Central Nervous System (CNS) Part 1 PDF

P ART1 I NTR ODUC TION&S ENS ORY BY DR. MOHAMEDELSHERI F DESI GNER REVI EWER DR. KHALEDAHMED DR....

P ART1 I NTR ODUC TION&S ENS ORY BY DR. MOHAMEDELSHERI F DESI GNER REVI EWER DR. KHALEDAHMED DR. MOHAMEDELMASRY  CENTRAL NERVOUS SYSTEM INTRODUCTION The nervous system along with the endocrine system, provide most of the control functions of the body. In general, the nervous system controls the rapid activities, such as muscular contractions. The endocrine system, regulates the metabolic functions of the body. 1  CENTRAL NERVOUS SYSTEM Organization of the nervous system Central Nervous System (CNS) Peripheral Nervous System (PNS) Includes the brain and spinal cord. It contains centers for integration of the input signals and Is further subdivided into : for production of output signals. There are three major levels of the CNS: a. Spinal cord level: for immediate automatic a. Sensory Division: (Afferent Division) activities such as withdrawal reflexes and Consists of the receptors, axons and cell bodies evacuation of bladder and rectum. of sensory neurons. b. Lower Brain Level: for control of subconscious activities of the body, e.g. b. Motor Division: (Efferent Division): is cardiovascular and respiratory functions. further subdivided into: Also maintenance of posture and equilibrium  Somatic division: consists of the axons of and emotional reactions. motor neurons that innervate skeletal c. Higher Brain or Cortical Level: for control muscles. of motor and sensory functions and other  Autonomic division: consists of the axons of higher functions including: thinking, motor neurons that innervate the viscera, learning, memory and speech. smooth muscles, cardiac muscles and glands. Organization of the nervous system 2  CENTRAL NERVOUS SYSTEM Synaptic Transmission Synaptic transmission means transmission of an impulse (action potential) from one neuron to another along a synapse. What are the types of synaptic transmission? Electric transmission Chemical transmission Where the neurons are communicated at the cell Occurs by release of a chemical substance (called membrane by low-resistance gap-channel a neurotransmitter) from the presynaptic neuron pathway which allows passage of the electric to act on receptors on the membrane of the current from one neuron to the other directly. postsynaptic neuron. This type of transmission is rare in humans and Almost all synapses in human nervous system are is common in invertebrates. chemical synapses. What is a synapse ? A synapse is a junction between an axon terminal of one neuron (presynaptic neuron) and a second neuron (post synaptic neuron). On average, each neuron divides to form over 2000 synaptic endings and may receive from only a few to as many as 200.000 presynaptic terminals. Functions of Synapses:  Transmission is not simply jumping of an action potential from the presynaptic to the postsynaptic neuron.  It is a complex process that permits grading and adjustment of neural activity necessary for integration, interpretation and processing of information at different levels of the CNS by, for example: a. Facilitating transmission from one neuron to the next. b. Blocking transmission from one neuron to the next. c. Amplification of impulses. d. Distribution of impulses. e. Changing one impulse to repetitive impulses f. Integration between different types of neurons. g. Storage of information. It should be noted that synapses are dynamic structures increasing and decreasing in complexity and number with use and experience. 3  CENTRAL NERVOUS SYSTEM Functional Anatomy of a Synapse 1) The Presynaptic Axon Terminal; (or synaptic knob): The synaptic knobs contain important internal structures: a. A large number of mitochondria which provides ATP needed for the synthesis and exocytosis of the synaptic transmitters. b. A large number of synaptic vesicles which contain the synaptic transmitters. There are three types of synaptic vesicles: 1. Small clear vesicles containing the rapidly acting chemical transmitters e.g. acetyl choline, glycine, glutamate and GABA. 2. Small granular vesicles containing catecholamines. 3. Large granular vesicles that contain slowly acting neuropeptides. Synaptic vesicles discharge their transmitters at areas of membrane thickening in presynaptic membrane called active zones c. SNARE proteins:  V-SNARE (Synaptobrevin) on the synaptic vesicle.  T- SNARE (Syntaxin) on the presynaptic membrane. 2) The synaptic cleft It is a definite space (30 - 50 nm width) containing extracellular fluid rich in Na+, Cl- and poor in K+. 3) The postsynaptic membrane (PSM) Contains appropriate Receptors for the neurotransmitters which may be one of two major types: a. Ionotropic receptors b. Metabotropic receptors which form part of a Ligand-gated (mostly G protein coupled receptors) which influence the ion channels; thus affect neuronal activity of the neuron indirectly by first initiating a second activity directly by activating: messenger system e.g. cAMP in the PSM, thus causing slower and more prolonged intracellular effects, such as: + + i) Cation channels: e.g. Na , K or Ca++ channels.  Open or close specific ion channels. ii) Anion channels: e.g. Chloride  Activate enzymes e.g. protein kinases that catalyze channels. phosphorylation of various intracellular proteins.  Activate gene transcription leading to formation of new proteins within the neuron, thereby changing its metabolic machinery or its structure. 4  CENTRAL NERVOUS SYSTEM Types of receptors on postsynaptic membrane Mechanism of Synaptic Transmission 1. Release of chemical transmitter a. Arrival of action potential in the presynaptic nerve opens voltage-gated Ca++ channels predominant in this area. b. Ca++ enters the knob according to concentration and electric gradients. c. Influx of Ca++ triggers binding of the SNARE proteins & fusion of the synaptic vesicles with the presynaptic membrane & exocytosis of their chemical transmitter into the synaptic cleft. d. The amount of the transmitter released is proportional to amount of Ca++ entered. 5  CENTRAL NERVOUS SYSTEM Mechanism of Synaptic Transmission 2. Binding of chemical Transmitter with its Receptors: Interaction of the chemical transmitter with its specific receptors changes the permeability of the postsynaptic membrane to one or more ions. 3. Generation of Postsynaptic Potential: Change in ion fluxes through postsynaptic membrane leads to change in its membrane potential (according to type of NT and/or type of receptor) which may become: a. Less negative causing excitatory postsynaptic potential. (EPSP). Or b. More negative causing inhibitory postsynaptic potential. (IPSP). The magnitude and duration of EPSP and IPSP depends on the amount of the released Neurotransmitter. Therefore they are not All or None. 4. Removal of Neurotransmitters from the Synaptic Cleft: Must be removed to terminate its effect, in one of following ways: a. Passive diffusion of the transmitter away from the synaptic cleft. b. Inactivation of the transmitter by specific enzymes within the synaptic cleft e.g. acetyl choline. c. Active reuptake of the transmitter into the axon terminals, e.g. catecholamines, dopamine, serotonin. d. Removal by glial cells. 6  CENTRAL NERVOUS SYSTEM Types of Synaptic Potentials A] Postsynaptic potentials: Excitatory postsynaptic potentials Inhibitory Postsynaptic Potential [EPSP]: [IPSP]: Local transient state of partial Local state of partial hyperpolarization of Definition depolarization of postsynaptic the postsynaptic membrane. membrane.  Release of excitatory  Release of inhibitory neurotransmitter will neurotransmitter and binding to its bind with its receptors  opening of ligand receptor  opening of ligand gated K+ or Cl- channels or closure of Na+ gated Na+ (or Ca++) channels (or Ca++) channels.  Influx of +ve ions makes the inside  Influx of -ve ions or efflux of +ve ions of the cell membrane less negative makes the inside of the cell membrane Ionic basis  nearer to the firing level  more more negative  away from the firing excitable. level  less excitable.  During this potential the membrane  During this potential the membrane is said is said to be facilitated i.e. needs a to be inhibited i.e. needs a stronger weaker stimulus to be excited than stimulus to be excited than at rest. at rest. EPSP reaches a maximum after 1.5 IPSP reaches a maximum after 1.5 msec then Duration msec then gradually declines due to gradually declines. current leakage. and duration depends on amount of IPSP is a local response and can be Magnitude neurotransmitter released, i.e. does summated by temporal or spatial summation not obey all or none rule. as in case of EPSP. IPSP: inhibitory presynaptic input moves the EPSP: activation of an excitatory presynaptic postsynaptic neuron farther from threshold input brings the postsynaptic neuron closer to potential threshold potential. EPSP is a local excitatory state. Up to 40-50 EPSPs have to be summated to reach threshold value needed. 7  CENTRAL NERVOUS SYSTEM Types of Summation: 1- Temporal (Time) summation: Summation of multiple EPSPs as a result of rapid repetitive stimuli originating from ONE presynaptic neuron. 2- Spatial (Space) summation: Summation of multiple EPSPs as a result of multiple simultaneous stimuli from MANY presynaptic neurons. Temporal & spatial summation at postsynaptic neuron with 2 synaptic inputs E 1 & E2 A typical neuronal cell body receives thousands of presynaptic inputs carrying sensory information from external and internal environment or from control centers in the brain. At any given time, many presynaptic neurons may be firing at the same time and thus influencing the postsynaptic neuron's level of activity. Grand postsynaptic potential (GPSP) is the sum of all EPSPs and IPSPS occurring at approximately the same time There are four possible outcomes of the GPSP: 1. If there is a balance of activated excitatory and inhibitory inputs  the postsynaptic membrane potential will remain close to resting level. 2. If excitatory input is slightly greater than inhibitory input  the postsynaptic neuron don't reach threshold and the membrane is said to be facilitated or in an excitatory state. 3. If excitatory input is much greater than inhibitory input  the postsynaptic neuron will reach threshold and have an action potential. 4. If inhibitory input is greater than excitatory input  the postsynaptic neuron will be away from threshold and the membrane is said to be inhibited or in an inhibitory state. Example: The micturition reflex is influenced by many signals at one time but the response will vary according to the circumstances: a- Sensory signals from receptors in the wall of the urinary bladder. b- Facilitatory and Inhibitory signals from the brain stem. c- Voluntary control from the cerebral cortex. 8  CENTRAL NERVOUS SYSTEM Initiation of Action Potentials at the Axon Hillock  Voltage gated Na+ channels are not present in the cell body and dendrites, however they are numerous in axon hillock making it considerably more sensitive to change in potentials.  EPSPs occurring anywhere on the cell body or dendrites will be summated and spread electrotonically (by current sink) throughout the whole neuron.  Upon reaching the axon hillock, and due to presence of many low threshold voltage-gated Na+ channels, it will be depolarized to the firing level thus initiating an action potential. 9  CENTRAL NERVOUS SYSTEM B] Presynaptic Potentials: Presynaptic Inhibition Presynaptic Facilitation The release of NT from presynaptic fibers can be facilitated or inhibited by a THIRD NEURON that influences the presynaptic terminals before they reach the synapse causing presynaptic potentials. a. The axon terminal of a 3rd inhibitory neuron a. The axon terminal of a 3rd excitatory neuron synapses axoaxonically with an excitatory synapses axo-axonically with an excitatory presynaptic neuron before the latter reaches the presynaptic fiber before it reaches the synapse. synapse. b. The inhibitory neuron releases an inhibitory b. The 3rd excitatory neuron releases “serotonin”  chemical transmitter (e.g. GABA), which either increases cAMP concentration in the presynaptic opens Cl- channels or K+ channels. terminals  phosphorylates K+ channels and closes them. c. This will hyperpolarize the presynaptic membrane c. This delays repolarization and leads to leading to reduced Ca++ influx to the synaptic prolongation of the depolarization state of the knob  reduced release of NT from the synaptic presynaptic knob, which in turn keeps the voltage knob and reduced transmission from the gated Ca++ channels opened for a longer period. presynaptic to the postsynaptic neuron. d. Ca++ influx increases the release of the NT from d. Example: pain inhibition (discussed later). the presynaptic neuron, which may continue for longer durations. e. Example: Sensitization of memory (discussed later). Arrangement of neurons producing presynaptic and postsynaptic inhibition. The neuron producing pre- synaptic inhibition ends on an excitatory synaptic knob. Presynaptic facilitation 10  CENTRAL NERVOUS SYSTEM Characters of Synaptic Transmission 1. Forward direction: Impulses are conducted at the synapse in one way directed only from presynaptic to postsynaptic neurons, because the neurotransmitters are formed and released from the presynaptic neuron not the postsynaptic. 2. Synaptic delay: It is the time taken by an impulse to be conducted through the synapse. It equals about 0.5 m. sec. 3. Fatigue: It is the decreased rate of impulses discharged from postsynaptic neuron after repetitive stimulation of presynaptic neuron. It may be due to: 1- Exhaustion of synaptic vesicles in the presynaptic terminals by repetitive stimulation. OR 2- Inactivation of postsynaptic receptors. The benefit of synaptic fatigue is to stabilize the nervous system e.g. stopping discharge from overexcited areas in CNS during epileptic seizures. 4. Synaptic plasticity:  Plasticity means the ability to change (or remodulate) the function according to the demand placed on the synapse.  So the synaptic transmission can be strengthened or weakened, for short or long duration, on the basis of past experience.  These changes are of great interest because they represent forms of learning and memory. Forms of Synaptic Plasticity 1. Post tetanic potentiation (PTP): a. Definition: Continuous discharge from the postsynaptic neuron after stoppage of application of brief tetanizing stimuli to a presynaptic neuron. b. Duration: It may last for few seconds to minutes. c. Ionic basis: PTP is caused by accumulation of Ca2+ in the presynaptic neuron after repetitive stimulation  continuous release of the neurotransmitter and enhanced EPSPs until the Ca2+ pump is able to remove it. d. Importance: it is the basic mechanism of immediate memory for a few facts, words, telephone numbers, etc.... 11  CENTRAL NERVOUS SYSTEM 2.Habituation 3.Sensitization Gradual loss of response to repeated Augmented response of the postsynaptic benign neutral stimuli (insignificant neuron to neutral stimuli after a events). First time the stimulus is habituated stimulus is coupled with a Definition applied, it evokes a reaction However, noxious one. e.g. the mother who sleeps after being repeated many times, it through many kinds of noise wakes up evokes less and less response  the promptly when her baby cries. person ignores it. Habituation is caused by gradual (presynaptic facilitation): inactivation of Ca2+ channels in the A noxious stimulus activates a 3rd neuron presynaptic terminal  decreased secreting serotonin  cAMP  closure Ionic basis intracellular Ca2+  decreased release of K+ channels  prolonged presynaptic of neurotransmitter  synaptic depolarization  prolonged Ca2+ influx transmission becomes gradually  excess neurotransmitter release  weaker. enhanced synaptic transmission. may be short term or long term if it may be short term or long term if it involves protein synthesis and growth involves protein synthesis and growth of Duration of the presynaptic and postsynaptic the presynaptic and postsynaptic neurons neurons and their connections. and their connections. Neglecting unimportant stimuli e.g. short term memory or long term memory. Importance getting used to noises. 12  CENTRAL NERVOUS SYSTEM 4.Long term potentiation (LTP) 5.Long term depression (LTD) Persistent increase in synaptic strength Persistent decrease in synaptic strength Definition after strong intensity high frequency after weak intensity low frequency stimulation. stimulation. It occurs in various parts of CNS, but Unlike LTP, it contributes to memory specifically in hippocampus where it decay. Importance contributes to memory storage  learning and long term memory. Ionic basis of LTP and LTD: Glutamate released from stimulation of presynaptic neuron binds to AMPA and Ionic basis NMDA receptors in the postsynaptic membrane. Activation of AMPA receptors causes Na+ inflow which depolarizes the PSM and thus relieves the Mg++ block in the NMDA receptor channel, and Ca++ enters the neuron. High frequency stimuli cause a rapid Low frequency stimuli cause a slow increase in cytoplasmic Ca++ which increase in cytoplasmic Ca++ which activates a signaling cascade activates a different signaling cascade (involving Calmodulin Kinase II) that (involving Calcineurin phosphatase I), moves more AMPA receptors into the which results in the removal of AMPA postsynaptic membrane. The insertion receptors from the postsynaptic of additional AMPA receptors membrane thereby decreasing the strengthens the synapse  LTP. synaptic response  LTD. Production of LTP & LTD 13  CENTRAL NERVOUS SYSTEM Factors affecting synaptic transmission 1. Changes in composition of internal environment: a. pH of the blood: Alkalosis: increases the excitability of neurons and facilitates synaptic transmission due to decrease in ionized Ca++. This may lead to convulsions, e.g. if an epileptic patient hyperventilates, this may precipitate a fit. Acidosis: decreases synaptic transmission due to increase in ionized Ca++. This may lead to coma, e.g. in diabetic Ketoacidosis. b. Hypoxia: Hypoxia inhibits synaptic transmission. Temporary Interruption of cerebral circulation for 3-5 seconds may cause unconsciousness & prolonged ischemia for minutes cause brain damage. c. Hypoglycemia: Glucose is the main fuel of the brain, so hypoglycemia inhibits synaptic transmission. d. Hypocalcemia: Decreased ionized Ca++ in ECF facilities synaptic transmission as it increases the excitability of the post synaptic membrane leading to tetanic convulsions. 2. Most of the drugs, which act on the CNS alter synaptic mechanism, e.g.: a. Theophylline, theobromine, and caffeine facilitate synaptic transmission by depolarizing the postsynaptic membrane. b. Analgesics, hypnotics and anaesthetics act by stabilizing the cell membrane causing hyperpolarization or by interference with synthesis, release or reuptake of certain neurotransmitters. c. Strychnine competes with the inhibitory neurotransmitter at the postsynaptic receptor sites. Thus postsynaptic inhibition is blocked leaving excitatory pathways unaffected leading to convulsions, muscle spasm and death. 14  CENTRAL NERVOUS SYSTEM 3. Diseases: a) Tetanus toxin: prevents the release of inhibitory GABA (or glycine) in the CNS causing spastic paralysis. This spasm occurs especially in jaw muscles giving rise to lock jaw then affects respiratory muscles leading to death. b) Botulism toxin: blocks the release of excitatory Acetyl Choline in the neuromuscular junction leading to flaccid paralysis. Effect of Tetanus toxin and Botulism toxin on synaptic transmission Chemical Transmitters (Neuro-Transmitters) What is a chemical transmitter? A substance that mediate chemical signaling between neurons  Neurotransmitters are endogenous chemical substances released from presynaptic neurons that transmit signals between neurons across a synapse.  A substance can act as a neurotransmitter in one region of the brain while serving as a hormone elsewhere. 15  CENTRAL NERVOUS SYSTEM Types of Neurotransmitters: More than 100 different chemical substances function as synaptic transmitters. In general, there are two different groups of synaptic transmitters: Small molecule, rapidly acting transmitters Large molecules, slowly acting neuropeptides 1. They are synthesized in the cytosol of the 1. They are synthesized in the soma of the neuron, presynaptic knobs then stored in small vesicles. then transported all the way to the terminal 2. The vesicles are continually recycled and knobs to be stored in large granular vesicles. reused in the presynaptic terminal. 2. After exocytosis, these vesicles are autolyzed and not reused. 3. They are released rapidly in large amounts. 3. They are released at a slower rate and in smaller 4. They stimulate ionotropic receptors leading to amounts than small molecule neurotransmitters rapid activation of ion channels. however they are a thousand times more potent. 4. They often stimulate metabotropic receptors leading to activation of 2nd messenger system. 5. They cause most of the acute responses of 5. They often cause more prolonged actions such nervous system e.g. transmission of sensory as, long term opening or closure of ion channels, signals to the brain and motor signals back to changes in number of receptors, synapses or the muscles. genes. 6. They include four categories: 6. They include many different groups, e.g.: a. Acetyl choline: a. Hypothalamic releasing peptides: TRH. CRH. b. Biogenic Amines: b. Pituitary peptides: GH, TSH, ADH.  Norepinephrine c. Opioid peptides: endorphins, enkephalins.  Dopamine d. GIT peptides: CCK, VIP, gastrin, secretin.  Serotonin e. Other peptides: substance P, Angiotensin II, c. Amino acid Neurotransmitters: Neuropeptide Y, ANP, BNP.  Excitatory: Glutamate and Aspartate f. Purines: adenosine.  Inhibitory: GABA and Glycine d. Gases: Nitrous oxide (NO) 16  CENTRAL NERVOUS SYSTEM Organization of Neurons for Processing of Signals in Neuronal Pools A neuronal pool is a collection of neurons carrying the same function in CNS e.g. cortical neuronal pool, cerebellar neuronal pool and so on. Although each neuronal pool has its own arrangement of neuronal circuits they all share certain similarities of organization. These similar organizations are: (1) Divergence: (2) Convergence: ONE neuron coming to the neuronal MANY neuronal inputs to the neuronal Definition pool stimulates MANY neurons. pool stimulate ONE neuron. a- Divergence in same direction: It allows SUMMATION of input signals. allows Amplification of the signal, a- Convergence of signals from a single e.g. one pyramidal cell in the cortex source: allows intensification of can supply hundreds of anterior subthresholdinput signals to bring the horn cells in the spinal cord that output neuron to threshold to discharge, supply many muscle fibers. e.g. convergence along the ascending b- Divergence in different sensory pathway. directions: b- Convergence of signals from different Functions allows Distribution of the signals, sources: e.g. a painful stimulus a) stimulates allows integration of input signals e.g. a anterior horn cells of muscles on motor neuron receives different the same and opposite sides, b) excitatory and inhibitory input fibers ascends to stimulate cells in the from brain stem, and sensory cortex. a) peripheral sensory fibers, b) reticulospinal tracts, c) corticospinal tract from the motor cortex. 17  CENTRAL NERVOUS SYSTEM “Convergence” of multiple input fibers on a single neuron. “Divergence” in neuronal pathways. (3) Excitation field: Definition: It is the number of neurons, with which one afferent neuron synapses. “Discharge” & “facilitated” zones of a neuronal pool a) The Discharge zone:  Neurons that lie in the center of the field receive large numbers of knobs. When the afferent nerve is stimulated, these cells are stimulated enough to reach to the threshold value and discharge nerve impulses. b) The Facilitated zone (subliminal fringe)  Neurons that lie in the periphery of the field receive few numbers of knobs. So they are only facilitated when the afferent is stimulated.  The area of discharge zone and subliminal fringe depends on the strength of the stimulus: the stronger the stimulus the wider the discharge zone.  This arrangement leads to development of two phenomena: 18  CENTRAL NERVOUS SYSTEM Facilitation Occlusion If the excitation fields of two input neurons If the excitation fields of two input adjacent overlap at the peripheral facilitation zones neurons overlap at the Discharge zones, the (subliminal fringe), the outcome of the two outcome of the two pools when stimulated pools when stimulated simultaneously is more simultaneously is less than the sum of outcome than the sum of outcome of both pools, when of both pools, when each neuron is stimulated each neuron is stimulated separately. separately. 19  CENTRAL NERVOUS SYSTEM (4) Inhibitory Circuits: Inhibitory circuits act as a mechanism for stabilizing the nervous system by help preventing excessive spread of signals in widespread areas of the brain. a) Lateral inhibition: Definition: It is the arrangement by which only the central neuron is stimulated while the neurons at the periphery (fringe zone) are inhibited by one excitatory input through inhibitory interneuron. Function: Sharpening of the sensation: lateral inhibition prevents the blurring effect of the fringe fibers and sharpens the sensation e.g. Horizontal cells in the retina inhibit the peripheral bipolar cells to sharpen the vision. 20  CENTRAL NERVOUS SYSTEM b) Negative feedback inhibition: When a motor neuron is stimulated it gives off recurrent collateral that synapse with an Inhibitory Interneuron (Renshaw cell) which terminates on the motor neuron itself and its surrounding neurons. Functions:  Allows focusing and sharpening of the effect.  Dampens activity of motor neurons and prevents over Excitation. Negative feedback inhibition of a spinal motor neuron via Renshaw cell c) Reciprocal Innervation: Definition: It is the stimulation of one muscle and inhibition of its antagonist by excitation of one nerve. This is carried through inhibitory interneurons. Function: Enables contracted muscle to carry its function unopposed e.g. A painful stimulus stimulates flexors and inhibits extensors so the limb is flexed and withdrawn from the injurious stimulus. The circuit in reciprocal inhibition 21  CENTRAL NERVOUS SYSTEM (5) Activating Circuits: (After Discharge)  Continued output discharge after stoppage of stimulation of input.  It may be caused by one of two arrangements. a) Parallel circuits:  The excitatory input signal reaches the output through many circuits formed of different number of interneurons forming different number of synapses.  Synaptic delay leads to arrival of successive impulses to output neuron to prolong its discharge. Parallel circuit b) Reverberatory (Oscillatory = closed circuits):  The output neuron sends collaterals to restimulate itself (positive feedback).  May continue to discharge for a long period or even throughout the whole life.  It is the base of wakefulness and sleep and other tonically discharging centers, e.g. respiratory centers. Duration of reverberatory circuits is determined by: a- Number of synapses in the circuit. b- Fatigue of the synapses. c- Facilitatory or inhibitory impulses entering the circuit. 22  CENTRAL NERVOUS SYSTEM SENSORY NERVOUS SYSTEM The term "sensory system" is applied to those parts of nervous system that consist of: Sensory receptors which receive stimuli from the external or internal environment. a. Neural pathways that conduct information from the receptors to the brain. b. Parts of the brain that deal primarily with processing the information. Information processed by the sensory system may or may not lead to conscious awareness of the stimulus. If the information does reach consciousness, it can be called a sensation. A person's understanding of the sensation's meaning is called perception. Sensory Receptors Definitions: Sensory receptor: specialized structure or modified ending present at the peripheral termination of afferent nerve fibers. Sensory unit: is a single sensory afferent with all its receptor endings. Receptive field of a neuron: is the region which contains all the receptor endings of a sensory neuron and from which a stimulus produces a response in that particular afferent neuron. Sensory unit and receptive field Functions: 1. Detectors: They detect adequate stimuli (changes in the internal or external environment) and inform C.N.S about different sensations. 2. Transducers: They transform any form of energy in the stimulus (chemical, mechanical, thermal, etc.) into electrical energy (receptor potential). 3. Generators: The receptor potentials lead to generation of action potential (nerve impulses) in the sensory nerves. The process by which a stimulus is transformed into an electrical response is called Signal Transduction. 1  CENTRAL NERVOUS SYSTEM Properties of receptors: 1) Specificity:  Each type of receptor is highly sensitive to one specific type of stimulus (or one form of energy) for which it is designed called adequate stimulus “e.g. light, sound, pressure, etc.”, and once stimulated, it gives rise to its particular sensation.  Receptors respond to much higher forms of energy other than their adequate stimulus; e.g. if the rods and cones in the retina can respond to a strong mechanical stimulus, however the sensation perceived is always light. 2) Excitability:  When adequately stimulated, a receptor generates a “graded electric response”, known as the “Receptor (or Generator) Potential”.  If it is of sufficient magnitude, the receptor potential triggers an action potential which is propagated along the sensory nerve connected to the receptor.  Paccinian corpuscle was chosen as an example to study the properties of receptor potential, how it is produced and how it elicits an action potential in the sensory nerve. Pressing on the capsule of Paccinian corpuscle by a rod leads to development of receptor potential. Transduction of Sensory Signals (Mechanism of Receptor Potential) 1. Stimulation of the receptor: a. Application of a stimulus (mechanical/ chemical/ thermal) causes deformation and opening of nonspecific ion channels (known as transduction channels) in the receptor membrane leading to Na+ or Ca++ ions inflow. b. The number of opened channels is proportional to the intensity of the stimulus 2. Creation of Receptor Potential(Generator Potential): Na+ or Ca++ influx creates an area of local partial depolarization called the receptor potential. 3. Electrotonic spread of receptor potential: a. The receptor potential induces a local circuit of current flow (or current sink) that spreads passively to the adjacent part of the sensory nerve (in nonmyelinated neurons) or the 1st node of Ranvier (in myelinated neurons). b. This area is called action potential (A.P.) generating zone because it has low firing level being richly supplied by voltage gated Na+ channels. 4. Generation of Action Potential: If the amplitude of the receptor potential is strong enough to depolarize (the A.P. generating zone) to threshold, it opens voltage gated Na+ channels and an action potential is produced in the sensory nerve and spreads to the CNS. 2  CENTRAL NERVOUS SYSTEM Receptor potential produced in a paccinian corpuscle Properties of Receptor Potential: 1. It is a non-propagated local state of partial depolarization, which spreads passively. 2. It does not obey all or none-law, i.e. can be graded. 3. It has no absolute refractory period, i.e. can be summated. 4. Its duration (5-10 msec.) is longer than action potential duration (2 msec.) so can cause repeated action potentials. 5. Its maximum amplitude is 100 mV (at maximum permeability to Na+ ions).  Relationship between the strength of the stimulus to the magnitude of the receptor potential: As the strength of the stimulus increases, the magnitude of the R.P. increases.  Note that: The amplitude increases rapidly at first but then progressively less rapidly at high stimulus strengths. This allows the receptor to have an extreme range of response, from very weak to very intense stimuli.  N.B. This is an exceedingly important principle that is applicable to almost all sensory receptors. It allows the receptor to be sensitive to very weak sensory experience and yet not reach a maximum firing rate until the sensory experience is extreme. 3  CENTRAL NERVOUS SYSTEM  Relation of the receptor potential magnitude to number of impulses generated in the sensory nerve  The duration of the receptor potential (5-10 ms) is longer than the duration of the action potential. This allows repetition of impulses (action potentials).  The more the receptor potential rises above threshold level, the greater becomes the frequency of the action potential. 3) Adaptation of receptors: Definition: gradual decline of the receptor potential and decrease in the frequency of spikes generated within the receptor neuron over time in spite of the continued presence of an appropriate stimulus of constant strength. Causes of adaptation: Each receptor has its own property of adaptation; adaptation of mechanoreceptors occurs by one of two mechanisms: a. Readjustment and remolding in the structure of the receptor itself. b. Accommodation of terminal nerve fiber or 1st node of Ranvier to the stimulus, due to inactivation of Na+ channels as result of continuous current flow. According to the rate of adaptation, receptors are classified into: 1- Rapidly adapting (phasic) receptors:  These receptors adapt rapidly to continuously applied stimuli.  But they discharge strongly when a change is taking place.  They show a response when the stimulus is “ON” and another response when the stimulus is “OFF”.  So they can detect movement, rate of movement and vibration e.g, touch and pressure receptors (Meissner's & Paccinian corpuscles). 2- Slowly adapting (Tonic) receptors:  These receptors continue to discharge as long as the stimulus is applied.  Keep the brain continuously informed about the body status e.g. pain receptors, muscle spindles, alveolar stretch receptors, and arterial baroreceptors.  They are either slowly adapting or they do not adapt at all 4  CENTRAL NERVOUS SYSTEM Some receptors have both aphasic and a tonic component, e.g. proprioceptors and thermoreceptors. The Sensory Code Definition:  Coding of sensory information means the ability of CNS to recognize the modality (type), the locality (site) and the intensity (degree) of sensation.  All stimuli produce action potentials which are all alike. The question is how can CNS convert a receptor stimulus into a recognizable sensation? A) Modality of sensation: depends on 1. Adequate Stimulus: Each receptor is highly sensitive to a particular type of stimulus. 2. Muller's law of specific nerve energy: Whatever may be the method of stimulation of the receptor, the sensation given is that the receptor is specialized to. 3. Labeled line principle: Each sensation reaches the CNS in a specific pathway or “labeled line”. Stimulation of this pathway at any point by any form of energy evokes its specific sensation. B) Locality of the stimulus:  Law of Projection: There is a separate representation area for each part of the body in the cerebral cortex, (i.e. point to point representation). When an impulse reaches the specific area in the cortex, it "projects" this stimulus to its original site.  Phantom limb: a phenomenon in which pressure on the nerves in the stump of an amputated limb makes the patient feel the pain as though it is coming from the absent limb. 5  CENTRAL NERVOUS SYSTEM C) Intensity of sensation: It is encoded by change in: 1- Number of receptors activated by the stimulus:  Higher intensity stimuli will recruit more receptors into the receptive field [“recruitment” of receptors] 2- Frequency of impulses:  The frequency of impulses is interpreted as the magnitude of the interpreted sensation.  Increasing stimulus intensity will increase the intensity of the sensation felt. Somatic Sensations Sensation is the feeling produced by change in the environment or by the application of a stimulus to the receptors or nervous pathway. Sensations are either: a) Special senses b) General sensations, which in turn are classified into: 1- Somatic sensations which arise from different parts of the body. 2- Organic sensations as thirst, hunger, and sexual sensations. c) Emotional as: fear, sadness and so on. Somatic Sensory Pathways All somatic sensations are transmitted in the form of nerve impulses from their specific receptors along afferent nerve fibers to the spinal cord where they ascend to their final destination in the cerebral cortex via one of two sensory pathways: 1- The Dorsal Column: shows unimodality, as it carries mechanoreceptive sensations Receptors: mechanoreceptors for: a. Fine touch and pressure. b. Vibration. c. Stereognosis. d. Position. Afferents: thick myelinated type Aα and Aβ fibers, First Order Neurons: dorsal root ganglia (DRG), fibers then ascend upwards on the ipsilateral (same) side as dorsal column (gracile and cuneate tracts). Second Order Neurons: gracile and cuneate nuclei in the medulla on the same side; Fibers then cross to the opposite side. Third Order Neurons: posteroventral (PVN) or ventrobasal (VBN) nuclei of the thalamus. Fibers then reach the somatic sensory cortex on the opposite side 6  CENTRAL NERVOUS SYSTEM 2- The Spinothalamic (Ventrolateral) Tract: Shows polymodality as it carries different types of sensations along its two divisions. Receptors for: a. Pain. b. Temperature. c. Crude touch and pressure. d. Tickle and itch. Afferents: Thin myelinated type Aδ and unmyelinated type C fibers First Order Neurons: Dorsal root ganglia (DRG). Second Order Neurons: Ipsilateral (same side) posterior horn cells of spinal cord.  Fibers carrying pain and temperature cross immediately in front of the central canal, and ascend as the lateral spinothalamic tract.  Fibers carrying crude touch, tickle and itch sensations cross farther from the central canal and ascend as the ventral spinothalamic tract. Third Order Neurons: PVN of the thalamus. Axons ascend to end in the somatic sensory cortex on opposite side On their pathway through the brain stem, fibers within the dorsal column and the ventrolateral On their are column pathway joinedthrough the brain by additional stem, fibers fibers from within nuclei of the dorsal column trigeminal and the ventrolateral nerve carrying column sensations from the are joined by additional fibers from nuclei of trigeminal head. nerve carrying sensations from the head. 7  CENTRAL NERVOUS SYSTEM Role of the thalamus and cortex in sensory perception a. All sensory tracts, except the olfactory pathway, synapse in the thalamus on their way to the cerebral cortex. b. On reaching the thalamus, the subject becomes crudely aware of the sensation but cannot perceive all its fine details. c. Fine gradations and sensory localization are appreciated at level of the cortex. d. Pain perception is discussed latter. Somatic Sensory Cortex A- Somatic sensory area I (SSI): Site: It occupies post central gyrus “area 3, 1, 2”. Body representation: SSI involves a topographic map of the body known as spatial orientation. a. It is crossed: SSI receives thalamocortical sensory signals from opposite side of the body. b. It is inverted: body is represented upside-down except the face. c. The area of representation is directly proportional to the number of specialized sensory receptors in this area. So thumb & lips have large representation area while the back and trunk have smaller areas and viscera are the least represented. Functions of somatic sensory area I: SSI is concerned with the following discriminative faculties: a. Recognition of fine touch, stereognosis, vibration and proprioceptive sensations. b. Localization of the source of sensation: spatial orientation. c. Discrimination of fine gradations of weight and temperature. B-Somatic sensory area II: (SSII) Site: occupies area 40, below the primary sensory area SSI. Connections: It receives sensory signals from both sides of body & from SSI. Body representation: Spatial orientation is not as detailed or as complete as SI. Face is represented anteriorly, arms centrally and legs posteriorly. 8  CENTRAL NERVOUS SYSTEM Representation of the different areas of the body along the Area of cortical presentation is proportional postcentral gyrus in SSI to Sensitivity of the part C- Somatic Association area: Site: occupies the area posterior to SSI, “areas 5.7” of the parietal cortex. Connections: it receives signals from: 1. S.S. I & II 2. Ventrobasal nuclei of thalamus. 3. Other areas of thalamus. 4. Visual cortex. 5. Auditory cortex. Functions: Integration and interpretation of different sensory inputs from different sensory areas to decode and understand their meaning. 9  CENTRAL NERVOUS SYSTEM Types of Somatic Sensations Mechanoceptive Sensations A) Tactile sensations: 1- Touch: a) Crude touch: Definition: Touch with poor intensity discrimination and localization, e.g, feeling of clothes and hair comb. It is tested by a piece of cotton passed on the skin. Receptors: Free nerve endings & Hair end organ. Afferent: Aδ Pathway: ventral spinothalamic tract b) Fine touch: Definition: Touch with high intensity discrimination and sharp localization. Receptors: Meissner's & Merkels. Afferent: Aβ fibers. Pathway: Dorsal column. Fine touch is tested by the following three tests with eyes closed I- Tactile localization: ability to localize the site of tactile stimulus on the skin. II- Two point discrimination: ability to detect two touched points applied to the skin at the same time and recognize them as two separate points. It is measured by a threshold distance, which is the minimal distance below which the two points are felt as one.  Tactile discrimination is better (i.e. threshold distance is short) When:  Number of receptors in this area is high.  Receptive field is small.  There is no convergence in the pathway.  Area of representation in the cortex is large.  Tactile discrimination is best at lips and fingertips (shortest threshold distance 2mm) and worst at the back (largest threshold distance 65mm).  Blind individuals benefit from the tactile acuity of the finger tips to facilitate the ability to read Braille. III- Texture: ability to differentiate between the texture of different materials e.g. silk or wool etc.., 10  CENTRAL NERVOUS SYSTEM 2- Stereognosis: Definition: is the ability to recognize familiar objects placed in the hand by touch and with eyes closed. Receptors: mixture of tactile receptors. Afferent: Aβ fibers. Pathway: dorsal column.  This sensation is a higher cerebral cortical associative function that integrates fine touch sensation with other somatic sensations (pressure, pain, temperature and position sensations) and depends on past experience.  Impaired stereognosis is an early sign of damage in the cerebral cortex (SSI & association area). 3- Pressure: Definition: feeling of sustained mechanical pressure (crude pressure) and discriminate between different weights (fine pressure). Receptors: Paccinian corpuscles and spray type endings. Afferent: Crude (Aδ fibers) and Fine (Aβ fibers). Pathway: Crude (ventral spinothalamic) and Fine (dorsal column). 4- Vibration sense: Definition: It is the ability to feel rapidly changing tactile stimuli (vibration of a tuning fork) on any part of the body, but more magnified on bony prominences. Receptors: Paccinian 500 c/sec. & Meissner 80 cycle/sec. Afferent: Aβ fibers. Pathway: Dorsal column.  Impaired vibration sense is an early diagnostic sign in diseases causing degeneration of posterior column such as pernicious anemia. 5- Tickling and Itching: Definition: Tickling: ability to feel light moving things on the skin (as insects) which cause local repeated mechanical stimulation. Itching: sensation caused by chemical substance secreted near the receptors, as histamine, kinins and proteolytic enzymes. Receptors: free nerve endings. Afferent: C fibers. Pathway: Ventral spino-thalamic. 11  CENTRAL NERVOUS SYSTEM B) Position (Proprioceptive) Sensation Definition: It is the conscious and subconscious perception of: a. the position of different parts of the body in space and in relation to each other. b. their movement and c. the rate of the movement. Receptors: (Proprioceptors have a tonic and a phasic component) 1- Rapidly adapting (phasic receptors): Paccinian corpuscles in joints. 2- Slowly adapting (tonic receptors): a. Muscle spindles in skeletal muscle. b. Golgi tendon organs in tendons. c. Ruffini endings in joint capsule and tissues around joint. Pathway: a. Dorsal Column (Conscious sensation) reaching SSI. b. Spinocerebellar tract (Sub-conscious sensation); collaterals from proprioceptive fibers reaching the cerebellum. Functions: inform the brain about the degree of angulation of all joints in all planes: 1- Static position sensation:  The slowly adapting receptors continuously inform the brain about position of different parts of the body in space and in relation to each other.  This is important to maintain posture. 2- Kinetic (Kinesthetic) sensation:  The rapidly adapting receptors increase their discharge when a change is actually taking place.  Thus they can measure the rate of movement of different parts and predict the next position of the body. II- Thermoceptive Sensations Definition: conscious perception of different grades of temperature. Receptors: Thermoreceptors are Free nerve endings. Afferents: C fibers (for warm) and Aδ fibers (for cold). Pathway: Lateral Spinothalamic tract. 12  CENTRAL NERVOUS SYSTEM Types of thermoreceptors: a. Warm receptors: respond from 30-45OC. b. Cold receptors: respond from 10-40OC. c. Warm pain receptors: start to be stimulated >45OC. d. Cold pain receptors: start to be stimulated < 10OC.  At zero OC, no receptors discharge and a state of anaesthesia occurs.  At area of overlap (between 30°C and 40°C) both cold and warm receptors discharge and are very sensitive to fine gradations of temperature changes. Distribution of thermal receptors: 1. Thermal receptors are located immediately under the skin, thus they respond to the temperature of the subcutaneous tissue surrounding them and not to the environmental temperature. 2. They are numerous in the lips then finger tips and least in the trunk. 3. Cold receptors are 4-10 times more numerous than warm receptors. 4. They are widely separated. So, to differentiate between different degrees of temperature, a wide area of skin has to be exposed to allow spatial summation. Adaptation of thermal receptors: a. Adaptation occurs between skin temperature 20-40OC, and warm receptors adapt faster than cold receptors. b. Both receptors adapt rapidly at first (phasic component) then continue to generate impulses at low frequency (tonic component). Mechanism of stimulation: 1- Thermoreceptors are stimulated chemically by changes in the concentration of metabolites accumulated due to change in metabolic rate (each 10°C increase, doubles the metabolite concentration). 2- When activated they open membrane ion channels known as “Temperature-activated Transient Receptor Potential” (TRP) ion channels. 3- They respond markedly to changing temperatures rather than steady states of temperature:  Warm receptors increase their firing when temperature is increasing.  Cold receptors increase their firing when temperature is decreasing. 4- Sensation produced by a transient change in temperature is relative, i.e. depends upon the original skin temperature. Thus, a stimulus of 35 OC will feel warm if the skin is at 30 OC and will feel cold if the skin is at 40OC 13  CENTRAL NERVOUS SYSTEM III- Pain Sensation  Pain is an unpleasant sensory and emotional experience for body protection.  It occurs whenever there is physical or potential tissue damage.  It causes the person to react to remove the pain stimulus or seek medical advice. Pain Receptors Types of Pain Receptors: (Nociceptors) Pain receptors are Free Nerve Endings attached to Aδ and C fibers. They are classified according to the mode of stimulation into: 1- Mechanical pain receptors: stimulated by mechanical injurious stimuli, e.g. cuts, bruises. 2- Thermal pain receptors: respond to extremes of temperature and capsaicin (substance present in hot chilli). 3- Chemical pain receptors: stimulated by chemical injurious elements or chemicals produced from tissue damage. 4- Polymodal pain receptors: respond to all types of stimuli. Distribution of Pain receptors:  They are most numerous in superficial layers of the skin.  They are also numerous in periosteum, peritoneum, pleura, joints, arterial walls, dura and tentorium of the cranial cavity.  They are less distributed in deep tissues and very few in internal viscera.  They are absent in liver parenchyma, lung alveoli, and brain tissue (pain insensitive structures). Adaptation: slowly or non-adaptive receptors. Pain Transduction by Nociceptors:  Noxious stimuli open transduction ion channels in pain receptors which increase membrane permeability to Na+ &/or Ca++  receptor potential  action potential.  Mechanical stimuli open specific “degenerin” ion channels.  Thermal stimuli open specific “temperature sensing TRP” ion channels.  Chemical stimuli open specific “acid sensing” ion channels. 14  CENTRAL NERVOUS SYSTEM Pain Sensitizers (OR Chemical mediators of pain):  After the nociceptors are stimulated, the damaged tissues and the surrounding blood vessels release a number of pain and inflammation producing chemical substances that are normally inside the cells, into the ECF.  These substances include: histamine, serotonin, K+, substance P, ATP, bradykinin and prostaglandins.  Prostaglandins further sensitize the nociceptors, lowering their pain threshold, and producing the primary hyperalgesia that often accompanies pain. On their pathway through the brain stem, fibers within the dorsal column and the ventrolateral Salicylates and other non-steroidal fibersanti-inflammatory analgesics (NSAID) reduce pain by column are joined by additional from nuclei of trigeminal nerve carrying sensations from inhibiting prostaglandin the head. synthesis. Chemical mediators of pain Threshold of Pain:  Threshold of pain is the same for all people but reaction to pain differs from one person to another.  Pain starts to be felt when the skin temperature reaches 45°C, this is considered as average threshold of pain. 15  CENTRAL NERVOUS SYSTEM Types of pain sensation: I- According to site of origin of pain, (discussed later) a. Cutaneous pain. b. Deep pain. c. Visceral pain. II- According to quality of pain: Single painful stimuli evoke two successive and qualitatively different sensations: a. Fast pain: also called sharp, immediate or first pain. (Aδ fibers) b. Slow pain: also called dull aching, delayed or second pain. (C fibers) The two types of pain can be dissociated from each other by: On their pathway through the brain stem, fibers within the dorsal column and the ventrolateral 1. Moderate compression of a nerve trunk will block the Aδ-fibers leaving the C-fibers. column are joined by additional fibers from nuclei of trigeminal nerve carrying sensations from The fast pain is lost while the slow type remains. 2. Low concentrations of local anaesthetic theblocks head. the C-fibers leaving the Aδ-fibers. The slow pain is lost while the fast type remains. Characters of fast pain and slow pain are summarized in the following table: Fast Pain Slow pain Quality Sharp, pricking, acute Dull aching, Burning, throbbing Onset Immediate Delayed Duration Short duration Long duration & increase with time Localization Well localized Poorly localized (diffuse) Stimulated Receptor Mechanical & thermal All types of pain receptors Skin and Parietal Felt in All tissues (Skin, deep tissues, viscera) surfaces Carried by Aδ fibers C fibers Blocked mainly by Hypoxia & compression Local anaesthesia (e.g. cocaine) Neurotransmitter Glutamate Substance P Neo-spinothalamic Pathway Paleo-spinothalamic Tract Tract Relay of 2nd order Reticular Formation  intralaminar VBN of thalamus neurons thalamic N Termination of fibers sensory cortex whole cortex In Thalamus and Pain perception Mainly in Thalamus Sensory Cortex Flexor Withdrawal Guarding: Motor reflexes reflex hypertonia of overlying muscles Pressor response: Depressor response: (BP & HR) Nausea Autonomic reactions (↑BP & HR) and vomiting Emotional reactions Anxiety Depression 16  CENTRAL NERVOUS SYSTEM Pain Pathway Afferents: Aδ (carrying fast pain) and C fibers (carrying slow pain). First order neurons: dorsal root ganglia (DRG). Second order neurons: Posterior horn cells (PHCs) on the same side. a. Type Aδ fibers release glutamate and synapse with PHCs in lamina I and V. b. Type C fibers release Substance P and synapse with PHCs in lamina II and III (i.e. substantia gelatinosa of Rolando or SGR). c. Pain fibers then cross and ascend in the lateral spinothalamic tract in the opposite side of the spinal cord. d. Fast pain fibers ascend as neospinothalamic tract. e. Slow pain fibers ascend as paleospinothalamic tract. Third order neurons: a. Fast pain fibers (neospinothalamic tract) end in the ventrobasal nuclei of the thalamus (VBN), then project to the somatic sensory cortex. b. Slow pain fibers (paleospinothalamic tract) reach the brain stem, where:  10% of the fibers join the neospinothalamic tract to synapse in the VBN of the thalamus then end in the somatic sensory cortex.  90% of the fibers synapse with neurons of the reticular formation, then synapse with the intralaminar (non-specific) nuclei of the thalamus (spino-reticulo-thalamic), then project to activate the whole cortex. Neospinothalamic tract Paleospinothalamic tract 17  CENTRAL NERVOUS SYSTEM Reaction to Pain: Along their way upwards, the pain fibers give tributaries to: a. Anterior horn cells in the spinal cord for accompanying motor reflexes. b. Reticular Activating System for cortical activation and arousal reactions. c. Hypothalamus for accompanying autonomic reactions. d. Limbic system for emotional reactions. Arousal reaction to pain signal:  The intralaminar (non-specific) nuclei of the thalamus and reticular formation of the brain stem have a strong arousal effect on nervous activities through the reticular activating system (RAS) of the brain. This explains why a person with severe pain is strongly aroused. Function of cerebral cortex in Perception of pain signals:  Cerebral cortex is not essential for perception (conscious awareness) of pain.  Pain perception can occur subcortically in the Thalamus.  Function of the Somatic Sensory Cortex in pain perception is: a. Localization of source of pain: fast pain is very localized. b. Discrimination of pain modality and intensity. c. Interpretation of its meaning. d. The prefrontal lobe of the cortex contributes to the accompanying emotional and behavioral effects of pain. Types of Pain Sensation A) Cutaneous Pain: - It is pain produced by stimulation of pain receptors in the skin or body surface. - It starts as fast sharp pain followed by more prolonged slow dull pain. - Unlike the other types of pain, it is accurately localized, due to: a) The high density of pain receptors in the skin. b) The fast pain fibers reach the sensory cortex. c) Besides, touch and vision help greatly in localization. B) Deep Pain Deep or musculoskeletal pain is the pain produced from injury to muscles, tendons, ligaments, joints and bones. It is conducted along thin C fibers. 18  CENTRAL NERVOUS SYSTEM Causes of deep pain: 1. Trauma: e.g. broken bone. 2. Inflammation in deep tissues or joints: e.g. rheumatic arthritis. 3. Muscle spasm: e.g. injury to bones, tendons and joints is associated with reflex contraction of nearby skeletal muscle  ischemia  more pain  spasm  ischemia  pain... etc (vicious circle). 4. Ischemia: block of blood flow to a tissue leads to Ischemic Pain: a- Ischemia may be caused by narrowing or compression to an artery by thrombosis, spasm or mechanical pressure by a tumor. b- Pain is produced by accumulation of metabolites and proteolytic enzymes in ischemic tissue. c- Pain is aggravated by increased activity of the muscle and relieved by rest. d- Example: Anginal pain in cardiac muscle and intermittent claudication in skeletal muscles C) Visceral Pain Pain produced from the internal viscera of the thorax, abdomen and pelvis.  Viscera of abdomen and chest have few pain receptors. That is why a localized injury to a viscus by a sharp cut does not cause pain, while diffuse stimulation of a large area cause dull aching poorly localized pain.  This pain is conducted along C fibers (Visceral pain).  On the other hand, the parietal walls of the viscera (pleura, peritoneum and pericardium) are richly supplied by pain receptors attached to Aδ fibers. Thus, if a disease spreads from a viscus to its wall, it causes sharp acute well localized pain (Parietal pain).  Pain innervation of the viscera: Afferent fibers from visceral structures reach the CNS via sympathetic and parasympathetic nerves. Causes of visceral pain: 1- Inflammation: inflammatory products stimulate pain receptors, e.g.: appendicitis. 2- Ischemia: leads to release and accumulation of pain producing metabolites such as H+, K+, bradykinin or prostaglandin. 3- Spasm of a hollow viscus: Spasm of smooth muscles of gut, gall bladder, ureter, uterus etc... causes pain by: a. Mechanical stimulation of mechanical pain receptors. b. Obliteration of the blood vessels causing ischemia. 4- Overdistention of hollow viscus: Extreme overfilling or overdistention causes mechanical and ischemic stimulation of pain nerve endings. 5- Chemical irritation of pain receptors e.g. by gastric acid in case of peptic ulcer. 6- Compression or infiltration of viscera by tumors. 19  CENTRAL NERVOUS SYSTEM Characters of visceral pain: 1- Dull aching pain (except if pleura or peritoneum are involved). 2- Diffuse (Poorly localized): due to few pain receptors in viscera and less accurate representation of the viscera in cortex. 3- Depressor autonomic responses: hypotension, bradycardia, nausea, vomiting. 4- Associated with Guarding: reflex spasm of skeletal muscles over affected area. 5- Usually referred to surface area. Referred Pain Pain which is not felt in the diseased viscus itself, but felt on a skin area originating from the same embryonic segment or dermatome as the diseased viscus (or deep structure), and therefore supplied by the same dorsal roots (Dermatomal rule). Mechanism of referred pain: 1- Convergence projection theory:  Afferent pain fibers from the skin and viscus converge on the same (SGR) that will finally activate the same neurons in the cortex.  Whatever may be the source of pain, the cortex will project it to a skin area, i.e. as if it is coming from the skin and not from the diseased viscus.  This misinterpretation is caused by: a. Brain is more accustomed to receive pain from skin than from viscera. b. Skin is rich in pain receptors and well represented in the cortex while viscera are not. c. Skin is more exposed to stimulation. 2- Facilitation theory:  Afferents from pain fibers of diseased viscera, give subliminal fringe to a nearby SGR (which also receive afferents from the skin), increasing their excitability, i.e. facilitating them.  Minor stimuli from the skin to these neurons can produce pain or hyperalgesia. Mechanisms of referred pain 20  CENTRAL NERVOUS SYSTEM Examples of referred pain: 1- Cardiac pain: felt in the retrosternal region, root of the neck, outer part of the chest and inner part of the left arm and also in the epigastrium. 2- Gastric pain: felt between the umbilicus and xiphoid process. 3- Gall bladder pain: felt in the mid-epigastrium and at tip of right scapula. 4- Renal pain: felt as a back pain radiating to inguinal region and testicles in males. 5- Appendicitis pain: felt around the umbilicus. 6- Headache. Some areas of referred pain from viscera 21  CENTRAL NERVOUS SYSTEM Headache Definition: pain referred to the surface of the head from deep structures. Causes: traction, displacement, inflammation, vascular spasm or distention of the pain-sensitive structures in the head or neck. It may be due to intracranial or extracranial origins: A-Headache of intracranial origins: Areas of the head to which headache is referred  The intracranial pain sensitive areas include: the venous sinuses, the tentorium, the dura and the dural arteries especially the middle meningeal artery at the base of the skull. However, the brain itself is insensitive to pain.  Stimulation of pain receptors in intracranial structures above the tentorium leads to frontal headache (referred to areas supplied by trigeminal nerve).  Stimulation of pain receptors in intracranial structures below the tentorium leads to occipital headache (referred to areas supplied by 2nd cervical nerve). Causes of intracranial headache: 1- Intracranial hemorrhage or intracranial mass. 2- Meningitis or meningeal irritation. 3- Rise or drop of intracranial tension: e.g. post lumbar-puncture. 4- Alcohol headache. 5- Hypertension: due to marked exparsion of cerebral blood vessels. 6- Migraine headache: unilateral headache resulting from abnormal vascular phenomena B-Causes of Headache of extracranial origins: 1- Tension-Type Headache: due to spasm of scalp and neck muscles. 2- Eye disorders: glaucoma and errors of refraction. 3- Sinusitis: Inflammation of the nasal sinuses. 4- Otitis media: inflammation of the ear. 5- Toothache. 6- Systemic disorders: e.g. anemia 22  CENTRAL NERVOUS SYSTEM Pain Control Pain transmission and perception inhibited in the central sensory pathways by ascending and descending impulses. Suggesting observations include: a. The degree that a person reacts to pain varies widely. b. Injuries caused in stressful conditions as accidents or battles are ignored. c. Irritation of the skin overlying a diseased viscus relieves pain. This results from the capability of the body itself to suppress pain signals to the CNS by activating pain control systems. The Gate Theory: The Gate theory of pain inhibition states that:  The dorsal horn cells of the spinal cord, in particular SGR cells, act as a gate for transmission of pain sensation to the brain.  Impulses coming along small diameter C pain fibers cause the release of substance P and open the gate.  This gate can be partly or completely closed by Presynaptic Inhibition which prevents release of substance P and thus reduces or blocks pain sensation by one of the following: a. Opioid peptides. b. Supraspinal (central) descending analgesic system. c. Spinal (peripheral) Impulses. (1) Opioid Peptides:  Morphine is a powerful (analgesic) pain killer found in opium seeds.  It acts by combining with receptors in the CNS.  Endogenous opioid peptides or morphine-like substances in the CNS act as endogenous ligands for these receptors Types of endogenous opioid peptides: Among about 12 opioid peptides found in mammals, three are more important: 1- Enkephalins: Nature: Pentapeptides derived from the large protein molecule pro-enkephalin. Site of release and function: a. In different areas of the CNS, both supraspinal (periaqueductal grey area) and spinal (SGR) where they produce their analgesic effects. b. They are also secreted in the limbic system where they promote a sense of well-being in the individual. 23  CENTRAL NERVOUS SYSTEM 2- Endorphins: Nature: β-Endorphin is a 31 amino acid polypeptide derived from a large precursor molecule, pro- opio-melano-cortin. Site of release: mainly in hypothalamus and pituitary gland. Function: it acts as: a. Neurotransmitter: secreted from arcuate nucleus and other areas of hypothalamus then project to the thalamus and periaqueduct grey area. b. Neurohormone: secreted from anterior pituitary gland with ACTH in stress conditions into the general circulation to reach opiate receptors in the body causing analgesia. This explains Stress Analgesia. 3- Dynorphin: Nature: a 17 aa polypeptide derived from prodynorphin. Site of release: neurons in different brain stern nuclei. It is related to addiction and tolerance. Opiate Receptors: Distributed in areas of CNS concerned with pain sensation, e.g. Periaqueductal gray area (PGA), SGR, thalamus, hypothalamus a. Delta: high affinity to enkephalin. b. Mu: high affinity to endorphin and morphine. c. Kappa: high affinity to dynorphin. (2) Supraspinal Descending Analgesia System: It consists of three major components (Fig 39). 1. Periaqueductal gray area (PGA): a. Present in midbrain and upper pons, surrounding the aqueduct of Sylvius. b. Neurons in this area are sensitive to β-endorphin. c. Their axon terminals secrete enkephalins and send their signals to raphe magnus nucleus. PGA may be stimulated by: a. β endorphin reaching them either :  As chemical transmitter secreted from neurons in the hypothalamus. OR.  As neurohormone from the pituitary and through the blood stream in response to stress. b. Collaterals arising from ascending pain pathway (Lateral spinothalamic tract). This means that noxious stimuli are important for activation of descending pain control system, i.e. pain suppresses pain. 24  CENTRAL NERVOUS SYSTEM 2. Raphe magnus nucleus: a. Located in upper medulla. b. Neurons in this area are sensitive to enkephalins. c. RMN neurons then descend in the spinal cord to terminate on dorsal horn inhibitory interneurons in the spinal cord where they secrete serotonin. 3. Pain inhibitory Interneurons a. In the dorsal horn of the spinal cord. b. Neurons are sensitive to serotonin. c. Secrete Enkephalins which causes presynaptic inhibition of the SGR, thus preventing the release of substance P. In this way, the descending analgesia system can block pain signals at the initial entry point to the spinal cord. Analgesic System 25  CENTRAL NERVOUS SYSTEM (3) Peripheral gate inhibition:  Simultaneous stimulation of large Aβ sensory fibers from peripheral tactile receptors carrying non-painful stimuli can suppress pain transmission in thin C fibers carrying pain signals from same body area.  These tactile fibers send collaterals to activate inhibitory interneurons  secrete GABA or Enkephalins  presynaptic inhibition of pain fibers at the SGR  closing the gate.  Examples: a. Rubbing or massage of skin inhibits pain. Gate Inhibition b. Counter irritation, e.g. mustard plaster. c. Acupuncture. Methods of Treatment of Pain A) Medical Treatment:  Analgesics, i.e. pain killer drugs: Either NSAID (non-steroid anti-inflammatory drugs) OR opiates.  Treatment of the cause, eg. Antiacids, antispasmodics or vasodilators in ischemic pain e.g. anginal pain. B) Electric Stimulation: to analgesia system or to large sensory Aβ fibers. C) Surgical Treatment: In case of uncontrollable severe pain:  Antero-lateral cordotomy, to cut the spinothalamic tract.  Prefrontal lobectomy: relieves the emotional reaction to pain as a last resort for relief of intractable pain in cancer patients. 26  CENTRAL NERVOUS SYSTEM Lesions of the Sensory System Lesions of sensory pathway can occur at any level from the afferent peripheral nerve to the somatosensory cortex. I - Hyperalgesia: Exaggerated pain response: 1. Primary hyperalgesia: a. Occurs in the injured or inflamed skin area. b. Caused by sensitization of peripheral nociceptors by inflammatory mediators. c. Thus there is lowered threshold of pain e.g. in sunburned skin. 2. Secondary hyperalgesia: a. Occurs in uninjured skin. b. Due to sensitization of the central neurons of pain. c. The pain threshold is increased, but when reached, the pain produced is prolonged, severe and intolerable. d. This may be accompanied by allodynia (exaggerated pain response to non-painful stimuli). E.g. Thalamic pain. II- Peripheral nerve lesions: 1. Mononeuropathy: Injury or lesion of one peripheral nerve leads to loss of all sensations in the area supplied by this nerve. 2. Polyneuropathy (peripheral neuritis): a. Diffuse lesion of all peripheral nerves, as in case of Vitamin B12 deficiency or diabetic neuritis. b. Affects the peripheral ends of sensory nerves at the distal parts of the limbs leading to “glove and stocking” sensory disturbance (numbness, tingling, burning then total sensory loss). c. Injury / damage to a peripheral nerve can lead to chronic neuropathic pain Mononeuropathy and Polyneuropathy 27  CENTRAL NERVOUS SYSTEM Neuropathic Pain Definition: chronic type of pain occurring due to damage to or pathological changes in nerve fibers either in the peripheral or central nervous system. Characters: a. It is often described as burning, electric, tingling or shooting pain. b. It characterized by occurring in bouts or paroxysms. c. It is usually accompanied by hyperalgesia and/or parasthesia. Examples: a. Trigeminal neuralgia: (tic douloureux) is a unilateral facial pain confined to areas supplied by the 2nd and 3rd divisions of the trigeminal nerve. b. Thalamic pain. c. Herpes zoster. d. Phantom limb pain. e. Diabetic neuropathy. f. Sciatica. 3. Herpes Zoster: a. It is a viral infection, in which the herpes virus attacks a dorsal root ganglion (DRG) in patients with history of varicella (chicken pox) infection. b. Virus starts to reproduce causing irritation of pain afferents in the DRG leading to severe pain felt in the dermatomal segment supplied by the infected ganglion. c. The virus also migrates with neuronal cytoplasmic flow towards the peripheral axons to their cutaneous terminals, where it reproduces leading to painful skin rash and vesicular formation. 28  CENTRAL NERVOUS SYSTEM III- Spinal cord Lesions: 1. Tabes Dorsalis: It is a neurosyphilitic disease that causes slow degeneration of the sensory nerves in the dorsal root and dorsal column mostly in the lumbosacral spinal cord leading to: a. Irritation of pain fibers and attacks of severe pain, followed by: b. Degeneration and Atrophy of the Dorsal Column leading to:  Loss of vibration sense.  Loss of proprioceptive sensation leads to incoordination of voluntary movements known as “Ataxia”. c. Sensory ataxia is characterized by high steppage (or stamping) gait and +ve Romberg's sign (the patient can't maintain his erect position with closed eyes). Tabes dorsalis Ataxia: Definition: Incoordination of voluntary movements without paralysis. Types of ataxia: On their pathway through the brain stem, fibers within the dorsal column and the ventrolateral column are joined a. Sensory by additional ataxia: fibers Due to loss of from nuclei position of trigeminal sensation nervedorsalis as in tabes carryingorsensations from pernicious the anemia head. which cause destruction of posterior column. b. Cerebellar ataxia: due to lesion in neocerebellum. c. Vestibular ataxia: due to lesion in the Vestibular division of the 8th nerve. 29  CENTRAL NERVOUS SYSTEM 2. Syringomyelia:  There is widening of the central canal by a fluid-filled cavity (or syrinx) in the spinal cord.  This leads to damage of pain and temperature fibers crossing immediately in front of the central canal first. Later, crude touch is affected.  The lesion is bilateral and usually affects the cervical region leading to “jacket” loss of pain and temperature sensations.  Dorsal column sensations remain intact (fine touch is intact) and the condition is described as dissociated sensory loss. 3. Spinal cord Hemisection: (Brown Sequard syndrome): Hemisection of the spinal cord results in the following manifestations: a. At the level of lesion: On the same side:  Sensory: Loss of all sensations at the dermatome supplied by that posterior root entering at the site of injury.  Motor: Flaccid paralysis (lower motor neuron lesion) and loss of all reflexes b. Below the level of lesion: On the same side:  Sensory: Lesion to the dorsal column leads to loss of all sensations carried by it (fine touch, pressure, vibration, sense of position and of movement).  Motor: Lesion to the corticospinal tract leads to spastic paralysis (upper motor neuron lesion), hyper-reflexia and +ve Babiniski. On the opposite side:  Sensory: loss of pain and temperature (Lesion to the crossed spinothalamic tract), touch is not lost but decreased on both sides.  Motor: no effect 30  CENTRAL NERVOUS SYSTEM IV. Thalamic Pain Syndrome: (Dejerine Roussy syndrome) Also known as central post stroke pain (CPSP) is a rare condition that develops after infarction of the ventro-postero-lateral thalamus. The Patient presents with: 1. Contralateral sensory loss. 2. Hemi-ataxia. 3. Thalamic pain: spontaneous bursts of intolerable burning pain sensation (accompanied by 2ry hyperalgesia and allodynia (discussed earlier). V- Cortical Lesions: 1- Lesion in the somatic sensory area SSI: Somatic sensations are not abolished. However, there is loss of the following types from the opposite side of the body: a- Fine touch, Stereognosis and Proprioceptive sensations. b- Discrimination of mild grades of weights and temperature. c- Localization of the source of sensations. d- Pain localization, but pain sensation is least affected. 2- Lesion in the somatic sensory association cortex: a- Astereognosis: The patient loses the ability to correlate shape, size, texture and weight of objects with previous experience. b- Amorphosynthesis (Neglect syndrome): The patient neglects the contralateral side of his body, i.e. ignores its presence. 31  CENTRAL NERVOUS SYSTEM 1- Discuss adaptation of sensory receptors. 2- Describe factors affecting synaptic transmission. 3- Discuss mechanism of receptor potential. 4- Discuss mechanism of referred pain. 5- Describe sensory manifestations Hemi-section of the spinal cord: (Brown Sequard syndrome). 6- Discuss pain control system. 1) During Excitatory postsynaptic potential: a- The postsynaptic membrane potential is more negative. b- The postsynaptic membrane potential is away from firing. c- The postsynaptic membrane is less excitable. d- The postsynaptic membrane potential is less negative. 2) Receptor potential initiated by an adequate stimulus: a- Develops always at it full magnitude. b- Undergoes temporal summation only. c- Undergoes spatial summation only. d- Could initiate an action potential. 3) Slowly adapting receptors include all the following types, except: a- Golgi tendon organs. b- Muscle spindles. c- Free nerve endings. d- Paccinian corpuscles. 4) The phenomena of occlusion occurs when: a- There is overlap of facilitation zones. b- There is overlap of discharge zones. c- The combined effect of two neurons is more than the sum of individual effects. d- There is stimulation of a muscle and inhibition of its antagonist. 5) A more developed two-point tactile discrimination: a- Indicates a greater threshold distance for feeling 2 points touched simultaneously. b- Is seen in the proximal regions of the body compared with the distal regions. c- Is inversely related to the size of receptive fields of the stimulated sensory units. d- Depends upon the type of the involved touch receptor. 32  CENTRAL NERVOUS SYSTEM 6) Stimuli which evoke true visceral pain include all the following, except: a- Sharp cutting. b- Stretching. c- Spasm. d- Chemical irritation. 7) Inhibitory postsynaptic potential: a- Is produced by increased Cl- conductance. b- Can be produced by an increase in Na+ conductance. c- Can be produced by an increase in Ca2+ conductance. d- Is produced as a result of the presence of an inhibitory 3rd neuron. 8) Concerning Synaptic transmission: a- Depends on presence of voltage-gated Ca2+ channels in postsynaptic membrane. b- Presynaptic knobs release only an excitatory transmitter. c- It is inhibited by hypoglycemia and acidosis. d- Presynaptic knobs contain vesicles which have t-snare in their membranes. 9) Cutaneous pain: a- Occurs in 2 phases slow pricking followed by fast burning pain. b- Receptors adapt to stimulation more rapidly than touch receptors. c- Is characterized by high density of receptors present in the skin. d- Is poorly localized, dull aching pain. 10) Visceral pain is: a- Carried by A alpha fibers. b- Accompanied by exaggerated autonomic responses. c- Produced by a sharp cut in the viscera. d- Felt in the deep tissues close to the diseased viscera. 33