Physiology Lecture (PNS) Flashcards
PNS
Function - Connects the CNS to the limbs + body + Skin + Organs
- PNS = not protected by bone of the BBB
- Divided into the somatic and autonomic nervous system
Location - Outside the CNS (outside the brain and the SC)
CNS vs. PNS
CNS - brain + Spinal cord
PNS - Peripheral nerves
What gives rise to the PNS
Neural crest cells gives rise to PNS during emroyogneisis (PNS comes from from nueronal crest cells)
- Neuronal crest cells = migrate to different places in the body to become PNS (migrate from the dorsal side of the nueronal tube)
Nueronal tube = becomes spinal cord
Characteristics of Nueronal Crest cells
- Nueronal crest cells = transient –> Only found during development
- Nueronal crest cells = stem cells –> differentiates to many nueronal and non-nueronal types of cells
- Example - Becomes all peripheral nerves + glial cells + Dorsal root ganglion + sympathetic/parasympathetic + entric + non-nueronal cells (melanocytes)
Nueronal Crest cell fate
Nueronal crest cells take different pathways + terminate at many peroheral locations + differentiates into many different cell
Moleculares in PNS development
There are many molecules that have been implciated in various steps of PNS development
Steps:
1. Transcription factors (Ngn + NeuroD + Brn3a) –> Determine cell fate and specification
- Example - express Transcription Factors in muscles - can turn muscle cell to nueronal cell
- Nuetrophils and receptors (NGF/TrkA and BDNF/TrkB)
- Determines cell fate and cell survival
- Growth factors/receptors = imoortant for nuronal survival (need in cell culture to keep culture alive)
- Axon guidence molecules (netrins + sema + Silt)
- used for Axonal outgrowth + pathfinding + branhcing + targeting
- Need nuerons to extend axons = need axon guidence molecule
- Can be attractice or repulsive molecules to get axonto target tissue
- Glutamate receptors
- Used for refinment of targeting pattern (once gets to location = need to refine targeting oatter)
Division of PNS
Divides into somatic and autonomic nervous system
Autonomic nervous system
Function - Controls vesiceral functions (heart rate + digestion + breathing + Salivation + sweating + diameter of pupil + urination + Sexual arousal)
Essential for mainating homeostatsis
Divided - into sympathetic + parasympathtic + entric divisions
Major nuerotransmitters - neopinephrine + acytlecholine
Function of Autonmic nervous system
Autonmic = functions largley below level of conciusness
BUT certain events can change the level of autonmic activity (Example - emotional stress + fear + sleep + sexual excitments)
Inervations of Autonomic Nervous system
Autonomic innervates (sends axon) cardiac masucles (control heart beats) + smooth muscles + glads to regulate basic viseral porcesses
ALSO - relays visceral sensory information to CNS
ALSO - induces release of hormones that medate energy metabolism (ex. releas einsulin + glucogon) + releases things that affect cardiovascular functons (Vssopressive - conrtols blood vessle pressur)
Nuerons in Sympathetic
Sympathetic = uses a two nueron system –> Sympathetc preganglionic nuerons –> Preganglionic exit the spinal cord –> Synapse with the post ganglionic nuerons in symathetic ganglion or chromaffin cells in adrenal glands –> Post ganglionic extend their axon to get to the tissue
- Cell bodies aregate to form synapse
Cell body of preganglionic = found in thoracic and lumbar region inside of Spinal cord (then axons extend outside of spinal cord)
Nuerons in Parasympathetic
Parasympathetic = uses a two nueron system –> preganglionic fibers lie in specific nuclei in the brainstem or in the lateral hrons of the spinal cord at the sacral levels –> Axons of preganglionic projects to postganglionic fibers in galanglia (ganglia are close to viceral targets or located in them)
Preganglionic = reside in brainstem/brain or the sacral region of spinal cord —> extend axon –> synapse with cell body with oarasympathtic ganglion
Sympathtic vs. Parasympathtic nueronal synaoses
Sympathetic –> Synapse - ganglion ate far from targets
Parasympathtic –> Synpasic ganaglion are close to their targets
Parasympathetic control vs. Sympathetic control
Parasympathic - controls maintaince of activities that help conserve the body’s energy and is responsible for rest and digest
- Constrict pupils + salivation + decrease heartbeat + constrict brochi + stimulate digestive
Sympathtic divsions - Mos active during times of stress fivering the fight and flight
- Dilates pupil + inhibits salivation + relax bronchi (breathing more) + increase heart rate + inhibits digestion
Parasymoathtic vs. Sympathetic = opposite functions
Enteric Nervous System
Consists of two plexuses embded in the wall of the Tract (Myentreic Plexuys + submuscosul plexus)
- Submucosoul plecues = close to lumen of GI tract
Composed of:
1. Local sensort nuerons that detect chnages in the tension of the gut and the chemical envirnment
2. Interneuons and motor nuerons
- Motor nuerons = conrtols the muscles of the gut wall + galnd secreation + local blood flow
Regulated by the extrinci innervation form the sympathetic and parasympathetic systems
Plexues
Netrowk of nuerons
In enteric system - consists of local sensory nuerons + internuerons + motor nuerons
What is the enteric nervous system considered
Considered the second brain - number of nuerons in the gut > the number of nuerons in the Spinal cord
Semetosensory Somatic nervous system
Function - reponsivle for receivig stimuli from the external and internal envirnments + coordinates body movements
- Acts under concious control
- Somatosensory = Processes toucb + pressure + temperature + pain + itch + muscle contraction + stretch + join position
Intiation and mediation = due to dorsal root gangkion + trigenminal ganglion
Major nuerotransmitter = Glutamate
Function of CRG and trigemnal in somatic nervous system
Dorsal root ganglion + trigeminal ganglion receive and interprets sensory inforation from inside the body and from the envirnments
- Envirnmental sensation = through the skin
Sensory nuerons in somatic nervous
Cell bodies of primart snesory nuerons locate in Dorsal root ganglion –> cel body of sensory form the dorsal root ganglion
How many pairs of DRG are theer
There are 31 pairs of DRG along the spinal cord
- Each gangion inervates a certain region of the body
Image - bulbs by the Spinal cord = DRG –> see the bundles extend out of the gangion
DRG vs. Trigeminal control
Dorsal root ganglion = controls sensory for the whole body + back of head/neck
Trigeminal ganglion = controls sensory for face (Ex. what is active when have migraine)
Axons of primary sensory nuerons
Primary sensory nuerons in DRG have two axons (neuron is psudedounipolar)
Axon 1 - projects to the periphery (organs - skin/muscle/joints/verscera) to get snesory information
Axon 2 - Projects to the CNS (Spinal cord)
DRG = outside the spinal cord
DRG - have two cell bodies
Primary sensor nuerons
Neurons in the DRG
Function - first to detect infomration (first to feel in skin)
Secondary nuerons
Spinal cord nuerons
Secondary neurons Decussate (cross the midline) –L axon crosses the midline to the other side of teh spinal cord to go to the thalumus (reason why the left brain controls the right side of body and vica cersa)
Somatic nervous system synapses vs. Autonmic nervous system synapses
Top - Somatic - 1 axon –> goes to the peripheral target and to CNS (to SC)
Bottom - Autonomic - 2 nueron system (preganglionic –> ganglion –> postgangliic –> periphery
Dermatome
The area of skin inervated by a single forsal root
Each pair of DRG sends an axon to different parts of the body – creates dermatomes
Tractile + pain + termapture dermatomes bounderies can be different
Mapping dermatimes
Repsonse of each dorsal root ganglion to different stimuli can be systematically tested and the bounderies of each dermatome can be mapped
map dermatimes by recording nerves and see where they innervatate –> see reponse of each DRG to stimuli –> map bounderies of dermatimes
Overlap of dermatomes
Adjacent dermatomes can overlap because of overlapping adjacent dorsal roots
Each DRG sends an axon —> Axons can branch to cover more area of the skin - at bounderies there can be overlap between where DRG send axons
Skin somatosensory nerve endings
Mechanocorecpetors (slow adpating) –> Mekel cells + ruffiniing endings
Pain/temp (rapidly adapting) –> Meinssner + passinean corpsucles
Free nerve endings - not associated with end organs just axon sent to skin
- Senses pain + temp
Slow vs. rapid adpating
Slow - innervates the area –> nerve first AP during duration of indentation (nerve keeps firing while applying pressure)
Rapid - Nerve first during onset and offset (when pressure is applied and taken off)
Rapid vs. slow adpating - allow syou to feel uintity of pressure/touch
Organs in skin innervted by nerves
There are 4 organs in skin innervated by nerves:
1. Meissners corsulcles
2. pasinean corpsucles
3. Ruffini endings
4. Merckles disks
Different end organs allow nerve to sense different types of sensation
Neurons in the spinal cord
Afferents enter the spinal cord - DRG axons (blue) + decesning afferent from the brain (green)
Nuerons in spinal cord - Projecton uerons (brown) + interneuons (purple_ + effernet neruons (Maroon)
Spinal cord cross sections
Image - Blue on upper left = dorsal horn ; Green on lower left = ventral horn –> BOTH have axons going to spinal cord (going to different regions of the spinal cord)
Image - Right = nuerons within the spinal cord (peripheral axons synapse with spinal cord nuerons_
- Brown line = seocndary axons crossing the midline
Axons = have different termmination based on sensation –> you can guess snesory function based on termination
- Dorsal horn = termpature + pain
- Ventral hron = muscle sensation
Divion of grey matter in spinal cord
Grey matter in spinal cord is subdivided into 10 laminae based on nueronal cytoarchitectire
Example - dorsal horn = pain + temperture + itch + touch
Example #2 - venral hron = controls muscle
order of nuerons in somatic nervous system (How sensroy detects information and sends information to the brain)
Order - Primary nuerons (Dorsal root ganalion detecting information from peripshery) –> Secondary nuerons (SC _ medual) send nueron to thalmus in the brain –> terta=irary nuerons in the thatmus nucleaus which send axon to cortext in brain –> 4 nuerons in cortext
Nerons in somatic = connected ina seriors by their nerve fibers for sensory infomration trasnfering from body to cortext
Have seperate pathways to touch/position vs. pain/tempeture
Two pathways in somatic
Have two major ascedning pathways sending somatic sensory information to the cortxt:
1. pain and Tempeture
2. tact (touch and vibration) + limb perioperceotion
Perioperception
Sensation of body - controled by nerves inervating muscles
Example - close etes and can still touch nose
IF have no perioperception = can’t stand (Ex. geentic issues where you loose nerves = become paralyzed)
Pain and temperture Somatic pathway
Anterolateral system - Axon goe sto spinal cord –> synapse with DRG –> Axon cross midline –> Axon goes to thalumus –> Axon goes to cortext
Acending = goes towards the brain
Tactile/periorperception Somatic pathway
Dorsal column medial lemniscal system - DRG synapsed with seocndary nueron in Spinal cord –> Axon ascedns but different from atherlolateral
Mapping somatosensory information
Sensory information is mapped somatotopically in the primary sensory cortex
Somatotopically - Adjacent area in the body are represnte dby adjacent areas in the cortex (area of the body is next to area of cortext that controls taht area of the body)
ALSO shows strength - bigger area = bigger strength of control
- Ex - representation of perioral region (face) and hand is large in human (because relay on hand and face more than other parts)
How many somatosensory maps can you make
There are multiple primary maps
Maps = anatomically distict - maps are asictaed with different snesory modailitues
Make map by probing different areas and seeing where there is movement in body
Barrel cortext
Part of the somatosensory cortext of rodents
Function - sensory inputs from wiskers
- Rodents = rely on wiskers for sense
Within barrel cortex –> Conatins discerte areas of layer 4 form - layer forms barrels
- Can visualize barrels in histologial staining
Discovery of barrels in rodents
Woolset and Van der Loos discoevred barraels –> Did Methylene blue staining –> found that 1 barrel structure containes 2500 neuerons arranged in a ring like straucture + 1 barrel processes tactile input form one wisker
- # barrels = # of wiskers
Barrel = formed 4 days after birth
Barel Arrangment
Barrels are arranged in pattern correspondong to topography of wiskers
Number of barrels in rodents
Number of barrels = the number of vibrassae (wiskers) on the controlateral side of the face
- one barell : 1 wisker relationship
Barrel experiment in Mice
WT mice - 1 barrel = 1 whisker in patter –> row arrangments correlates well
Mice with extra whisker = have extra barrel –> IF pluck wisker out the barrel disappears
- Shows there are cues from the peripheral (sensory input) –> if lose that peripheral input then lose barrel
Patterns of wiskers throughout other systems
The dicrete pattern of wiskers is replicated throughout the central pathways of the trigeminal system BUT the orientation at each station is dufferent
- Arrangments (having different orientations) allow organisms to know where on the face the information is being sensed + what kind of sensory information is being received (Ex. wiskers moving in certain directins activate specific nerurons in the corresponding barrel)
- Still is always 1:1 ratio
- EXCEPTION - the arrangment is not maintained in the trigeminal ganglion
Example - Face wiskers have point facing left vs Brinastain have point facigng rigt etc.
Reffered Pain
Activation of nociceptive nuerons innervating visceral organs is felt as pain elsewhere in the body
Example - when have a herat attack (myocordian infarction) or angima –> left arm and chest hurt NOT The heart
Hypothesis for why - convergence of visceral and somatic afferents on the same projection nuerons in teh dorsal horn
- Convergence of 2 dorsal root ganglion to same neuron in spinal cord
Example refered pain
If internal organ has pain = feel it comes from the skin because they synapes to the same secondary nueron in the spinal cord
1 neuron in organ –> SAME secondary nueron in SC
1 nueorn in skin -> SAME secondary nueron in SC
Primary sensory nuerons in Dorsal root ganlgion (image)
Dorsal root ganalion = stained with 3 markers
Eaxch dot in image = 1 nueron
Each DRG = has 10-15 nueroms (have many cells in one ganglion) ; Cells are heterogenous
- Red nueroms are larger (have biggger cell body - bigger cell body becase sending axon far awat = need to maintain metabolsim on long axon) vs. yellow have smaller cell bodies
Discovery of pain nuerons
1906 - Charles Sherrington postuled the existnce of pain sensing nueron nociceptive nuerons)
- Specilated that certain neurons sense pain
1967 - Ed perl and colegues experimentaly demonstarted the esxistence of these nuerons
Nociceptive neurons
Cells detecting noxious stimuli capable of casuing tissue injury
Nocicpetive nuerons = normally only respind to noxious stimulu NOT innoculous stimuli (wont be active if have gentle touch only sense pain)
- Subsets of nociceptive nuerons also mediate itch
Pain Sensation
Pain sensation is multidemensional with sensory discminiation + cgnitive + evaluative + emotional compoennets
- Inlcudes sensory compeoent but also emotional (example - how bad the pain is)
Identification of Nociceptive nuerons
Overall - shows nocireceptors exist
Looked at nerves in skin –> record nerve activity –> Add stimulation to the skin
When add a blunt probe = no pain even if increase force = no nuerons firring
When use needle = painful –> when increase pressure –> nerve fires AP
- Add more force = more painful = fires more
New ways to study pain nueroins
NOW = can image nerves instead of recording action potentials
Cause nerve to express GcAMP – Activate the nerve = have flourence
- Image - faint lines = nerves –> when apply painful stimulation the nerves light up
Neruons in Dorsal root ganglion
- Large
- Medium
- Small
Large nuerons in DRG
Large diameter cell body
Myleinated axons + Axon is thick diamter = fast conductons
Fast conduction velocity - when sending Action Potential –> conduscts well = fast conductions = feel sensation instantaneously
Invloved in body position + light not painful) touch
Medium nuerons in DRG
Medium diamter cell body
Thinly mylinated axons + smaller axon (smaller than large)
Medium conduction velocity (slower conduction than large)
Invloved in intial sharp pain
Small diamter nuerons in DRG
Smaller diameter cell body
Un-mylinated + axon is thin
Slowest conductino velocity
Invloved in delay burnig pain
- Example - if cut the tail of a dinaosor it would take time for it to feel because slow conduction velocity
Nociceptor for different modalities
Nociceptor is different for different modalities BUT some nociceptors are polymodal menaing they can feel multiple modalities
- Different nocicpetors detect different type of pain
Example - mechanimcal vs. temperure vs. chemical (chili pepper)
Feeling tempeture pain
> 45 degrees - Feel hot pain
<15 degrees - feel cold pain
15-45 = pleansnt
Chemical pain
When have injury ATP + ACID + capsaicain (pepper)
When screted from cell = painful
Chanels in pain mechanims
1.Volatge gated Na, K, Ca chanels –> essential for generation and propegaion of AP and NT release
- Ligand gated catino chanles - activated by pain stimuli and depolarize nueron
- Ex. - Acid Acivated + ATP activated + Tempetire activated
- GPCR - activated by molecules and mediate ion chanel acitivities
Modailities of feeling pain
- Nociceptor detects stimulus - have volatge gated Na, Ca, K chanels –> allow nerves to do AP and release nuerotransmitters
- Have ligand gated chanels –> chanels are activated by pain stimulus = depolarized nueron = activates voltage haoted chanel to get AO
- Have G-protein coupled recetor
- Have inhibitory (ex. opiary recetors) –> inhibit pain _ inhibit nueronal activity
- Have Activatory (Ex. Prostaglandin) –> make pain worse Ipotentiate channels = worse pain)
TRPV1
Transient receptore poential vanilloid I - a molecule sensor for noxious heat (>42 degrees + Noxious heat)
TRPV1 experiment
Previous reserach - showed that capsacain activaes subset of Dorsal Root Ganglions nueorns and induces Ca influx in cells
- Culture DRG –> give culture Capcasian –> Activates a subset of DRG (see Ca influx = see activation using Ca sensitive dye)
- Add capsacian = get Ca release
Experiment = used expression cloning approach into heterologous cells
- Generation dorsal root ganglion cDNA library (reverse trasncriped from mRNA from DRGs) –> express different pool of cDNA in heterologous cells –> Monitor capcasian activatiion by Ca imaging
- Looking at DRG cDNA that makes cells repond
TRPV1 experiment Results
Blue = heterologous cells
IF No DRG genes cDNA = no difference in cells with or without cacaccian
Add 1 cDNA library - have certain nuerons that light up when adding CAP
Second cDNA library (narrowing down to 1 gene) = epressed one ene –> When add CAP most cels respond
TRPV1 Protein sequence + structure
sequenced the cDNA of protein –> found that the protein has every feature of an ion chanel
Protein has:
1. 6 trabsmembrane domains
2. 1 pore domian (opens so ions can go into cells)
BOTH - show TRPV1 is a chanel
What is TRPV1
TRPV1 - ion chanel actuvated by capsacian and heat
- Expressed in pain sensing neurons (expressed in small diameter niciceptor)
In Gain of function exepeiriment - If look a recoding in chanels:
1. Adding CAP = inward current (+ ions go into the cellls)
2. Add heat (>42 degress) = current goes into cells
SHOW - chanels repsond to heat and CAP
TRPV1 knockout mice
Did a Loss of Function (LOF) experiment –> delete TRPV1 and look at Ca test
TRPV1 defeincent = fails to respond to a speciifc range if nixious heat:
1. WT - respond at 45 degrees
2. Knockout - Don’t respond at 45 dgerees
BUT at a higher threshold (>45 degrees) a smaller percent of nuerons repsond in WT and a small percent rescpond in knockout –> possible that there is another ion chanel contributing >50 degrees
TRPV1 defeinceit mice
Behvaioral response to heat is reduced in TRPV1 KO mice
When poke hind legs - no difference in WT or KO –> no differences for mechanimcal sensory –> shows TRPV1 is not involoved in mechanical
When put tail in hot water (temperture) - See KO take longer to withdraw at 50 degress ; at >5 degrees there is a string delay to withdraw in KO
When use hot plate (Temperature) - see difference in KO vs. WT –> KO respond in the end
Why do TRPV1 KO mice repsond to heat
THink that KO reponde >45 dgerees is because other chanels might also respond to heat = other chanels are compensating = animals can still feel some heat and respond
TRP chanels
TRP chanels = molecular sensors of various tempeture and chemicals (cover a spectrum of temperture and chemicals)
- Dfferent TRP chanels for difefrent tempertures - Example - TRPV2 = used for >50 degrees - epxlains why KO still repond to temperature>50 degrees
- TRPA1 - avtivated ny wasabu + te,p <15
- TRPM8 - <20 degrees + mint = cooling sn
Sensitization of Nocicpetive nuerons
Nociceptive nueroms become sensitized under chronic pain states (ex. tissue injury or inflamaton) –> means that thinsg that would nrammly be les spainful cause strong pain
- Example - when gently touc injury = pain (because nocieptor becomes sensitized)
Hyperalgesia vs. Allodynia
Hyperalgesia = more pain
Alldoynia = when a normallly not painful stimulus beccomes painful
Reasons for nociceptor sensitization
- Increased expression of ions channels –> leads to more channels on the memebrane = detect more pain
- Increase sensitivity of ion chenals
- Example - temperture threshold is lower
- Reduction in inhibitory ion chanel acitivity
What causes sensitization
Most sensitization = due to G-protein coupled receptor – have some release of ATP if H+ or Acid OR released liptes –> Acivates the GPCR on nerves = sensitzes nerve
Most receotors of the agents are GPCRs
GPCR signaling pathway
GPCR signlaing pathway = modulates ion chanel activities
Ligand binds to GPCR and get sentization of ion chanels
Effect of Bradykinin on TRPV1
Bradykinin lowered the temperture threshold of TRPV1
Experiment - Look at receptor on nociceptor –> record nocicpetor
- add heat with no bradykinin –> get activation inwards at 42 (Nociceptor was activated by 42)
- Add Bradukinin = threshodl shofts to 35 degrees (at a temper where TRPV1 would always be open because normal body temp)
Bradykinin = phosphorlates TRPV1 = sentizes chanels.= shifts the temperture threshold
Central Sensitizarion
Strengthens synpatic transmission between primary afferent neurons and second order nuerons in the dorsal horn in spinal cord
- Enhances pain
High requencey noniceptive input increase synaptic strength in a NMDA-dependent manner whicg resemble long term potentiation
Somatosensaton intiated by small + meiduam diamter neurons iin DRG
- Pain –> refleces = withdrw + avoidance
- Itch –> reflex = scratzhing (remove iratant to supress itch)
- Induce mechanimcal pain = supress itch + mobilize immune cells
Itch
Unpleasant sensation that elicits the desire or relex to scratch
- Intiated by small-medium DRG nuerons
- Different toes of itch = Histamine (allergy) vs. non-histamine
Pain vs. Itch
Pain and itch antagonize each other
Scratch = mechanical pain = supressed it
Morphine = supress pain = induces itch
Animal model of itching
Observe mouse sratching behvior in response to a pruiogen
- Can give different chemicals or induce different skin conditions to induce itch (Ex. Give histamine + chloroquine + compiund 48/80 + seratonin + cowhage + chronic itch models)
- Give compund at the level of rostral back of animal –> if animal tcihes = uses hind paw to sratch –> can record animal for 30 minutes and count how many times scratch
Animal model itching vs. Pain
Pain = wiping - uses fore paw to gently wipe
Itch = Scratching - use hind paw to scratch
Sratch vs. wipe = distigusible (different sensations)
Example - giving histamine = get straching and no wiping vs. give Capsaicin have wiping and no scratching
Models of pain and itch coding
- Intensity - uses the same popultion –> have one nueron to meidate pain and itch AND will feel different senation depending on the intesity of the stimulatiion
- Strong stimulation = pain ; wekaer = itch
2, Labeled line - Two different nueronal popultions (one popultion for pain and one popultion for itch)
- Strong stimulation = pain ; wekaer = itch
Evidence for Intensity theory
Hypoethsis for theory = scientists idetofied ithcinga dn pain spots in skin –> had one spot on skin that gives pain and itch - thought that because this was a small spot it could only be one nueron
Evidence Against Intesity theory
Experiment - Activate nerves with electical stimulus 0 see how person feels
THEN Increase the frequencey of stimuli –> person will feel a stronger itch but no pain
THEN increase frefrequncey more –> intensity of itch increase BUT there is no chnage from itch to pain
***Did the same expeirmnet with pain where they start at a higher frequencey and decrease = people feel less pain but never feel itch
Evidence for Labeled line theory
Experiment - record human skin –> apply histamine –> see sensation –> When add Histamine –> Get AP –> person reprots an it –> THEN find subtype of nocicptpr (C-fiber subtype)
- C-fiber repsonds to Histamine (thought that C-fiber is an itch specific fiber)
THEN did the same experriment where you add Histamine and the C-fibers repsonsed BUT when Add CAP C-fiber still repsonds = NOT itch specific
- C Fiber with histadine are slective but not specific for pruritogenic substances
MRG expressing nuerons
Have MRG expressing nuerons –> expressive MRG on nocicpetors –> nocicpetors repsond to itcj when hadd chloquinon (CQ binds to MRG –> Get itch)
- MRG = type of GPCR
Studying MRG in transgenic mice
Used GMP cre loc –> to get MRG on DRG cells + only to 5% of DRG cells
MRG nuerons = respond to pruritogens + Capscacin (Itch + pain)
- See nueron in live mouse –> Apply stimulus to paw because neuron sends axon to hind paw –> get reponse to CQ + histamine + CAP = not itch specific
Where do MRG3+ Axons inervate
MRG3+ axons only innervate the skin
Experiment - lavels nureons using cre loc – found that nueron axon only goes to the apical surface of the skin not visceral organs
Ablation of MRG3+ nuerons in DRG
Add toxin to 5% nuerons = ablate (kill 5% nuerons) –> other nuerons are not affected –> then see how animla feels
WHEN add CQ = less scratch (itch sensation is reduced = know MRG can mediate irch)
Pain (chamical + mechanical + temp) = normal
ALL together = no more itch BUT normal pain
Ablation of TRPV1
Experiment:
Activates 5% with MRP and TRVP1
All other uerons knock out TRPV1
ADD CAP
- WT = lots of wiping (Lots of pain) + No scratching
- TRPV1 knockout = no pain + no scratch
- 5% with TRPV1 = only scratch + no pain (witch the quality of the sensation because get scratch with CAP)
When have TRPV1 = feel pain not itch???
His new model
5% cells and the total have TRPV1
Activate bother popultions = they should feel pain + itch BUT they feel pain ecause you have an interneuon that blocks the itch sensation = only feel pain
When you delete the internuon = have lots of itch and no pain
Overall - there is an itch nueron and pain specific nueron BUT there is als an inhibitor internuron to modify itch sensation
Getting itch from CAP
Can you acheive itch with cap - When add CAP to skin = reach itch nerve fiber first because itch nerve is closer to the skin –> topically apply CAP = get itch BUT when CAP penetrates more you get only pain because pain will inhibit the itch
MrgA3
MargA3 = defines a popultion of itch deetced nuerons in DRG
Model - Have pain nuerons and itch nuerons and for snesation where you should feel both pain and itch you only feel pain because there is an internueron that inhibits itch but allows for pain
