ) (B).

With both axonotmesis and neurotmesis, the continuity of the axon is disrupted, and the portion of the axon separated from the anterior horn cell or posterior root ganglia undergoes wallerian degeneration . Axonotmesis occurs when axonal continuity is disrupted; however, the connective tissue, including the endoneurium, is preserved . Axonal regeneration and regrowth along the endoneurial tubes is still possible as long as the connective tissue along the endoneurial tube remains intact. Neurotmesis is a more severe stage of injury, where the axon, myelin, and connective tissue sheath, including the epineurium, are disrupted and the two ends of the nerve are separated. In this stage, effective recovery is very unlikely or impossible, depending on the amount of separation of the two ends of the nerve.

When NCS are performed in this setting during the first week after an axonotmetic or neurotmetic injury, and a nerve is stimulated electrically distal to the site of injury, the portion of the axon that is separated from the cell body will temporarily continue to have the ability to propagate an action potential. However, once an entire week of axonal wallerian degeneration occurs, the disconnected segment of the axon can no longer respond to electrical stimulation to conduct an action potential. Therefore the CMAP amplitude will be reduced or absent with distal and proximal stimulation sites. The motor fibers are more sensitive and lose their ability to conduct at about 7 days, whereas one may still obtain a sensory nerve action potential (SNAP) up to about 10 days.

Impulse Propagation

In the normal propagating action potential, only a small section of the membrane is active at one time. As a result, part of the current associated with the action potential in the active region passes through adjacent, inactive parts of the axonal membrane. This spread of current is the factor responsible for the propagation of nerve impulses.

Action Potential Propagation . Three stages illustrate the propagation of an action potential past a point on an axon at which microelectrodes have been positioned to record intracellular and extracellular potentials, each with respect to “ground” (the bath fluid). The intracellular electrode records the transmembrane potential, while the extracellular electrode records the much smaller voltage changes produced by the flow of current through the extracellular fluid.

Stage 1. The nerve impulse is approaching the recording point from the left. Inward current flow at the active region gives rise to compensatory outward current flow through a section of axonal membrane on either side of the active region. (The inward flow of sodium ion [Na ⁺ ] current in excess of that required to charge the membrane capacitance must be balanced by the outward flow of other ionic currents.) The outward current flow is passive in that it is not initiated by a change in membrane permeability, as is the inward Na ⁺ current. According to Ohm's law, such a passive flow of outward current through the membrane resistance causes a voltage drop that depolarizes the axonal membrane at the recording point. The intracellular electrode therefore records depolarization of the membrane, and the extracellular electrode records a positive voltage shift caused by the outward flow of current away from the recording point.

Stage 2. As the activity approaches, the transmembrane depolarization at the recording point becomes greater, until it reaches the threshold for action potential initiation. At this point, the membrane becomes active. The passive outward current flow shifts to an active inward flow of Na ⁺ current. In accordance with this reversal in the direction of current flow, the voltage recorded by the extracellular electrode shifts from positive to negative. Rather than changing sign, however, the intracellular potential moves farther in the depolarizing direction. This happens because the inward current flow is caused by a change in membrane permeability to Na ⁺ , which shifts the membrane potential toward E _Na + (+50 mV).

The strong flow of inward current at the recording point gives rise to a passive flow of outward current through the axonal membrane to the right and to the left. Depolarization caused by this current triggers an action potential in the axon to the right. Re-excitation of the axon to the left does not occur immediately because the membrane is temporarily refractory as a result of the passage of the nerve impulse.

Stage 3. The axon to the right has become active, while the potential at the recording point has fallen to −75 mV. This takes place because Na ⁺ inactivation has returned Na ⁺ permeability to a low level, and potassium ion (K ⁺ ) permeability has increased, thus moving the potential toward E _K ⁺ (−90 mV). The increase in K ⁺ permeability and the active zone to the right give rise to an outward current flow, which is revealed by a final positive extracellular voltage. Because of the altered permeability of the membrane to K ⁺ and Na ⁺ inactivation during the refractory period, this outward current cannot give rise to another action potential.

Conduction Velocity

The velocity of action potential propagation along an axon depends on the distance that suprathreshold depolarization spreads in front of the active zone. This distance can be increased either by increasing the axonal diameter (which decreases the longitudinal resistance of the axoplasm), or by increasing the transverse resistance of the outer covering of the axon. Increasing the axonal diameter alone (as would be needed in unmyelinated fibers) would require excessively large diameters to attain the high action potential conduction velocities observed in the human nervous system. In myelinated fibers, where the transverse resistance is increased by the addition of the myelin sheath, conduction velocities in excess of 100 m/sec are achieved with axonal diameters of less than 20 µm.

In a myelinated nerve fiber, successive 1- to 2-mm segments of axon, called internodes , are enveloped by multiple layers of Schwann cell membrane. Between these segments are short lengths of axon with little or no covering, called nodes of Ranvier . According to the saltatory conduction theory, myelin increases the transverse resistance of the internodes, while the resistance at the nodes remains normal. As a result, when the axonal membrane at a node becomes active (part A), the passive outward currents produced by this activity are prevented from flowing through the membrane of the adjacent internode; instead, they flow through the membrane of the next node.

The resulting depolarization triggers an action potential at this node. Thus, unlike impulse propagation in an unmyelinated axon (part B), which proceeds continuously in very small steps, the impulse in a myelinated axon jumps from node to node and results in a much greater conduction velocity.

As shown in C, mammalian peripheral nerves contain myelinated fibers with diameters of 0.5 to 20 µm and conduction velocities of 3 to 120 m/sec, and unmyelinated fibers with diameters of less than 2 µm and conduction velocities of 0.5 to 2.0 m/sec. In 1930, Erlanger and Gasser published a classification of peripheral nerve fibers, based on conduction velocity. Three groups of fibers were defined according to descending conduction velocity, designated A (with subgroups α, β and γ), B, and C. A further subgroup, Aδ, was added later. This classification refers to both afferent (sensory) and efferent (motor) fibers, whereas a more recent classification of nerve fibers into groups I, II, III, and IV refers only to afferent fibers.

The properties and functions of the different classes of nerve fibers are summarized in part C. In the somatic efferent system, fibers supplying skeletal muscle fibers (alpha motor axons) have conduction velocities ranging from 50 to 100 m/sec (Aα and Aβ ranges), and fibers supplying the intrafusal muscle fibers of muscle spindles (gamma motor axons) have conduction velocities ranging from 10 to 40 m/sec (Aγ and Aδ ranges). Autonomic efferent fibers fall either into group B (preganglionic fibers) or group C (postganglionic fibers). In the afferent system, the larger myelinated fibers carry information from specialized receptors that respond to only one type of stimulus, whereas many smaller myelinated fibers carry information about noxious stimuli that give rise to the sensation of prickling pain. The function of unmyelinated sensory fibers (group IV, or C, fibers) is not entirely clear. Stimulation of these fibers as a group evokes only the sensation of burning pain, but experiments have shown that many of these fibers carry information about a specific type of stimulus (touch, pressure, temperature), and only a restricted group is specifically sensitive to noxious stimuli.

Visceral Efferent Endings

Efferent endings involved in the control of smooth muscle and glandular activity and in neurosecretion do not exhibit the discrete one-to-one type of relationship between presynaptic endings and postsynaptic cells characteristic of neuromuscular junction or central synapse. Instead, neural transmitter substances released by such efferent endings are discharged into the interstitial space or into the bloodstream, where they can influence the activity of numerous effector cells. Consistent with this functional difference, ultrastructural studies of visceral efferent endings have failed to demonstrate the type of close apposition of specialized presynaptic and postsynaptic membranes that characterizes other chemical synaptic junctions. A functional visceral efferent junction can be as wide as 2,000 Å.

Autonomic neuromuscular endings control such diverse functions as heart rate, intestinal and urogenital activity, pupillary size, and blood pressure. The morphologic features of this type of ending are shown in A, which illustrates a three-dimensional reconstruction of the smooth muscle lining the colon. Bundles of the unmyelinated postganglionic fibers that innervate intestinal muscle are enveloped by individual Schwann cells. As these bundles run between smooth muscle cells, each axon exhibits beadlike swellings filled with synaptic vesicles at various points along its length. At these varicosities (“boutons en passant”), the surrounding Schwann cell membranes are drawn back so that the released transmitter substance can diffuse into the interstitial space and act on nearby smooth muscle cells. After forming numerous varicosities, an individual axon loses its Schwann cell sheath; after a short distance, it forms a final terminal ending similar in structure to the earlier varicosities.

Autonomic nerve endings in exocrine glands are structurally similar to autonomic neuromuscular endings. In the case of the mandibular gland (B), bundles of unmyelinated postganglionic fibers in Schwann cell sheaths form varicosities and terminal endings in the spaces between secretory cells. In this gland, as in many structures innervated by autonomic fibers, two types of endings are seen. Sympathetic endings , which in this gland excite mucous cells to produce mucous saliva, are filled with densely staining vesicles indicating the presence of the transmitter norepinephrine. Parasympathetic endings , which act on serous cells to produce watery saliva, are filled with clear vesicles that contain acetylcholine.

The neurosecretory endings of the posterior pituitary gland (C) and adrenal medulla are adapted to allow the transmitter substance released by the arrival of an action potential in the nerve terminal to enter the bloodstream and be carried to target cells in other parts of the body. In the posterior pituitary, axons of neurons in the supraoptic and paraventricular nuclei of the hypothalamus run between supporting cells called pituicytes, to terminate directly on the basement membrane that delimits the collagen space around a capillary. Vesicles within the terminals contain one of the two posterior pituitary hormones, oxytocin and vasopressin (antidiuretic hormone). The morphology of the endings suggests that a hormone released by the arrival of action potentials in the terminals is able to diffuse through the collagen space and enter the capillary via pores between the endothelial cells. This diffusion process may be aided by mast cells, which are known to play a role in capillary permeability.

Cutaneous Receptors

Glabrous and hairy skin both contain a wide variety of receptors for the purpose of detecting mechanical, thermal, or painful stimuli applied to the body surface Because of the difficulty in visualizing these receptors and in stimulating an individual receptor in isolation, the identification of the function of different receptor types is still tentative in many cases. The situation is further complicated in that a receptor specialized to respond to one stimulus may also respond (usually more weakly) to another stimulus. How “crosstalk” of this kind is resolved by the central nervous system (CNS) is still unknown.

Three types of receptors are common to glabrous and hairy skin: pacinian (lamellated) corpuscles, Merkel disks, and free nerve endings. The pacinian corpuscle has been identified as a quickly adapting mechanoreceptor, and its mechanical transduction process has been extensively studied. The primary role of pacinian corpuscles appears to be the sensing of brief touch or vibration.

Merkel disks are slowly adapting mechanoreceptors structured to respond to maintaining deformation of the skin surface. Typically, one afferent fiber of large-to-medium diameter branches to form a cluster of Merkel disks situated at the base of a thickened region of epidermis. Each nerve terminal branch ends in a disk enclosed by a specialized accessory cell (Merkel cell). The distal surface of the Merkel cell is held to nearby epidermal cells by cytoplasmic protrusions and desmosomes, while the base of the cell is embedded in the underlying dermis. Thus movement of the epidermis relative to the dermis will exert a shearing force on the Merkel cell. The Merkel cell also contains numerous granulated vesicles, which suggests that some form of chemical synaptic transmission may occur, although attempts to demonstrate this have failed. Direct mechanical transduction by the nerve ending has not been ruled out as a possibility. However, whatever the transduction mechanism, the Merkel-cell/Merkel-disk ending appears to play a role in the sensing of both touch and pressure.

The so-called free nerve ending is made up of a branching nerve axon, which is entirely or partially surrounded by Schwann cells. The axon/Schwann-cell complex is further surrounded by a basement membrane. Free nerve endings originate from fine myelinated or unmyelinated fibers that branch extensively in the dermis and may penetrate into the epidermis. These endings respond to strong mechanical and thermal stimuli, and they are particularly activated by painful stimuli.

The other receptors found in glabrous skin are Meissner corpuscles (tactile corpuscles), in which the terminal branches of a myelinated axon intertwine in a basket-like array of accessory cells, and Krause end bulbs , in which a fine myelinated fiber forms a club-shaped ending. Meissner corpuscles have been tentatively identified as quickly adapting mechanoreceptors subserving the sense of touch, whereas Krause end bulbs may be thermoreceptors.

The most important receptors in hairy skin are the hair follicle endings , in which axon terminals of sensory nerve fibers wrap themselves around a hair follicle. These endings are quickly adapting mechanoreceptors that provide information about any force applied to the hair and, thus, to the skin. Hairy skin also contains the spraylike Ruffini terminals , which may be involved in the sensing of steady pressure applied to hairy skin.

Pacinian Corpuscle

The pacinian corpuscle is one of a group of receptors, known as mechanoreceptors, which transform mechanical force, or displacement, into action potentials. In a simple mechanoreceptor, such as the pacinian corpuscle, transduction of the mechanical stimulus into action potentials occurs in three stages. First, the mechanical stimulus is modified by the viscoelastic properties of the receptor and the accessory cells surrounding it. Then, the modified mechanical stimulus acts on the mechanically sensitive membrane of the receptor cell to produce a change—a generator potential—in the transmembrane potential of the receptor cell. Finally, the generator potential acts to produce action potentials in the afferent nerve fiber linked to the mechanoreceptor.

The pacinian corpuscle consists of the unmyelinated terminal part of an afferent nerve fiber that is surrounded by concentric lamellae formed by the membranes of numerous supporting cells. The axon terminal membrane is adapted in such a way that its ionic permeability increases when it is deformed by applied pressure. Although the permeability change appears to be nonspecific, the principal ion flux that occurs is an inflow of sodium ions (Na ⁺ ) because of the great difference in the electrochemical potential of this ion on the two sides of the membrane. The Na ⁺ influx causes a depolarizing current to flow through the axon terminal and the nearby nodes of Ranvier of the afferent fiber. The depolarization caused by this current comprises the generator potential. If the depolarization is great enough, it will produce an action potential at the point of lowest threshold, in this case, at the first node. This action potential then propagates along the afferent fiber to the central nervous system (CNS).

The pacinian corpuscle is specifically adapted to respond to rapidly changing mechanical stimulation. Experiments on isolated pacinian corpuscles have shown that this adaptation involves both the physical structure of the receptor and the properties of the action potential–generating mechanism.

When pressure is applied to an intact pacinian corpuscle, single-action potentials are evoked at the beginning and end of the pressure pulse. If action potentials are blocked by a drug such as tetrodotoxin, the generator potentials evoked by the pressure pulse can be recorded. In the intact pacinian corpuscle, these potentials consist of rapidly decaying depolarizations that occur at the beginning and end of the pulse.

If all the lamellae of the sheath, except the innermost, are dissected away, the response of the pacinian corpuscle to the pressure pulse is modified. The generator potential now decays slowly throughout the period of applied pressure, and no additional depolarization appears at the termination of the pulse. This finding indicates that the viscoelastic properties of the intact capsule dissipate applied pressure, which means that only sudden pressure changes can reach the membrane of the nerve terminal and produce a generator potential.

Muscle and Joint Receptors

Several types of mechanoreceptors located in the joints and muscles (see Plate 6-12 ) provide the central nervous system (CNS) with vital proprioceptive information about the position of the parts of the body and the length and tension of various muscles.