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146 Cards in this Set

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Lecture 5-6: Hersh
-The peripheral nervous system is divided into somatic (voluntary) which controls skin, joint, and skeletal muscles, and visceral (ANS) that controls the viscera or organs
-The ANS is divided into sympathetic and parasympathetic
Somatic Nervous System (voluntary) Overview
-Has a single efferent nerve fiber going from the CNS to the end organ (skeletal muscle) where it synapses at the neuromuscular junction (endplate). This nerve fiber is the postsynaptic fiber.
-Afferent is stimulation going into the CNS
-A nerve is a collection of axons outside the CNS
-The neurotransmitter is acetylcholine and the receptor is Nicotonic M Cholinergic
Neuromuscular Junction
-Also called the motor end plate
-the presynaptic terminal releases an ester, acetylcholine which binds the postsynaptic terminal nicotonic M cholinergic receptors. This leads to muscular contraction
-The action of acetylcholine is short because it is degraded by cholinesterase into choline and acetate
-The choline can be re-uptook at the terminal and combined with ACO to make acetylcholine
Neuromuscular Junction Agonist/Antagonist
-the agonist is a receptor stimulator while the antagonist is a receptor inhibitor
-The agonist will rapidly blind and release the receptor while the antagonist will bind tightly and slowly disocciate
Somatic NS Drugs (1)
1) Myasthenia Gravis - autoimmune disease that targets the Nicotinic M Receptor leading to decrease skeletal muscle contraction
-one treatment is apheresis to filter blood and remove the auto-antibodies
-Another is physostigmine or neostigniine. These are cholinesterase inhibitors which block the acetylcholine split and prolong the their actions at the synapse
-The problem with neostigmine is that it is charged and cannot get into the brain.
-Donepezil (Aricept) is lipid soluble and gets into the brain. It is used for alzheimers
Somatic NS Drugs (2)
Curare - It blocks the nicotinic M cholinergic receptors and is a competitive blocker of acetylcholine
-Curare leads to skeletal muscle paralysis. It is useful for surgery but not a anasthetic. It lasts 60-90 minutes so the patient must be on a ventilator
-Since it is a competitive blocker you can overcome the blockage by giving acetylcholine or cholinesterase inhibitors like (donepezil, neostigmine)
-The problem with cholinesterase inhibitors that reach the brain is that there are side effects since acetylcholine will also target non nicotinic M receptors - this leads to slow heart and diahhrea due to increased peristalsis
Somatic NS Drugs 3
Succinylcholine (Anectine R) - It blocks muscle contraction by depolarizing the muscle end plate until it becomes unresponsive to ACh (paralysis)
-Becuase this action is non-competitive it cannot be overcome until the body metabolizes it, no drug will help
-People who have aypical cholinesterase can actually have the drug around for 24 hours
Autonomic Nervous System Overview
-2 neurons output on the efferent side
-divided into parasympathetic and sympathetic
-The parasympathetic is the bodies fine control which is generally calming. It conserves body energy and discretely makes organs respond when needed
-The sympathetic is fight/flight/freight and controls our organs when under stress. The goal is to energize the body and put it in a survival mode
Parasympathic Overview
-Has a 1:1 relation between pre/post synaptic neuron
-The end organ is usually smooth muscle, glandular tissue, and cardiac tissue
-The has a long preganglionic fiber starting at the CNS and a short postganglionic fiber that stops at the end organ (also pre/post synaptic neuron)
-The preganglionic receptor (on the postganglionic neuron) is nicotinic N cholinergic and the neurotransmitter is acetylcholine
-The postganglionic receptor (on end organ) is muscarinic cholinergic (5 subtypes) and the neurotransmitter is acetylcholine
Parasympathic Overview 2
-the system eminaes from the cranial and sacral areas of the spinal column (cranio-sacral)
-It is important to keep in mind that while acetylcholine can target receptors at the NMJ (nicotinic M) as well as the parasympathic receptors (nicotinic N and muscarinic) the drugs selectively act on the receptors to affect acetylcholine in one location or another
-Each presynpatic fiber communicates with just 1 postsynaptic fiber, control...
-sphincter muscle + ciliary bodies of eye for pupil constriction
-glands to increase smooth muscle contraction for serous saliva
-Via the vagus nerve excitation it polarizes the SA slowing heart rate
-Via the vagus nerve excitation it constricts smooth muscle in the bronchi to reduce oxygen flow
-Via the vagus nerve excitation it stimulates secretions in the stomach and GI to digest
-Via the sacral nerves it controls urination and defecation in the bladder, colon, rectum
Parasympathetic Drugs (1)
-side effects of increase acetylcholine or a cholinesterase inhibitor on parasympathetic division is drooling, heart rate slow, trouble breathing, shitting
-stimulating muscarinic receptor in the GI stimulates peristalsis, as does smoking which increases stomach acids
Parasympathetic Drugs - Receptor Blockers
1) Atropine/Probanthine - Use by dentist to make mouth dry (xerostomia) before a procedure, especially image taking
-Blocks acetylcholine at the muscarinic receptor but not the nicotinic M receptor so the patient isn't paralyzed
-it leads to a increased heart rate, constipation, and increase fluid in the back of the eye so avoid with glacomic patients. Also cause urinary retention and pupullary dilation
-These side effects result because blockage fo the parasympathetic allows the sympathetic to predominate
Parasympathetic Drugs - Receptor Stimulator
Pilocarpine (salagen) is used in chronic xerostomia (Sjorgen's syndrome) to stimulate the muscarinic receptor
-also used to treat gluacoma because it constricts the smooth eye muscles
Parasympathetic Drugs - Anti-cholinesterases
-these work at the ganglionic site to bind acetylchonesterase irreversibly leading to SLUDGE
-Soman and sarin were used for war nerve gas because they are very lipid soluble
-SLUDGE leads to salivation, lacrimation, urination, deficiation, grand mal convolsion, and emesis
Sympathetic Nervous System Overview
-can have 1 short resynaptic neuron for multiple long post-synaptic neurons
-nerves come out of the thoraco-lumbar spinal region
-postsynaptic ganglia are connected by interneurons, also known as gray rami
-the preganglionic receptor is Nicotinic N and the preganglionic neurotransmitter is acetylcholine
-The postganglionic neurotransmitter is norepinephrine, epinephrine, and dopamine whiel the postganglionic receptors are alpha 1/alpha 2/beta 1/beta adrenergic
-the end organ is smooth muscle and heart
-the role of the sympathetic nervous system is simultaneous energizing of all body organs
-end organs effects are contrary to the parasympathetic NS
Sympathetic Nervous System Explained
-the main postganglionic neurotransmitter and receptor are alpha 1 and norepinephrine
-The sympathetic NS has a backup plan. Presynaptic fibers can synapse with the adrenal medulla which acts as a postsynaptic fiber and releases epinephrine into the blood
-Epinephrine reinforces norepinephrine at both the alpha 1 and 2 beta receptors
-The beta receptors work at the SA node and at the vascular beds of striated muscle where they enhance flow
SNS Effects
Generally...
-alpha receptors cause constriction of smooth muscle like blood vessels and sphincter muscles
-beta cause smooth muscle relaxation and stimulate heart
1) Pupil Dilation (a1)
2) Increase heart rate (b1)
3) Skin B.V. constrict (a1) while skeletal muscle/brain, and liver B.V dilate (b2) (contrary functions draw blood to where it is needed, and this function is mediated by receptors at those organs that respond to the same chemical in different ways)
4) Increase respiration and bronchi dilate (b2)
5) Constrict anal and urethral sphincters (a1)
6) Relax GI smooth muscle (b2)
7) Mucous secretion from salivary gland (a1)
8) Action of adrenal medulla - B
Sympathetic Drugs
1) Mecamylamine (inversine) - Given to hypertension patients. It shuts down the SNS at the pre-synaptic point so it also has an effect on the parasympathetic system which can lead to xerostomia
2) Alpha Blockers - Antihypertensive and deplete norepinephrine stores and prevent its release from nerve terminals. Durgs like Prazocin (minipress) dilate blood vessels by blocking the alpha 1 receptor
3) Beta Blockers - Used to treat angina, hypertension, and cardiac arrhythymias.
-Propranol blocks mostly B1 but some B2 so you don't give to asthmatics
4) Amphetamine - Enhance the release or mimic the effects of norepinephrine and epi. Causes peripheral increase in BP and respiration
Dopamine
-made by the neural tissue and the adrenal medulla
-in the family of catchecholamines with epi/nor
-goes from phenyl alanine to tyrosine and then goes to the nerve terminal as DOPA. It is converted to DOPA decarboxylase and then dopamine
-leads to renal vasodilation in the kidney
-too little in the brain can lead to Parkinson's Disease while too much leads to Bipolar Depression and Schitzo
-Post-ganglionic nerve fibers can hydorxylate dopamine to norepinephrine while adrenal medulla can methylate norepinephrine to epinephrine
Sympathetic Nervous System on the body
-Many organs are dually innervated with SYM and PARA so when 1 is blocked the other predominates
-During quiet periods the PARA dominates and converses energy
-During stress the sympathetic prepares for battle with pupil dilation (better vision), thick saliva, bronchi maximally dilated for mor oxygen, and the blood supplies are shirted from the periphery and splanchic areas to the central system, straited muscle beds, and the heart
Sympathetic NS on the Heart
-B1 receptor controls increasing rate and force of contraction. Epinephrine acts on this receptor
-These receptors are in the atria SA node and the ventricle
-Braking the heart is done by the parasympathetic muscarinic receptors in the SA node whereby acetylcholine release slows heart rate and contraction
-Propranol blocks the B1 receptor by competitive inhibition leading to decrease HR and contraction because w/o sympathetic the PARA takes over
Review of PNS and SNS
1) Overaction sympathetic leads to hypertension, fast heart, hyperglycemia and hyperventilation due to too much epinephine
2) Underactive SNS leads to hypotension
3) Overactive parasympathetic can lead to diarrhea and ulcers while underactive leads to constipation, urinary retension, and tachycardia.
4) Patients on antipsychotic and antidepressants have concomitant sympathetic blocking and anticholinergic activities leading to xerostomia and hypotension
Acute vs. Chronic Pain
-dentist deal with 95% acute and 5% chronic pain
ACUTE: provoked by a identifiable cause and disappears in a short time due to routine analgesics or intervention as surgery
-it serves a protective biological function and and stimulates the sympathetic

CHRONIC: The pain lingers longer than expected and pain relievers and therapy don't work. It serves no biological function and is associated with changed behavior
-Depression and chronic pain are intertwined
Addiction
Emotional - Whole life is about getting the drug

Physical - Removal of drug stimulates the part of the NS that was depressed. FOr example removing a depressent leads to sweat and increased heart rate
Inflammation
-dying cells are the surgical site or area infected have their membrane phospholipase A2 cleave membrane phospholipid to arachidonic acid
-A.A. is acted on by cyclooxygenase to form prostaglandins
-Prostaglandins do not cause pain but they lower the free nerve ending threshold to other inflammatory mediators histamine, bradykinin, H+ (lower pH) and potassium
Mechanism of Peripherally Acting Analgesics
-includes aspirin and the NSAIDs which block COX inhibiting prostaglandin production
-Glucocorticoids block the action of phospholipase A2 at the membrane (coritcol)
-can target other pain causers like seratonin released from platlets, nitric oxide from damaged blood vessels, and release of substance P from free nerve endings
Types of Pain Receptors
-divided into chemical, mechanical, and thermal stimulation
-Thermal: The TrpV receptors that are activated by temperature. TrpV1 (40) and TrpV2 (50)
-Chemical: ATP and bradykinin which binds beta adrenergic 1 and 2
SIde Effects of Aspirin
-aspirin's acetyl salicyclic acid is metabolized to salicylic acid which inrreversibly inhibits COX so no prostaglandins made
1) PGs in the stomach increase mucus and bicarbonate formation in parietal cells so their limitation leads to stomach bleeding
2) Platlets have thromboxane synthetase metabolizing PGs to thromboxanes which cause platlets to aggregate. WIthout COX (esp. in platlet without a nucleus to make more COX) these cannot aggregate and there is increased bleeding
-Prostacyclins are involved in pain and sensation and naturally found in endothelial BV. Do the opposite of thromboxane and inhibit platlet aggregation
Prostaglandins
-act on the hypothalmus to produce a fever
-in kidney it leads to renal blood flow and sodium/K excretion
COX Classes
-two COX enzymes
-COX 1 is always on and it converts AA to PGE2 and thromboxanes which protect the GI, aggregate the platlets, vasoconstriction and renal function
-COX2 is induced on and it makes PGE2 and prostacyclin PGI2. This leads to inflammation, pain, fever, and inhibits platlet aggregation (reason COX2 blocker vioxx was pulled for increasing heart attacks)
-Anything with coxib on the end is a COX2 inhibitor
Peripheral Nerve Transmission
-action potentials are free nerve endings at transmitted to the CNS via primary afferent nerve fibers (2 types)
1) Myelinated A delta fibers - fast components leading to sharp, well-localized pain
-has a protective role to remove hand from stove
2) Unmyelinated and thin C fibers that conduct the slow component of pain leading to a diffuse, prolonged, dull, pain. Could play a major role in chronic pain conditions
-no biological role known
Blocking Peripheral Nerve Transmission
-local admides like lidocaine block action potential on these fibers by inhibiting the sodium inflex needed for depolorization
-lidocaine has a lipid and water soluble end
-Since lidocaine is removed by the vasculature, the injections include epinephrine to constrict the BV and increase the time lidocaine relieves pain
-Puffer fish tetrodotoxin also blocks sodium channels, but in the entire body
Hersh Drugs
1) Benzocaine - Topical anesthetic to relieve tooth aches
2) Transmucosal patch to believe anesthetics through a band-aid
3) Intranasal Spray - anesthetized patients from 2nd pre to 2nd pre
Pain Transmission
-all synapses except ANS occur in the CNS (all afferent)
-cell bodies of primary afferent neurons are in a nerve ganglion
SPINAL: The afferent nerves pass their axons from the ganglion to synapse at the CNS second-order neuron
-many of these afferent nerve fiber ganglia are at the dorsal root ganglion
-pain impulses pass through the dorsal root ganglion to synapse with second-order neurons in the dorsal horn where the signal usually crosses over the spinal cord
-Second-order neurons ascend to the thalamus via spinothalamic pathways and synapse with third-order neurons in the thalamus which project to different areas in the sensory cerebral cortex and forebrain
TRIGEMINAL: Primary afferent nerves pass through the trigeminal ganglion to the trigeminal brain-stem sensory nuclear complex where they synapse with conecting second order neurons in the brain stem complex
-this brain-stem complex extends from the pons into the upper cervical cord and is divided into the main trigeminal sensory nucleus and the trigeminal spinal tract nucleus
-WIthin the spinal tract nucleuc is the nucleus caudalis which acts as the main brain-stem relay site of orofacial nociceptive information
-From here the signal is carried on 2nd order neurons to the thalamus via trigeminothalamic pathways and synapses with third-order neurons in the thalamus
Second Order Neurons
-second order neurons are divided into nociceptive-specific, wide dynamic range, and low-threshold mechanoreceptors
-NS neurons respond exclusively to noxious stimuli and receive input from small-diameter A fibers and C dibers
-The final output of nociceptive-specific neurons is influenced by the convergence of several afferent inputs, and this central convergence on the same 2nd order neurons helps explain referral pain
-this is multiple primary afferent neurons synaping on the same 2nd order neurons. Brain can't tell where pain is coming from
-Interneurons at these referral pain sites can release enkephalin, nor, GABA, and glycine to block the referred pain
Neuropeptides
-many primary afferent nerve terminals that synapse on the CNS for pain carry the neurotramsitter substance P
-others are glutamate
-Other neurons synapse on the terminal to modulate the signal like enkephalinergic interneuron and these contain opiates
-Enkephalins which are endogenous opioids bind primary afferent nociceptive terminal and block inward calcium flux needed to release substance P
-substance P is a 11 amino acid neuropeptide that can be found at the dorsal horn or free nerve endings
Drugs for Substance P
-drugs have been created to inhibit substance P release at free nerve endings
-You can use capsaicin or anything that stimulates TrpV receptors to deplete the nerves of substance P, eventually creating an analgesic effect
Descending Analgesic Pathway
-originates in the midbrain and moves through the medulla to the spinal cord
-fibers whose terminals contain serotonin (5-HT) or norepinephrine synapse with the enkephalin interneuons in the spinal and lower medullary dorsal horns.
-This stimulates the interneurons to release enkephalins which blocks substance P release on primary afferent nociceptors
Descending Analgesic Pathway
-can be activated by pain or stress to trigger release of endorphins from the pituitary gland into systemic circulation
-These endogenous opioids activate descending analgesic pathways at the periaqueductal gray, the nucleus raphe magnum, and the medullary and spinal dorsal horns
-so seratonin can cause stimulate pain in the peripheral primary afferent nerve by release at free nerve endings, OR it can inhibit pain in descending analgesic pathways by stimulating interneurons
Opioids
-natural opiates come from the poppy plant and these look like endorphins/enkephalins (morphine, codeine, oxycodone)
-We also make synthetic opioids like methadone, meperidine, and propoxyphene
-There are 3 opioid receptors in the body; mu, kappa, and sigma (oxycotin binds to mu for repiratory depression)
-If too much of an opioid consumed doctors use opioid receptor antagonist like naloxone which bind the receptor strongly. This one is a good morphine analog
Large Myelinated Neurons
-when you bang your knee you rub the area for pain relief
-When you rub your knee you can stimulate the large myelinated periphery neurons which can activate enkephalin interneurons to release endogenous opioids
-acupuncture strives for the same goals
Reflexes
-you can have motor and sympathetic reflexes
-stimulated primary afferent nociceptors can synapse with sympathetic preganglioning nerve fibers at the dorsal horn to stimulate blood vessel constrictions and enhance pain
-These same cutaneous nociceptors can synapse with efferent nerve fibers leaving the cord to synapse with skeletal muscle
Membrane and Transport Overview
-membrane act as permeability barrier to selectively control entry and exit
-membranes are phospholipid bilayers (5nm) with proteins embedded and the protein/lipid location is very structured
Types of Membrane Lipids
-a fatty acid chain connected to a glycerol, phosphate, and polar head group
-all of these were amphipathic
1) Phospholipids (75%) - choline-phospholipids (sphingomyelin) and amino-phospholipids (phosphatidylserine)
2) Cholesterol (20%) - Adds stiffness and assist in protein clustering
3) Glycolipid (2-3%) - Present in outer leaflet important for cell signaling and Ab binding
-lipid bilayer is NOT symetrical - external glycolipids and sphingomyelin and internal phosphatidyl-X
Lipid Rafts
-clusters of cholesterol, proteins, and sphingolipids
-Cholesterol and spinolipids with the help of caveoloe cluster together proteins that work together in a signaling process - enzymes, receptors
-raft disruption in gingival epithelial cells prevents P. Gingivitis membrane vesicle from entering cell and signaling
Membrane Proteins
1) Integral - span bilayer
2) Peripheral - restrcited to 1 side and either move throughout membrane or anchored to a lipid

-membrane proteins function as transporters (pumps, channels, carriers), receptors, enzymes, structural, and glycoproteins which bind Abs
Membrane Transport
-membranes are selective semipermeable barriers
-charged molecules need help, small nonpolar go right through

Passive - No energy required
1) Simple Diffusion -move due to random thermal Brownian motion. Good for short distance
2) Facilitated Diffusion - Uses a channel or carrier to move large or charged particles

Active - Requires energy - divided into primary and secondary
Fick's First Law of DIffusion
-diffusion is proportional to area of the membrane and difference in solute conc between the 2 sides
-diffusion time increases with the square of distance
J = -DA (deltaC/deltaX)
J = rate of diffusion in moles or grams/unit time
D = diffusion coefficient of the solute. Inversely proportional to the size and charge of the particle (lipid solubility) and viscosity of the solvent
A = membrane area
deltaX = conc difference across the membrane
deltaC = thickeness of membrane
Facilitated Diffusion
-solutes move down their electrochemical grandients
-Facilitated diffusion enzymes exibit a Km and can reach a Vmax (unlike simple diffusion)
-Carriers and channels exhibit chemical and stereo specificity and be competitively inhibited

Carriers - carrier proteins exibit "ping-pong" conformational change

Channels: Ions flow through the pore "downhill"
-some channels are always open, some require a conformation change by voltage, ligand, or stretch
Active Transport
-requires energy to move solutes against their gradients
-Proteins exhibit Vmax and chemical/stereo-specificity
-primary uses ATP through transporters being ATPases
-secondary couples energy from gradients. Use energy to get one molecule in, and as that molecule diffuses it lets another molecule in
Na-K-ATPase Pump
-Uses a lot of cellular ATP
-used to get up gradients
-Pumps 3 Na+ out of the cell and 2 K+ into the cell. This makes Na+ higher outside the cell and K+ higher inside the cell
-The pump is electrogenic since there is a net change in charge
-phos/dephos create allosteric change altering protein structure (open/close flap)
1) 3 Na+ bind to internal site
2) ATPase phosphorylzes pump
3) Phosphorylation exposes Na to outside and assist in their release
4) K+ now can bind to site
5) K+ stimulates dephosphorylation
6) Pump returns to original conformation and releases K+
-ouabain can bind the extracellular side to block the pump. Used clinically to slow the heart
v-HATPase
-a pump that moves H+ across gradient, used in golgi and lysosome since they need to be acidic. In osteoclast sealing zone too
-KO mice or with bafilomycin don't have tooth development
-Has a portion that hydrolyzes ATP and a portion that moves H+
-Bafilomycin blocks the pump and you see a raise in pH
-v-HATPase used to balance the charge in synaptic vesicles filled with negatively charged neurotransmitters
-the pump in the parietal stomach cells can increase acidity too much leading to tooth decay so some therapies try to block this pump in the stomach to raise pH
Secondary Active Transport
-the downhill gradient of one particle is coupled to provide energy for another particle to move uphill on gradient
-NO ATP is used in this part of the process. But to create the huge downhill gradient we must use ATP
-If direction of movement same it is symport, if opposite it is antiport
Ex: Na+/Glucose in stomach - Na downhill, G-uphill
1) Na binds protein
2) Na binding opens a glucose binding spot
3) Glucose binding creates a carrier conformtation change so molecules are inside
4) Na is released into the cytosol and glucose follows, Na is then pumped out of the cell using Na-K-ATPase pump
Na+/H+ Antiporter
-to keep proton level below gradient
-important in taste bud cells for sour taste
Symport - Na/Glucose in stomach
Antiport - Na/K on plasma membrane
H+-K+ ATPase in gastric mucosa and renal tubules
Active/Passive Help
1) The Na/K pump to establish the gradients is primary active transport
2) The energy of Na is used to get glucose into the intestinal epithelial cell using secondary active transport
3) Using facilitated diffusion with a carrier glucose flows down its gradient from epithelial cell to the lumern
Osmosis
-goes from high solute conc to low solute conc to equal concentration
-osmotic pressure is the pressure needed to stop water movement
-osmoslarity is the concentration of solute particles per liter
Osmotic Pressure
pie = RT phi ic
RT = ideal gas constant * the absolute temperature = 22.4atm
phi = osmotic coefficient
i = ions formed by dissociation
c = molar concentration of solution

osmolarity = phi *i *c
Aquaporins
-because water is polar, it has to cross the cell membrane using aquaporins (water channels)
-pore stabilized by nonpolar amino acid facing out and polar facing in
-in Sjorgen's syndrome there is a defective AQP5 so water cannot get across the membrane and there is a reduced saliva secretion
Typical Membrane Ion Concentrations
-measured in mM
-Na+ greater outside
-K+ greater inside
-Cl- greater outside
-Mg++ greater outside
-Ca++ greater outside

Chemical driving force of solute across semipermeable membrane is (chemical or concentration gradient):
=-RT ln ([G]i/[G]o) inside and outside
Electrochemical Gradients
-ions have chemical and electrical gradients that must be balanced
-chemical potential gradients move from highest conc to lowest
-electrical potential gradients move towards opposite (cations move towards ions)
-if equal number of K and Cl on one side and membrane permeable to K. The chemical gradient will drive K to the other side, as this happens the electrical gradient driving it back will increase. Once the chemical (concentration) and electrical gradient are equal there will be no net movement
FIguring Out Nerst
Electrical energy = zFV
z= valence (charge)
F= faraday constant (charge/ion)
V= voltage across membrane

-at equilibrium a molecules chemical and electrical energy inside/outside cell is equal
1) zFVi + RT ln (Ki) = zFVo + RT ln (Ko)
2) deltaV = -RT/Fz * ln [K]i/[K]o

-equation 2 is the Nernst equation which lets you balance the electrical and chemical driving forces for permanent ions

-at body temperature when K is at equilibrium the equation to know is

Ex= -60/z log [Ki)/(ko)
-Ex is expressed in mV
-for z you use charge and valence (Cl- is -1, Calcium is +2)
-Ex is membrane potential at which there is no ion flow when inside XmV in respect to outside (always inside to outside)
-For a catio negative value means there is more inside that wants to leave so you need the Ex outside to reach equilibrium. For a anion the opposite is true
-For our example of sodium with more outside than inside and a Ex of +60. We need the inside to be +60 compared to the outside for no sodium to flow. At +60 inside the electrical charge overrides the chemical gradient
-For chloride there is more outside than inside and the Ex is -68. We need inside to be -68 compared to outside (or outside +68 compare to inside) to stop chloride from moving. Makes sense cause if outside was +68 then negative chloride would electrical want to stay outside
-bigger Ek indicates greater disparity in the concentration so it wants to move more and requires more to keep from moving
Goldman-Hodgkin-Katz (GHK) equation
-typical membrane has a -60mV charge (inside -60 more than outside)
-the permeability of the membrane to different ions varies (different permeability to calcium than chloride); however, the more permeable the membrane is to a ion the more it contributes to the potential (loudest douche at a party)
-the GHK equation helps decide the contribution of each ion to the membrane potential
GHK Additional
Pna[Na]i/Pna[Na]o the P is the realtive membrane permeability to the ion
-for cations it is inside/outside and for anions it is outside/inside
-brackets is concentration
-Add them all up
Donna Equilibrium
-used to move cell closer to a real cell by considering the osmotic and electrochemical gradients
-tells us how water and ions are distributed across the membrane
Rules:
1) Outside solution has no net charge
2) Of ions AT equilbirium
[CatA]outside/[CatA]inside = [CatB]outside/[CatB]inside = [AnC]inside/[AnC]outisde
3. Inside solution has no net charge
4. Osmotic pressure equal if water is permeable

a/c make the electrical gradient equal
b "donnan ratio" is because the ratio is the same if at equilibrium and Nerst potentials the same
Donnan Example
Ko=X, Ki=X
Clo=50, Cli=10
sucrose=X, protein=X
step 1: read what membrane permeable to. Permeable to water, K, and Cl
1) Since no net charge outside Ko balance -50 so it equals 50
2) Since ratios are equal
Ko[50]/Ki[X]=Cli[10]/Cli[50]
Ki= 250
3. For no net charge inside the Cl=-10 and the K=+250 so the balance is off 240. Therefore the protein is 240
4. To make osmotic pressure equal then equal solutes on both sides, count them up
Outside = 50 + 50 = 100
Inside = 240 + 10 + 250 = 500
inbalance of 400 so sucrose = 400
Donnan In Real World
-impermeable molecules like intracellular anionic proteins make it possible for the ions to be at equilibrium while their concentration are not
-if the ions had to be at balance then osmotic forces would be too much
-Na/K pump helps keep Na outside and water follows
What sets resting membrane potential at -60mV??
1) Negatively charged proteins are impermeable
2) Na+ K+ pump keeps Na high outside the cell
3) Large K conductive which is opposite of membrane potential
-these allow the intracellular and extracellular ion conc to be very different
-These also create large electrochemical gradients which the cell uses to signal quickly like in voltage gates and firing
Membrane Random Summary
-don't need a large ion conc difference to get membrane potential or change voltage
-osmotic pressure equal if water permeable
-if ion X is at equilibrium then Ex=Vm, otherside ions move down gradient or are pumped against it to maintain potential
-the more permeable a cell is to a particular ion, the more Vm moves to Ex
Nernst: Gives the membrane potential at which ions are in equilibrium or a given concentration
GHK: sums the contributions of multiple ions based on their conc and permeabiliy to give the membrane potential
3: Donnon balance out electrochemical and osmotic gradients and takes into account impermeable protein anions
Ion Channels
-K+ channel has 4 subunits, a pore, and voltage sensors which open pore in response to change in membrane voltage
-subunits each have 6 transmembrane units with hydrophobic inside and hydrophilic on extracellular face and inside the pore
Characteristics of an Ion Channel
1) Gates open and close pores
- can be open via second messenger (include phosphate), neurtransmitter binding, and voltage change through cell membrane change. All lead to allosteric change in ion pore
2) They are selective and pass ions - due to charge and size - at certain speeds
-have selectivity filter inside
3) They can become inactivated after conductance
4) They can become blocked
-use patch clamp to measure activity from a single channel
Ion Channels 2
1) Selectivity - Can determine which ion flows through channel by seeing the voltage at which no current, equilibrium.
2) Conductance/Resistance - conductance is how quickly it can pass through a channel. Resistance is opposite.
-Each channel is different, a greater conductance let more ions through per second (also a bigger current)
-Current is constant for a given channel at a given gradient
-To increase total current across membrane at more open channels or increase time they are open
Ion Channels 3
-channel can be closed, open, and inactive, all totally different conformation
-Protein loops moves when the channel is open. There is also a inactivation site that the protein loop can move to to inactivate the channel (ball and chain model)
-channel blocker binds to channel so no ions can pass. Drugs like lidocaine block the sodium channels
Membrane Potential
-use voltage clamp to measure electrical signal for nerve
-since ion has a nerst potential you can measure voltage needed to maintain potential
-optical measurements are great to see location and signal course
Action Potential
-time dependent changes in the permeability to Na+ and K+ underlie action potential
1) Resting membrane at -90mV based on electrochemical potential. Very close to K+ Nearnst Potential so K+ permeability domaintes
2) As membrane becomes positive it is depolarized.
3) Once it crosses a threshold it depolarizes quickly. Na+ permeability dominates so membrane potential near Na+ nearnst
4) It will repolarize past the original -90mV, this is the refractory period. During this period the influence on potential from Na+ decrease since permeability decrease. At the same time permeability to K+ increases and greater permeability at refractory period
Action Potential 2
-conductance in action potential is related to permeability. Na/K tug-of-war over conductance drives the action potential
1. at first the permeability/conductance of K>Na so cell at -90mV
2. action potential due to a switch. Na+ permeability becomesd larger than K leading to depolarization. The permeability increases for Na as sodium channels are opened. As channels open the cell depolarizes further leading to a positive feedback-key to rapid depolarization
3. During depolarization the K channels also open but more slowly than the sodium
4. The influence of sodium channels are short because they go inactive with time and remain shut during the refractory period
5. After Na shuts down, the K still opening. The K channels shut more slowly as the membrane gets more negative
Additional Action Potential
-as the Na channels open and it's permeability/conductance increase the cell is depolarized in a feedback loop that continues to open more sodium channels (sodium rushes in)
-at the same time slow K+ channels are opened and K rushes out
-Eventually the Na+ channels close at the overshoot and the K+ channels help repolarize the cell until both sodium and potassium channels are closed (refractory period)
Voltage-Gated Ion Channels
-ion channels opened by neurotransmitted, voltage change, and second messengers
-I believe that the sodium channels only close when enough K channels are open to hyperpolarize the cell
Ion Channel
-4 subunits with 6 transmembrane
-Sodium channels are all linked, K+ are individual polypeptides
-Segment 4 is the voltage sensor with charged amino acids. This is also the gate
-Btw D3-D4 is the IFM (isoleucine, phenylalanine, methionine) inactivating ball which flips into pore openeing and stops current flow
-often the receptor during hyperpolarizes can switch from open to inactivated
Working Na Channel
1) At resting membrane potential the D4 voltage-sensor keeps receptor closed, even while inactivation gate open
2) Depolarized membrane brings in positive charged molecules which repel the voltage sensor causing it to open and current flow (conductance)
3) After a few the IFM will flip in do time-dependent inactivation. The IFM cannot flip into inactivation until the positive charge cause an allosteric change moving S4 which opens the gate and opens the inactivation site
Action Potential Shapes
-influenced by distribution of ion channels
1) Cardiac - Has calcium with a high nernst potential due to its permeability. Helps to prolong action potential
2) Skeletal Muscie
3) Motoneuron
Cardiac Action Potential
-Cardiac ventricle has calcium channels with a high nerst potential (talk loudly at the party) which functions to prolong the action potential. Extracellular calcium critical for heart contraction
-The long action potential is due to the slow inward Ca++ current through the voltage-gated L-type Ca2+ channel. This triggers release of Ca from the sarcoplasm reticulum which is needed for the contraction. Without the L-type calcium channels there would be a shorter action potential and no contraction
-The long depolarizing plateau is needed for a longer contraction to pump blood out
-eventually the battle between Vm of Eca and Ek goes in K+ favor and the cell repolarizes
Cardiac Action Potential 2
Phase 0: Na+ enters the cell and it depolarizes
Phase 2: Depolarization opens the Ltype and DHP Ca channels and Ca enters the cell down its gradient to initiate contraction (l-type long and slow)
Phase 3: K channels open more slowly to repolarize cell by K+ exiting. Eventually the L-type Ca channels close and Ek wins
Spontaneous Rhythmicity
-SA node
-instead of usual potential channel you have iFunny (permeable to sodium and potassium) leads to a slow depolarization (phase 4)
-At -50mV the transient T-type Ca open to depolarize further
-At -40mV the L-type Calcium channel open to drive it to threshold and action potential (phase 0)
-K-channels open and cell is repolarizied (phase 3). Remember as Ca close the only other option is iFunny so the cell isn't completely repolarizing because Na is also rushing in. Kind of a slow repolarization, a tug-of-war
-the cell is continually depolarizing, NO steady state
Ion Channel Pathology
1) Long QT Syndrome - there is a mutation in the K+ channels leading to reduced conductance and weak, delayed repolarization
-This distorts the rhythm and a new AP kicks in before the membrane fully repolarized
-Because it takes so long to pull the membrane potential towards Ek there is a delay between the Q (begin action potential) and T waves
-seen in cystic fibrosis
2) Erythermalgia - Mutations in Na+ channels cause it to be more active. The sodium channel that respond to pain in the dorsal root ganglion fire more so there is more pain there
Action Potential Review
1) Resting membrane potential dominated by Ek
2) Rising phase of AP dominated by a increase in the permeability of Na (Pna) until it reaches Ena
3) THe repolarizing is done by a increase in Pk until it reaches Ek
4) The refractory period is due to a INACTIVATION of the sodium channels
Nerve Anatomy
1) Dendrites - Receive signals and convey it to the soma (receptor region). Have dendritic spines which allow additional synapses to gather extra info and these are plastic, can change on the level of input. Grow/shrink in life
2) Soma - Collects signal from dendritie and sends it to the axon. Has nissl bodies which are collections of ribosomes for protein synthesis. Dendrite electrical signal can change nuclear transcriptrion. Needs losts of housekeeping to degrade/rebuild material
Nerve Anatomy 2 - Axon
-axon hillock (no nissl bodies) has lots of sodium channels to convert a graded potential to the action potential. Where the conductive region begins
-Axon transmit electrical signal to the effector region (end organ)
-Tons of proteins, GF, and waste goes to and from the soma from here. Without axon no GF reach soma and it can die
Nerve Signals
-dendrites role is input and processing a passive signal to the soma
-the soma processes and a signal and is involved in maintainence
-axon isn't just passive, it modulates the signal and is the cells output
Depolarization
1) There is a passive/active flow of the depolarizing current which moves additional voltage sensors to open neighboring Na+ channels helping to propagate the action potential (current can escape nerve through membrane and enter through channel)
-this is a positive feedback cycle where opening Na channels lets Na in the cell which further depolarizes the membrane opening more Na channels
2) The K+ channels open with a delay to repolarize the area. At this time the Na+ channels will become inactivate to make sure that the potential moves in 1 direction
Maintaining the potential
-if the current was only passive the low resistance membrane would allow the current to leak out and the potential would not make it long distance
-This is because our thinner membranes are a large capacitor which makes them less resistant to leakage so it takes a lot of energy to set the membrane potential. This would not allow the AP to move quickly. What we need is a thicker membrane with a lower capacitor and large resistance so it would take less energy to set membrane potential because channel not as leaky.
-So therefore, if only passive current with our cell membranes then the AP could not make it a long distance
Real Nerve Physiology
-to minimize leakage and transmit a super quick AP we have the following mechanisms
1) Increase temperature speeds it up
2) Our axons have a thick diameter to transmit a quicker signal
3) Myelin Sheath - Acts as a conductor to thicken the membrane so the capacitor decreases and resistance increases. Voltage-gated channels at the nodes of Ranvier which help pump in more of a positive charge (has sodium channels) and jump the action potential - this is a saltatory propagation
-myelin phospholipid membrane made by periphery schwann cells and CNS oligodendrocytes decrease capacitance and increase resistance to increase transmission 100 fold
-myelin increase resistance 5000x and decrease capacitance 50x (charge between inner/outer membrane further apart lowers capacitance)
-With only myelin sheath the signal would go longer but eventually (even though low capacitance) it would leak. The nodes allow a jump to propagate the signal
Myelin Pathology
-in multiple sclerosis there is a auto-immune destruction of myelin
-this makes the action potential slow and the neurons develop damage
Synaptic Transmission Overview
1. Presynaptic Terminal - The electrical signal triggers voltage-related transmitter release (chemical signal)
2. Synaptic Cleft - DIffusion of neurotransmitter
3. Postsynaptic Region - Change back from chemical to electrical signal by receptors that bind neurotransmitter
Presynaptic Terminal
1) Voltage-gated channels conduct AP from the axon to the terminal
2) The terminal depolarization opensvoltage-gated calcium channels which bring calcium into the cell
3) The calcium helps synaptic vesicles with neurotransmitter at the membrane to fuse with it and release into the synaptic cleft
-the process is made more efficient because the calcium channels are near the already docked vesicles
-The vesicle is a phospholipid bilayer and has a H+-ATPase pump to neutralize negative neurotransmitters
- Calmodulin and synapsin 1 help bring the vesicle to the docking site
-Synaptotagmin helps bind to the docking site. It binds calcium to initiate vesicle release
Vesicle Endocytosis
0) Once synapsin 1 and calmodulin target the membrane the cell's v-SNARE binds the membrane t-SNARE to dock the complex. This is reversible until calcium is released
1) In the absence of Ca++ synaptotagmin (and brevin) C2B binds weakly to PIP2 in target membrane (part of v-SNARE complex)
2) With Ca there is a allosteric change in taglin and the SNARES twist together and the C2 domains (A+B) penetrate the membrane
3) Vesicle fuses with the membrane and releases content. Not a complete fusion "kiss and run" hemifusion. Will endocytos back into the presynaptic terminal
4) Botox cleaves the v-SNARE/t-SNARE complex to prevent NT release. CLeaves SNAP-25 (t), Syntaxin(t), and synaptobrevin (v)
Diffusion of NT
-NT move across small synaptic cleft to postsynaptic membrane
-synaptic cleft filled with matrix and proteins
-NT either taken up, inactivated by enzymes in the cleft like cholinesterase, or return to presyanptic terminal (choline returns). Can also diffuse away from the terminal.
-The cleft matrix is designed to control NT release in a temporal and spatial manner
Postsynaptic Region
-postsynaptic receptors bind NT and convert chemical back to electrical signal
-receptors are ionotrophic or metabotrophic
1) Ionotrophic - ion channel open by binding of NT (ligand-gated). This leads to a rapid but short signal
2) Metabotrophic - NT binds a GPCR which activates second messenger pathway. This can open a ion channel to simulate the ionotrophic affect or have a long-term transcription mediated effect
-the result of metabotrophic stimulation is slow synaptic potential and long-term effects
Postsynaptic Binding Results
-the ion flowing through the channel determines whether to effect is excitatory (EPSP) or inhibitory (IPSP)
-Na+ is usually excitatory while K/Cl is inhibitory under the right condition
-eventually the postsynaptic membrane changes Vm in one direction or another
Ionotrophic Receptor
-ligand gated ion channels
-short, rapid signal
1) NMDA - are Na/Ca permeable to depolarize the cell (EPSP), common in the CNS
-have multiple subunits that mix and match to give particular characteristics
-reuiqres binding of co-factor glycine (S1)
-Can be voltage-dependently blocked by Mg2+ in pore and voltage-independently blocked by Zn on 2A
-Subunit 2B binds glutamate and polyamines to modify conductance

2) GABA - Respond to NT GABA to bring Cl- into the cell and hyperpolarize

3) P2X - Respond to NT ATP and seen in dental pain.
-found in dental pulp nerves and responds to ATP which might be released from inflammed dental tissue
Metabotrophic Receptors
-includes GPCR and tyrosine kinase receptors that initiate multiple steps before changing potential
-much slower than ionotrophic but can have longer modulating effect
-links to depolarize/hyperpolarize more variable because additional steps
-Once GPCR binds NT there is a allosteric conf-C released Ga from Gby. Ga gets GTP and active to do different things in different cells
-can activate adenylate cyclase
-can activate PLC to cleave PIP2 into DAG and IP3 which releases intracellular calcium (imp for protein activation (PKC) and gene transcription)
Postsynaptic Density
-at the postsynaptic intracellular membrane is a molecular scaffold to keep the receptors in place to help mediate the effects
-Examples include PSD, cytoskeletal elements, cluster of ionotrophic/metabotrophic
-important in long-term potential of NMDA-CaMKII transcription
Neuromuscular Junction
-the NT is acetylcholine and the receptor is nicotinic N cholinergic
-nicotinic is a 5-subunit ligand-gated ion channel pore, requires 2 ACh to activate and bring in Na+
-nicotinic receptor hangs on postsynaptic junctional folds
-acetylcholinesterase hangs on basal lamina to cleave ACh

-synaptic drugs can act at many sites
1) Production of NT
2) The production/leakage of vesicles
3) The release/prevention of the vesicle
4) The activation/inhibition of autoreceptors
5) Postsynaptic receptor increase/decrease
Electrical Synapses
-besides chemical synapses, the cells can transmit a electrical synapse using a gap junction (faster, bidirectional)
-It takes 12 connexins to make 2 connexons to make 1 gap junction
-gap junctions allow sharing in addition to electrical signal small compounds
-gap junction important in glial-glial or glial-neuronal interactions
Neuronal Transmission
-Inhibitory post-synaptic potential hyperpolarizes membrane with K+ out or Cl- in
-Excitatory post-synaptic depolarizes the membrane with Na+/Ca++ in
-NT release can happen spontaneously through miniature excitatory post-synaptic potential (MEPSP)
Summation
-CNS requires multiple synaptic events for a action potential
-takes a collection of synaptic events, vesicles, and NT to reach threshold
-In the CNS each synaptic EVENT depolarizes the cell.5-1mV and requires multiple for at least a 10-20mV depolarization
-The effectiveness of summing dependent on where and when release is
More Neuronal Transmission
Presynaptic Inhibition - Inhibitory synapses can contact presynaptic terminals to prevent NT release, important in pain management
-Molecules like GABA, glycine, endorphins, and enkephalins can hyperpolarize the cell by allowing Cl to enter or prevent depolarization by blocking Ca/Na channels

Spation Summation: Stimuli from multiple presynaptic neurons sum together to reach AP. Can also cancel each other out if EPSP/IPSP

Temporal Summation: Stimulus from NT only last a short while. If multiple NT from same presynaptic terminal come at the same time they can add for AP. If they come at different times then even same amount of NT won't make a AP
-the decision on whether the graded potential leads to a AP is determined at the axon hillock if they can fire voltage-gated Na channels
-takes the summation/inhibition of all the dendrites into account
-Not only are dendrite numbers and signals important, but also the distance since a closer dendrite will loose less signal due to leakage
Neuronal Transmission 4
Adaption - change in responsiveness over time
-in rapidly adapting neurons on and off are signaled, while in slowly adapting neurosn the response can be sustained (slow depolarizing)

Facilitation: Each time a signal reaches the presynaptic terminal calcium remains for period of time whether or not a threshold was released. Therefore, during the next round, since calcium already there and the synaptic vesicles ready to be released, the same stimulus CAN lead to a greater change vesciel release and post synaptic response.
-At same time following a sub-threshold input, the post synaptic nerve is facilitated and will produce a large response given the next imput

Synaptic Efficacy - How efficient coupling between neurons is. Depends on many factors like pH (higher more excitable), hypoxia (inhibitory) and anesthetics (inhibitory). Changes in efficacy underlie learning and memory

Synaptic Fatigue - If you over excite a cell it can deplete its NT and become nonresponsive. Can be due to a loss in ionic gradients
Neurotransmitters
To be a neurotransmitter...
1) Must be synthesized in neuron and stored in terminal
2) Upon depolarization NT released
3) Application of NT exogenously must generate same response as normal conditions

1. Amines
a. Catecholamines - dopamine (movement, motivation), epinephinre (fight/flight), and norepinephrine (stress, attention)
b. Cholinergic - acetylcholine does peripheral muscle contraction and CNS learning and short term memory (release at NMJ)
c. Indolamine - seratonin (anger, mood) and histamine (sleep, sex, immune)
Neurotransmitters 2
Amino Acids
a. Excitatory - glutamate and aspartate. Bring Na+ into cell, good for learning and memory
b. Inhibitory: Glycine and GABA - Bring Cl- into the cell

3. Neuropeptides - Very potent because they diffuse to great distances and work at low concentrations. Usually act at GPCR metabotrophic receptor
Substance P - important for pain
Neuropeptide Y
Somatostatin
Vasoactive Intestinal Polypeptide
Neurotransmitter 3
4. Opioids/Opiates - endorphin, enkephalin. Work at CNS and GI and can be ESPS/ISPS depending on target. Can act presynaptically. Enkephalin important for dental anesthesia

5. Other - Nitric oxide, cAMP, cGMP, and ATP
-Gaseous NT have diff prop than water soluble like moving backward/forward btw membranes
Somatosensory System
-how we perceive body sensations like touch, temperature, pain, and proprioception
-function to protect us, distinguish noxious from innocuous stimuli/sensations, and to process inputs that contact our body
-all inputs except smell go through the thalamas to the cortex
Somatosensory Receptor Overview
1) Touch - the mechanoreceptors sense light/heavy touch and vibrations. Accomplish by Meissner Corpuscles, Merkel Cells, Pacinian Corpuscles, Ruffini Corpuscles, Hair Tollicles, and Tactile Nerve Endings

2. Proprioception - Proprioceptors distinguish static vs. dynamic position. The receptors are joint receptors (position of a limb), muscle spindles (length of muscle fiber) and golgi tendon organ (tension on a muscle)

3. Pain - Nociceptors distinguish sharp, quick, localized vs. dull,slow, diffuse pain via free nerve endings

4. Temperature - Thermoreceptors distinguish warm vs. cold using free nerve endings
Mechanoreceptors of the Skin
-2 kinds of skin; hairy and glaberous (palms and feet)
-tactile nerves classified on the size of their receptive field. Type I is a small field (superficial to skin) and type II is a large field (deep to skin)
-due to this the density of a type of receptor varies between receptors and area of skin
-Tactile fibers also vary in their rate of adaptation between fast adapting and slow adapting
-each type of skin and area has a different array of receptors with these varying properties
Type of Receptors in Detail
-F = fast adapting, S= slow adapting
-1 = small field (superficial), 2 = large field (deep)
-fast adapting has no static response (fire only when on or off - feeling goes away eventually) and slow has a static response (fires throughout - sensation remains)
1) Meissners - FAI. Feels tapping at glabrous skin
2) Pacini - FAII. Feel vibrations at subcutaneous intramuscular
3) Merkel - SAI. Feel pressure/texture in all skin
4) Ruffini - SAII. Feels stretch in all skin
5) Hair Receptor - FA or SA. Feel brushing on hairy skin
Mechanoreceptor Density
-dyanmic vibrations (FA) is good for knowing you're moving or a material roughness. Static vibration good for horses coming
-Density changes with body part and where on that body part
Hand:
1) Merkel - Density decreases from fingertip to palm.
2) Meissner - Fingertip highest, finger/palm equal
3) Ruffini's - More on palm/finger than fingertip
4) Pacinian - Dense on fingertip and less on rest
Two-Point Discrimination
-good measurement of mechanoreceptor sensitivity. Find the distance on a body part where you can distinguish 2 fine wires
-Mouth and hand very sensitive, back/upper arm/thigh not as sensitive
-can also use grating orientation threshold, or letter recognition threshold
A Little Tongue...
-the lingual papilla density and size differs between people (higher density = more sensitive to bitter)
Proprioceptors
-provides information about static and dynamic limb position
1) Golgi Tendon Organ - Nerves that innervate the tendon. As you fill mug with beer even though hand doesn't move the organ is tensed
2) Muscle Spindle Fiber - Within muscle fiber you have intrafuscal muscle innervated by nerves. When the muscle changes in length it stretches the neurons
3) Joint Fiber - Access the position of the limb. When beer added and your hand falls you feel it in the joint fiber and muscle spindle fibers
Thermal Receptors
-we have several TRP channels that are active at different temperatures
-example of label-line coding, one receptor, 1 temperature. Opposite of cross fiber pattern system where collection of receptors gives us a sensation
Trp
-Code for temperature and pain (nociceptor receptor as well)
-That's why capsaicin feels hot, activates thermal receptor, and menthol feels cool.
-represent cold/warm until extreme temp then express pain
Somatosensory Innervation
-the somatosensory nerve fibers course from the body part to the dorsal root ganglion
-a particular part of the body is innervated by nerve branches that have zones called dermatomes
-head/mouth is trigeminal, rest is spinal including lower mandible and tragus
Somatosensory Sensory Pathways
-inputs are grouped into neural tracts
-brain cortex deals with contralateral world so all pathways decussate eventually
-info from body processed separately from face
-all sensory info must synapse through thalamus
-touch and proprioception in one bundle and pain/temperature in another bundle. Travel together
-touch/proprioception come through the dorsal column in the back of the spine through/medial lemniscus and doesn't synapse to the otherside until the brain stem. Carry discriminative touch
-innervate by AB fibers
-temperature/pain move through the anterolateral column or spinothalamic pathway and synapse to otherside immediately. Carry crude touch
-input is unmyelinated C fibers which synapse slow, unlocalizable, dull pain/temp as well as alpha/delta myelinated fibers which synapse fast, sharp, and localizable pain/temp
Trigeminal System
-caries information about touch, proprioception, pain, and temperature from the face
Dorsal Column/Medial Lamniscus Pathway
-carries large A-beta myelinated fibers up spinal column
-includes touch, vibration, propriosensation, and light pressure
-called medial lamniscus cause it crosses over in that part of the medulla
-legs input cross over at gracile fasciculus and arm at cuneate fasciculus of medulla
Anterolateral/Spinothalamic Pathway
-carried on small A-delta myelinated and unmyelinated C-fibers
-caries pain, thermal sensation, deep pressure, tickle, itch, and unlocalized touch (why you rub skin after banging)
-Crosses spinal cord immediately
Trigeminal System
-still contralateral inputs
-main sensory or principal nucleus of V carries discriminative touch and proprioception
-spinal nucleus of V carries crude touch, pain, and temperature
Brain Organization
-Wilder Penfield showed that every axon of the cortex gets share of brain. More sensitive areas get more brain
-sulcus divide brain to front/back lobe
Pain Sensation
-occurs at free nerve endings due to neuropeptides, cell damage releasing inflammatory mediators, a lower pH - Why sticking tongue in coke so painful, CO2 lowers pH
-fast/sharp pain carried by superficial A-delta fibers
-slow/dull pain carried by unmeylinated deep C-fibers
Neural Coding
-different fibers and combination of fibers code pain (histamine + capsaicin = itch)
-capsaicin activates a cation channel to depolarize cell for signal
-specific Trp ion channel are sensitive to different stimuli (heat, capsaicin, acidic pH, cold, menthol). These act on ionotrophic channel
-some mediators act on metabotrophc channel GPCR to activate 2nd messenger pathway (bradykinin, serotonin, adenosine, histamine)
-the pathway can activate gene transcription and also activate some of the ionotrophic pathways like bradykinin eventually lead to TRPV1
Random Wrappings...
-hyperalgesia people have a lower threshold for pain
-allodynia people have a higher threshold for pain
-Due to cross-fber coding different thermal, nociceptive, and mechanical signals can cross each other out or amplify
Lesions
-spinal lesions provide ipsilateral and contralateral loss and complete loss at that level of the lesion
-Lesions in pons and above and you loose everything contralaterally
-lesion of cortex you loss everything but pain and crude touch can return
-in posterior parietal syndrome you lose the ability to integrate sensory information from the side of the body opposite lesion, like that side not even there
Brain
-inferior to superior the brain stem includes the medulla, pons, and midbrain
Taste Overview
-taste combines with odor and other oral sensations to produce flavor (flavor is due to perception in the mouth/nose and processing/recognition in the brain)
-taste buds are tongue in the anterior/posterior tongue, soft palate, and pharynx
-60% of taste come from the posterior tongue, the rest is split between anterior tongue and soft palate/pharynx
-also taste receptors in GI tract. Sweet receptor in stomach, liver, and pancreas. In the pancreas the sugar receptor on B-islet helps with insulin metabolism
Papilla
-posterior circumvallate, anterior/dorsal fungiform, and posterior/lateral folliate papilla contains many taste buds, each of which has many taste cells
-the taste bud has a pore that pokes through cornified epithelium to interact with surroundings. Does not contain neurons but cells that behave like neurons and innervated by axons
-Taste buds regenerate frequently in life
-tastes detect..
1) Sweet - calorie rich, carb meal. Taste sugars and artificial sweetners
2) Bitter - toxins
3) Sour - avoid spoiliage, signal tissue damage
4) Salty - Regulate NaCl
5) Umami - Detect amino acids, MSG, glutamate, and nucleotide enhancers
Taste Bud Cells
1) Type I Dark Cells -a few tall microvilli
2) Type II Light Cells - Lots of short microvilli
3) Type III Intermediate Cells - 1 tall/thick microvilli
4) Type IV Basal Cells (not stem)
Taste Receptors
1) Umami - Class 1 Metabotrophic GPCR Heterodimer of T1R1 + T1R3
2) Sweet - Class 1 Metabotrophic GPCR Heterodimer of T1R2 + T1R3
3) Bitter - Class II Metabotrophic GPCR Heterodimer of T2Rs
-sour and salty are most likely ionotrophic receptors
-Sour likely PKD2LI which tastes acids (citric acid)
Taste Transduction
Type II - Release ATP
Type III - Have voltage-gated Ca channels and release serotonin
1) GPCR
-When tastant binds the receptor on the microvilli it will activate a GPCR
-This leads to PLC - IP3 - and Calcium release
-Calcium release triggers voltage-gated TRP channels to bring in Na+ which depolarizes the cell. Other second messengers can directly trigger the channels
-After a certain threshold hemichannels release ATP and serotonin to the surroundings. These bind local nerve endings which send the signal to the brain
2) Ionotrophic - Stimuli act directly on ion channel in apical membrane to depolarize cell and trigger release of ATP/serotonin
-it seems that the receptor on the taste neuron is P2X
Taste and Brain
3 CN for taste
1) CN VII - anterior tongue and soft palate using the chorda tympani and greater petrosal
2) CN IX for posterior tongue using the lingual tonsilar nerve
3) CN X for pharynx using the superior laryngeal nerve
-the information is first processed in the brain stem in the nucleus of the solitary (Gustatory nucleus)
-it then bifurcates dorsally to the thalamus (VPM) and then cortex (gustatory cortex) (lemniscal system) or ventrally to the hypothalamus and amygdala (visceral limbic system)
-in the forebrain you evaluate and make decisions on food. After passing the gustatory nucleus it can also trigger a reflex through brainstem motor and premotor nuclei
Taste Coding
-taste is mainly label line coding, but also cross-fiber pattern coding
Olfactory Overview
-olfactory epithelium is high in the nasal cavity
-olfactory epithelium has increased surface area due to twisting bones called turbinates
-These not onlyincrease SA, they also increase sensitivity, and control temperature/humidity of air
-The olfactory receptor cells are neurons embedded in the epithelium which project axons directly into the brain through the cribiform plate to the olfactory bulb
-The olfactory receptor neurons dendrites end in cilia which residue in the mucus layer
-The cilia contain the receptors to which airborn molecules must go through the mucus and are detected by GPCR on the cilia
Olfactory Histology
-olfactory epithelium has supporting cells which hold the olfactory receptor cells
-the axons carry the signal and synapse at the olfactory bulb in the anterior ventral brain via CN 1
-Some animals have a vomeronasal organ that goes to a accessory olfactory bulb for pheromones
-Odorants can be carried through the nose (orthonasally) or up the back of the throat (retronasally)
Olfactory Signaling
1) Odorant binds the GPCR - Similar to the small T2R GPCR
2) The G-protein activates adenylate cyclase which makes cAMP
-in taste the second messenger was IP3 and in smell it is cAMP
3) cAMP activates nucleotide-gated ion channels to bring in Na/Ca and depolarize the cell
4) Intracellular Ca can also activate chloride channels to send Cl out which further depolarizes the cell and amplifies the signal
Olfactory Signal OFF
1) Phosphodiesterase in the PM can break down cAMP to AMP
2) A Na/Ca exchange sends calcium out and sodium in. Since calcium has an extra charge the cell is repolarized
3) The CNG (cyclic nucleotide gated channel) turns itself off. The calcium it brought it inhibits it so it cannot respond to cAMP anymore
Olfactory Neural Connections
-divided into 4 zones which connect with corresponding zone on the olfactory bulb
-Within the zones the ORN are distinguished by the receptors they have. All of the ORN with the same receptor project to the same glomeruli on the olfacotory bulb
-The olfactory receptor neuron (or sensor neuron OSN) synapse with mitral cells at the specific glomeruli
Olfactory Sharpening and Inhibition
-to help sharpen the neural signal and identify the correct odorant, inhibitory neurons are in the glomeruli. These include periglomerular (go from glomeruli to glomeruli) and granule cell
-A mitral cell will respond to a specific odorant, and the range around that odorant will decrease synapse (respond well to 5-CHO, ok to 6-CHO, and not at all to 7-CHO
-So a mitral cell will respond to a specific stimuli. It is connected via granule cells to neighboring mitral cells. As it binds its odorant, it will inhibit neighbors that bind to similar odorants. If the neighbor is stimulated, it will inhibit the original mitral. In this way the mitral responds to a specific stimulus and the flanking stimuli (look similar) inhibit it
Olfactory Additional
-Odors are likely to be coded by a highly distributed pattern since lesions and removing much of the bulb does not affect them as much
-Input to the cortex not gated by thalamus
-Goes from receptor to bulb to piriform cortex, olfactory tubercle, amygdala, and entorhinal cortex
-From the amygdala it goes to the orbitofrontal cortex, thalamus, and hypothalamus
-From etorhinal cortex it goes to the hippocampus which connects smell to memory