Chapter 49 Nervous Systems Key Concepts

Concept 49.2 Ion pumps and ion channels maintain the resting potential of a neuron

Every cell has a voltage, or membrane potential, across its plasma membrane. All cells have an electrical potential difference (voltage) across their plasma membrane). This voltage is called the membrane potential. In neurons, the membrane potential is typically between ? 60 and ?80 mV when the cell is not transmitting signals. The membrane potential of a neuron that is not transmitting signals is called the resting potential. In all neurons, the resting potential depends on the ionic gradients that exist across the plasma membrane. In mammals, the extracellular fluid has a Na+ concentration of 150 millimolar (mM) and a K+ of 5 mM. In the cytosol, Na+ concentration is 15 mM, and K+ concentration is 150 mM. These gradients are maintained by the sodium-potassium pump. The magnitude of the membrane voltage at equilibrium, called the equilibrium potential (Eion), is given by a formula called the Nernst equation. For an ion with a net charge of +1, the Nernst equation is: Eion = 62mV (log [ion]outside/[ion]inside) The Nernst equation applies to any membrane that is permeable to a single type of ion. In our model, the membrane is only permeable to K+, and the Nernst equation can be used to calculate EK, the equilibrium potential for K+. With this K+ concentration gradient, K+ is at equilibrium when the inside of the membrane is 92 mV more negative than the outside. Assume that the membrane is only permeable to Na+. ENa, the equilibrium potential for Na+, is +62 mV, indicating that, with this Na+ concentration gradient, Na+ is at equilibrium when the inside of the membrane is 62 mV more positive than the outside. How does a real mammalian neuron differ from these model neurons? The plasma membrane of a real neuron at rest has many open potassium channels, but it also has a relatively small number of open sodium channels. Consequently, the resting potential is around ?60 to ?80 mV, between EK and ENa. Neither K+ nor Na + is at equilibrium, and there is a net flow of each ion (a current) across the membrane at rest. The resting membrane potential remains steady, which means that the K+ and Na+ currents are equal and opposite. The reason the resting potential is closer to EK than to ENa is that the membrane is more permeable to K+ than to Na+. If something causes the membrane's permeability to Na+ to increase, the membrane potential will move toward ENa and away from EK. This is the basis of nearly all electrical signals in the nervous system. The membrane potential can change from its resting value when the membrane's permeability to particular ions changes. Sodium and potassium play major roles, but there are also important roles for chloride and calcium ions. The resting potential results from the diffusion of K+ and Na+ through ion channels that are always open. These channels are ungated. Neurons also have gated ion channels, which open or close in response to one of three types of stimuli. Stretch-gated ion channels are found in cells that sense stretch, and open when the membrane is mechanically deformed. Ligand-gated ion channels are found at synapses and open or close when a specific chemical, such as a neurotransmitter, binds to the channel. Voltage-gated ion channels are found in axons (and in the dendrites and cell bodies of some neurons, as well as in some other types of cells) and open or close in response to a change in membrane potential.

Concept 49.3 Action potentials are the signals conducted by axons

Gated ion channels are responsible for generating the signals of the nervous system. If a cell has gated ion channels, its membrane potential may change in response to stimuli that open or close those channels. Some stimuli trigger a hyperpolarization, an increase in the magnitude of the membrane potential. Gated K+ channels open, K+ diffuses out of the cell, and the inside of the membrane becomes more negative. Other stimuli trigger a depolarization, a reduction in the magnitude of the membrane potential. Gated Na+ channels open, Na+ diffuses into the cell, and the inside of the membrane becomes less negative. These changes in membrane potential are called graded potentials because the magnitude of the change—either hyperpolarization or depolarization—varies with the strength of the stimulus. A larger stimulus causes a larger change in membrane permeability and, thus, a larger change in membrane potential. In most neurons, depolarizations are graded only up to a certain membrane voltage, called the threshold. A stimulus strong enough to produce a depolarization that reaches the threshold triggers a different type of response, called an action potential. An action potential is an all-or-none phenomenon. Once triggered, it has a magnitude that is independent of the strength of the triggering stimulus. Action potentials of neurons are very brief—only 1-2 milliseconds in duration. This allows a neuron to produce them at high frequency. Both voltage-gated Na+ channels and voltage-gated K+ channels are involved in the production of an action potential. Both types of channels are opened by depolarizing the membrane, but they respond independently and sequentially: Na+ channels open before K+ channels. Each voltage-gated Na+ channel has two gates, an activation gate and an inactivation gate, and both must be open for Na+ to diffuse through the channel. At the resting potential, the activation gate is closed and the inactivation gate is open on most Na+ channels. Depolarization of the membrane rapidly opens the activation gate and slowly closes the inactivation gate. Each voltage-gated K+ channel has just one gate, an activation gate. At the resting potential, the activation gate on most K+ channels is closed. Depolarization of the membrane slowly opens the K+ channel's activation gate. How do these channel properties contribute to the production of an action potential? When a stimulus depolarizes the membrane, the activation gates on some Na+ channels open, allowing more Na+ to diffuse into the cell. The Na+ influx causes further depolarization, which opens the activation gates on still more Na+ channels, and so on. Once the threshold is crossed, this positive-feedback cycle rapidly brings the membrane potential close to ENa during the rising phase. However, two events prevent the membrane potential from actually reaching ENa. The inactivation gates on most Na+ channels close, halting Na+ influx. The activation gates on most K+ channels open, causing a rapid efflux of K+. Both events quickly bring the membrane potential back toward EK during the falling phase. In fact, in the final phase of an action potential, called the undershoot, the membrane's permeability to K+ is higher than at rest, so the membrane potential is closer to EK than it is at the resting potential. The K+ channels' activation gates eventually close, and the membrane potential returns to the resting potential. The Na+ channels' inactivation gates remain closed during the falling phase and the early part of the undershoot. As a result, if a second depolarizing stimulus occurs during this refractory period, it will be unable to trigger an action potential. Nerve impulses propagate themselves along an axon. The action potential is repeatedly regenerated along the length of the axon. An action potential achieved at one region of the membrane is sufficient to depolarize a neighboring region above the threshold level, thus triggering a new action potential. Immediately behind the traveling zone of depolarization due to Na+ influx is a zone of repolarization due to K+ efflux. In the repolarized zone, the activation gates of Na+ channels are still closed. Consequently, the inward current that depolarizes the axon membrane ahead of the action potential cannot produce another action potential behind it. Once an action potential starts, it normally moves in only one direction—toward the synaptic terminals. Several factors affect the speed at which action potentials are conducted along an axon. One factor is the diameter of the axon: the larger the axon's diameter, the faster the conduction. In the myelinated neurons of vertebrates, voltage-gated Na+ and K+ channels are concentrated at gaps in the myelin sheath called nodes of Ranvier. Only these unmyelinated regions of the axon depolarize. Thus, the impulse moves faster than in unmyelinated neurons. This mechanism is called saltatory conduction.

Concept 49.1 Nervous systems consist of circuits of neurons and supporting cells

Nervous systems show diverse patterns of organization. All animals except sponges have some type of nervous system. What distinguishes nervous systems of different animal groups is how the neurons are organized into circuits. Cnidarians have radially symmetrical bodies organized around a gastrovascular cavity. In hydras, neurons controlling the contraction and expansion of the gastrovascular cavity are arranged in diffuse nerve nets. The nervous systems of more complex animals contain nerve nets, as well as nerves, which are bundles of fiberlike extensions of neurons. With cephalization come more complex nervous systems. Neurons are clustered in a brain near the anterior end in animals with elongated, bilaterally symmetrical bodies. In simple cephalized animals such as the planarian, a small brain and longitudinal nerve cords form a simple central nervous system (CNS). In more complex invertebrates, such as annelids and arthropods, behavior is regulated by more complicated brains and ventral nerve cords containing segmentally arranged clusters of neurons called ganglia. Nerves that connect the CNS with the rest of the animal's body make up the peripheral nervous system (PNS). The nervous systems of molluscs correlate with lifestyle. Clams and chitons have little or no cephalization and simple sense organs. Squids and octopuses have the most sophisticated nervous systems of any invertebrates, rivaling those of some vertebrates. The large brain and image-forming eyes of cephalopods support an active, predatory lifestyle. Nervous systems consist of circuits of neurons and supporting cells. In general, there are three stages in the processing of information by nervous systems: sensory input, integration, and motor output. Sensory neurons transmit information from sensors that detect external stimuli (light, heat, touch) and internal conditions (blood pressure, muscle tension). Sensory input is conveyed to the CNS, where interneurons integrate the sensory input. Motor output leaves the CNS via motor neurons, which communicate with effector cells (muscle or endocrine cells). Effector cells carry out the body's response to a stimulus. The stages of sensory input, integration, and motor output are easy to study in the simple nerve circuits that produce reflexes, the body's automatic responses to stimuli. Networks of neurons with intricate connections form nervous systems. The neuron is the structural and functional unit of the nervous system. The neuron's nucleus is located in the cell body. Arising from the cell body are two types of extensions: numerous dendrites and a single axon. Dendrites are highly branched extensions that receive signals from other neurons. An axon is a longer extension that transmits signals to neurons or effector cells. The axon joins the cell body at the axon hillock, where signals that travel down the axon are generated. Many axons are enclosed in a myelin sheath. Near its end, axons divide into several branches, each of which ends in a synaptic terminal. The site of communication between a synaptic terminal and another cell is called a synapse. At most synapses, information is passed from the transmitting neuron (the presynaptic cell) to the receiving cell (the postsynaptic cell) by means of chemical messengers called neurotransmitters. Glia are supporting cells that are essential for the structural integrity of the nervous system and for the normal functioning of neurons. There are several types of glia in the brain and spinal cord. Astrocytes are found within the CNS. They provide structural support for neurons and regulate the extracellular concentrations of ions and neurotransmitters. Some astrocytes respond to activity in neighboring neurons by facilitating information transfer at those neuron's synapses. By inducing the formation of tight junctions between capillary cells, astrocytes help form the blood-brain barrier, which restricts the passage of substances into the CNS. In an embryo, radial glia form tracks along which newly formed neurons migrate from the neural tube. Both radial glia and astrocytes can also act as stem cells, generating neurons and other glia. Oligodendrocytes (in the CNS) and Schwann cells (in the PNS) are glia that form myelin sheaths around the axons of vertebrate neurons. These sheaths provide electrical insulation of the axon. In multiple sclerosis, myelin sheaths gradually deteriorate, resulting in a progressive loss of body function due to the disruption of nerve signal transmission

Concept 49.5 The vertebrate nervous system is regionally specialized

Vertebrate nervous systems have central and peripheral components. In all vertebrates, the nervous system shows a high degree of cephalization and has distinct CNS and PNS components. The brain provides integrative power that underlies the complex behavior of vertebrates. The spinal cord integrates simple responses to certain kinds of stimuli and conveys information to and from the brain. The vertebrate CNS is derived from the dorsal embryonic nerve cord, which is hollow. In the adult, this feature persists as the narrow central canal of the spinal cord and the four ventricles of the brain. Both the canal and the ventricles are filled with cerebrospinal fluid, which is formed in the brain by filtration of the blood. Cerebrospinal fluid circulates through the central canal and ventricles and then drains into the veins, assisting in the supply of nutrients and hormone and the removal of wastes. In mammals, the fluid cushions the brain and spinal cord by circulating between two of the meninges, layers of connective tissue that surround the CNS. White matter of the CNS is composed of bundles of myelinated axons. Gray matter consists of unmyelinated axons, nuclei, and dendrites. The divisions of the peripheral nervous system interact in maintaining homeostasis. The PNS transmits information to and from the CNS and plays an important role in regulating the movement and internal environment of a vertebrate. The vertebrate PNS consists of left-right pairs of cranial and spinal nerves and their associated ganglia. Paired cranial nerves originate in the brain and innervate the head and upper body. Paired spinal nerves originate in the spinal cord and innervate the entire body. The PNS can be divided into two functional components: the somatic nervous system and the autonomic nervous system. The somatic nervous system carries signals to and from skeletal muscle, mainly in response to external stimuli. It is subject to conscious control, but much skeletal muscle activity is actually controlled by reflexes mediated by the spinal cord or the brainstem. The autonomic nervous system regulates the internal environment by controlling smooth and cardiac muscles and the organs of the digestive, cardiovascular, excretory, and endocrine systems. Three divisions make up the autonomic nervous system: sympathetic, parasympathetic, and enteric. Activation of the sympathetic division correlates with arousal and energy generation—the "flight or fight" response. Activation of the parasympathetic division generally promotes calming and a return to self-maintenance functions—"rest and digest." When sympathetic and parasympathetic neurons innervate the same organ, they often have antagonistic effects. The enteric division consists of complex networks of neurons in the digestive tract, pancreas, and gallbladder. The enteric networks control the secretions of these organs as well as activity in the smooth muscles that produce peristalsis. The sympathetic and parasympathetic divisions normally regulate the enteric division. The somatic and autonomic nervous systems often cooperate in maintaining homeostasis. Embryonic development of the vertebrate brain reflects its evolution from three anterior bulges of the neural tube. In all vertebrates, three bilaterally symmetrical, anterior bulges of the neural tube form the forebrain, midbrain, and hindbrain during embryonic development. Over vertebrate evolution, the brain became further divided structurally and functionally, providing additional complex integration. The forebrain is particularly enlarged in birds and mammals. Five brain regions form by the fifth week of human embryonic development. The telencephalon and diencephalon develop from the forebrain. The mesencephalon develops from the midbrain. The metencephalon and myelencephalon develop from the hindbrain. The telencephalon gives rise to the cerebrum. Rapid growth of the telencephalon during the second month of human development causes the outer portion of the cerebrum, the cerebral cortex, to extend over the rest of the brain. The adult brainstem consists of the midbrain (derived from the mesencephalon), the pons (derived from the metencephalon), and the medulla oblongata (derived from the myelencephalon). The metencephalon also gives rise to the cerebellum. Evolutionarily older structures of the vertebrate brain regulate essential automatic and integrative functions. The brainstem is one of the evolutionarily older parts of the brain. Sometimes called the "lower brain," it consists of the medulla oblongata, pons, and midbrain. The brain stem functions in homeostasis, coordination of movement, and conduction of impulses to higher brain centers. Centers in the brainstem contain neuron cell bodies that send axons to many areas of the cerebral cortex and cerebellum, releasing neurotransmitters. Signals in these pathways cause changes in attention, alertness, appetite, and motivation. The medulla oblongata contains centers that control visceral (autonomic, homeostatic) functions, including breathing, heart and blood vessel activity, swallowing, vomiting, and digestion. The pons also participates in some of these activities. It regulates the breathing centers in the medulla. Information transmission to and from higher brain regions is one of the most important functions of the medulla and pons. The two regions also help coordinate large-scale body movements. Axons carrying instructions about movement from the midbrain and forebrain to the spinal cord cross from one side of the CNS to the other in the medulla. The right side of the brain controls the movement of the left side of the body, and vice versa. The midbrain contains centers involved in the receipt and integration of sensory information. Superior colliculi are involved in the regulation of visual reflexes. Inferior colliculi are involved in the regulation of auditory reflexes. The midbrain relays information to and from higher brain centers. The reticular activating system (RAS) of the reticular formation regulates sleep and arousal. Acting as a sensory filter, the RAS selects which information reaches the cerebral cortex. The more information the cortex receives, the more alert and aware the person is. The brain can ignore some stimuli while actively processing other input. Sleep and wakefulness are regulated by specific parts of the brainstem. The pons and medulla contain centers that cause sleep when stimulated, and the midbrain has a center that causes arousal. Serotonin may be the neurotransmitter of the sleep-producing centers. All birds and mammals show characteristic sleep/wake cycles. Melatonin, a hormone produced by the pineal gland, appears to play an important role in these cycles. The function of sleep is still not fully understood. One hypothesis is that sleep is involved in the consolidation of learning and memory, and experiments show that regions of the brain activated during a learning task can become active again during sleep. The cerebellum develops from part of the metencephalon. It functions to error-check and coordinate motor activities, and perceptual and cognitive functions. The cerebellum is involved in learning and remembering motor skills. It relays sensory information about joints, muscles, sight, and sound to the cerebrum. The cerebellum also coordinates motor commands issued by the cerebrum. The embryonic diencephalon develops into three adult brain regions: the epithalamus, thalamus, and hypothalamus. The epithalamus includes the pineal gland and the choroid plexus, one of several clusters of capillaries that produce cerebrospinal fluid from blood. The thalamus relays all sensory information to the cerebrum and relays motor information from the cerebrum. Incoming information from all the senses is sorted in the thalamus and sent to the appropriate cerebral centers for further processing. The thalamus also receives input from the cerebrum and other parts of the brain that regulate emotion and arousal. Although it weighs only a few grams, the hypothalamus is a crucial brain region for homeostatic regulation. It is the source of posterior pituitary hormones and releasing hormones that act on the anterior pituitary. The hypothalamus also contains centers involved in thermoregulation, hunger, thirst, sexual and mating behavior, and pleasure. Animals exhibit circadian rhythms, one being the sleep/wake cycle. The biological clock is an internal timekeeper that regulates a variety of physiological phenomena, including hormone release, hunger, and sensitivity to external stimuli. In mammals, the hypothalamic suprachiasmatic nuclei (SCN) function as a biological clock. The clock's rhythm requires external cues to remain synchronized with environmental cycles. Experiments in which humans have been deprived of external cues have shown that the human biological clock has a period of 24 hours and 11 minutes. The cerebrum is the most highly developed structure of the mammalian brain. The cerebrum is derived from the embryonic telencephalon and is divided into left and right cerebral hemispheres. Each hemisphere consists of an outer covering of gray matter, the cerebral cortex; internal white matter; and groups of neurons deep within the white matter called basal nuclei. The basal nuclei are important centers for planning and learning movement sequences. In humans, the largest and most complex part of the brain is the cerebral cortex. It is here that sensory information is analyzed, motor commands are issued, and language is generated. The cerebral cortex underwent a dramatic expansion when the ancestors of mammals diverged from reptiles. Mammals have a region of the cerebral cortex known as the neocortex. The neocortex forms the outermost part of the mammalian cerebrum, consisting of six parallel layers of neurons running tangential to the brain surface. The human neocortex is highly convoluted, allowing the region to have a large surface area and still fit inside the skull. Although less than 5 mm thick, the human neocortex has a surface area of about 0.5m2 and accounts for about 80% of the total brain mass. Nonhuman primates and cetaceans also have exceptionally large, convoluted neocortices. The surface area relative to body size of a porpoise's neocortex is second only to that of a human. The cerebral cortex is divided into right and left sides. The left hemisphere is primarily responsible for the right side of the body. The right hemisphere is primarily responsible for the left side of the body. A thick band of axons known as the corpus callosum is the major connection between the two hemispheres. Damage to one area of the cerebrum early in development can frequently cause redirection of its normal functions to other areas.

Concept 49.4 Neurons communicate with other cells at synapses

When an action potential reaches the terminal of the axon, it generally stops there. However, information is transmitted from a neuron to another cell at the synapse. Some synapses, called electrical synapses, contain gap junctions that do allow electrical current to flow directly from cell to cell. Action potentials travel directly from the presynaptic to the postsynaptic cell. In both vertebrates and invertebrates, electrical synapses synchronize the activity of neurons responsible for rapid, stereotypical behaviors. The vast majority of synapses are chemical synapses, which involve the release of chemical neurotransmitter by the presynaptic neuron. The presynaptic neuron synthesizes the neurotransmitter and packages it in synaptic vesicles, which are stored in the neuron's synaptic terminals. When an action potential reaches a terminal, it depolarizes the terminal membrane, opening voltage-gated calcium channels in the membrane. Calcium ions (Ca2+) then diffuse into the terminal, and the rise in Ca2+ concentration in the terminal causes some of the synaptic vesicles to fuse with the terminal membrane, releasing the neurotransmitter by exocytosis. The neurotransmitter diffuses across the narrow gap, called the synaptic cleft, which separates the presynaptic neuron from the postsynaptic cell. The effect of the neurotransmitter on the postsynaptic cell may be direct or indirect. Information transfer at the synapse can be modified in response to environmental conditions. Such modification may form the basis for learning or memory. Neural integration occurs at the cellular level. At many chemical synapses, ligand-gated ion channels capable of binding to the neurotransmitter are clustered in the membrane of the postsynaptic cell, directly opposite the synaptic terminal. Binding of the neurotransmitter to the receptor opens the channel and allows specific ions to diffuse across the postsynaptic membrane. This mechanism of information transfer is called direct synaptic transmission. The result is generally a postsynaptic potential, a change in the membrane potential of the postsynaptic cell. Excitatory postsynaptic potentials (EPSPs) depolarize the postsynaptic neuron. The binding of neurotransmitter to postsynaptic receptors opens gated channels that allow Na+ to diffuse into and K+ to diffuse out of the cell. Inhibitory postsynaptic potential (IPSP) hyperpolarizes the postsynaptic neuron. The binding of neurotransmitter to postsynaptic receptors open gated channels that allow K+ to diffuse out of the cell and/or Cl? to diffuse into the cell. Various mechanisms end the effect of neurotransmitters on postsynaptic cells. The neurotransmitter may simply diffuse out of the synaptic cleft. The neurotransmitter may be taken up by the presynaptic neuron through active transport and repackaged into synaptic vesicles. Glia actively take up the neurotransmitter at some synapses and metabolize it as fuel. The neurotransmitter acetylcholine is degraded by acetylcholinesterase, an enzyme in the synaptic cleft. Postsynaptic potentials are graded; their magnitude varies with a number of factors, including the amount of neurotransmitter released by the presynaptic neuron. Postsynaptic potentials do not regenerate but diminish with distance from the synapse. Most synapses on a neuron are located on its dendrites or cell body, whereas action potentials are generally initiated at the axon hillock. Therefore, a single EPSP is usually too small to trigger an action potential in a postsynaptic neuron. Graded potentials (EPSPs and IPSPs) are summed to either depolarize or hyperpolarize a postsynaptic neuron. Two EPSPs produced in rapid succession at the same synapse can be added in an effect called temporal summation. Two EPSPs produced nearly simultaneously by different synapses on the same postsynaptic neuron can be added, in an effect called spatial summation. Summation also applies to IPSPs. This interplay between multiple excitatory and inhibitory inputs is the essence of integration in the nervous system. The axon hillock is the neuron's integrating center, where the membrane potential at any instant represents the summed effect of all EPSPs and IPSPs. Whenever the membrane potential at the axon hillock reaches the threshold, an action potential is generated and travels along the axon to its synaptic terminals. In indirect synaptic transmission, a neurotransmitter binds to a receptor that is not part of an ion channel. This binding activates a signal transduction pathway involving a second messenger in the postsynaptic cell. This form of transmission has a slower onset, but its effects have a longer duration. cAMP acts as a secondary messenger in indirect synaptic transmission. When the neurotransmitter norepinephrine binds to its receptor, the neurotransmitter-receptor complex activates a G-protein, which in turn activates adenylyl cyclase, the enzyme that converts ATP to cAMP. cAMP activates protein kinase A, which phosphorylates specific channel proteins in the postsynaptic membrane, causing them to open or close. Because of the amplifying effect of the signal transduction pathway, the binding of a neurotransmitter to a single receptor can open or close many channels. The same neurotransmitter can produce different effects on different types of cells. Each of the known neurotransmitters binds to a specific group of receptors. Some neurotransmitters have a dozen or more receptors, which can produce very different effects in postsynaptic cells. Acetylcholine is one of the most common neurotransmitters in both invertebrates and vertebrates. In the vertebrate CNS, it can be inhibitory or excitatory, depending on the type of receptor. At the vertebrate neuromuscular junction, acetylcholine released by the motor neuron binds to receptors on ligand-gated channels in the muscle cell, producing an EPSP via direct synaptic transmission. Nicotine binds to the same receptors. Acetylcholine is inhibitory to cardiac muscle cell contraction. Biogenic amines are neurotransmitters derived from amino acids. One group, known as catecholamines, consists of neurotransmitters produced from the amino acid tyrosine. This group includes epinephrine and norepinephrine and a closely related compound called dopamine. Another biogenic amine, serotonin, is synthesized from the amino acid tryptophan. The biogenic amines are usually involved in indirect synaptic transmission, most commonly in the CNS. Dopamine and serotonin affect sleep, mood, attention, and learning. Imbalances in these neurotransmitters are associated with several disorders. Parkinson's disease is associated with a lack of dopamine in the brain. LSD and mescaline produce hallucinations by binding to brain receptors for serotonin and dopamine. Depression is treated with drugs that increase the brain concentrations of biogenic amines such as norepinephrine and serotonin. Prozac inhibits the uptake of serotonin after its release, increasing its effect. Four amino acids function as neurotransmitters in the CNS: gamma aminobutyric acid (GABA), glycine, glutamate, and aspartate. GABA is the neurotransmitter at most inhibitory synapses in the brain, where it produces IPSPs. Several neuropeptides, relatively short chains of amino acids, serve as neurotransmitters. Most neurons release one or more neuropeptides as well as a nonpeptide neurotransmitter. Neuropeptides usually operate via signal transduction pathways. The neuropeptide substance P is a key excitatory neurotransmitter that mediates our perception of pain. Other neuropeptides, endorphins, act as natural analgesics. Opiates such as morphine and heroin bind to receptors on brain neurons by mimicking endorphins, which are produced in the brain under times of physical or emotional stress. Some neurons of the vertebrate PNS and CNS release dissolved gases, especially nitric oxide and carbon monoxide, which act as local regulators. During male sexual arousal, certain neurons release NO into the erectile tissue of the penis. In response, smooth muscle cells in the blood vessel walls of the erectile tissue relax, allowing the blood vessels to dilate and fill the spongy erectile tissue with blood, producing an erection. Viagra inhibits an enzyme that slows the muscle-releasing effects of NO. Carbon monoxide is synthesized by the enzyme heme oxygenase. In the brain, CO regulates the release of hypothalamic hormones. In the PNS, it acts as an inhibitory neurotransmitter that hyperpolarizes intestinal smooth muscle cells. NO and CO are synthesized by cells as needed. They diffuse into neighboring target cells, produce an effect, and are broken down, all within a few seconds.