biology and physiology Flashcards
what are action potentials
Differences in ion concentrations across the nerve cell membrane provide the potential energy required to transmit nerve impulses.
plasma membrane potential is due to…
due to the separation of electrical charges across the cell membrane
What allows charge separation across the plasma membrane to happen
action of the NA=/k+ atoase activekly transporting na and k+ in different directions across the membrane
na/k ATpase role
replenish the K+ lost from the cell
remove the Na+ accumulated within the cell
Na+/K+ ATPase mechanism
- Binding of cytoplasmic Na+ to the protein stimulates phosphorylation by ATP.
- Phosphorylation causes the protein to change the conformation.
- The conformational change expels Na+ to the outside and extracellular K+ binds.
- K+ binding triggers release of a phosphate group.
- Loss of phosphate restores original conformation.
- K+ is released and Na+ sites are receptive again. The cycle repeats.
Role= replenish the K+ lost from the cell
=remove the Na+ accumulated within the cell
resting membrane potential
Due to the relatively high membrane permeability of K+.
Inside and outside the cell= electrical neutrality
Outside Na+ balanced mainly by Cl-.
Inside K+ balanced mainly by A-.
Other anions present= PO4-, Cl-
leak channels
negatively charged ions line up on the other side of the membrane
K+ leaks out
separation of charges constitues to the membrane potential
Electrochemical equilibrium
Concentration gradient tends to drive K+ out of the cell but the negative charge inside attracts K+ back in.
Equilibrium is established where the electrical potential balances the chemical potential.
chemical gradient can be balanced by an electrical potential
what produces chemical force and what is this equal and opposite to in order to reach equilibrium potential
chemical force produced by the concentration gradient
chemical force is equal and opposite to THE ELECTRICAL FORCE EXPERIENCED BY AN ION VIA A VOLTAGE
nerst equation
enrst equation describes equilibrium potential
The voltage across the membrane is proportional to the ratio of the ion concentrations on either side of the membrane.
goldmans equation
a more realistic approxmatuon of memrbane potential
Effect of external K+ concentration on membrane potential of skeletal muscles
Increase in external potasiunnion concentration increases membrane potential
Doing the log of external potassium concentration with membrane potential give a linear relationship which suggests that
Increasing extra cellular concentration depolarises the cell
what controls the membrane potential
changes in ion permeability due to opening and closing of protein ion channels in the membrane
neuronal signalling
Rapid changes in membrane potential (action potential)
Neuronal firing
Rapid depolarization caused by opening of voltage gated cation channels.
4 types of ion channels:
- voltage gated
- Ligand gated (extracellular ligand)
- Ligand-gated (intracellular ligand)
- Stress activated
Initiating an AP
Initial change in membrane potential (depolarization) is required.
Threshold comes from the opening of small capacitance ligand-gated cation channels.
(Nicotinic acetylcholine receptors at skeletal NMJ,
5HT3 receptors and P2X at CNS synapses +smooth muscle)
what causes the initial depolarization
Opening of small capacitance cation channel.
Graded responses.
stages of an action potential
- if local potential change;graded potential reaches the threshold potential na channels open
na channels open and influx of calcium causing depolarization
repolarization-na channel closes and efflux of potassium channels to reverse the increase in membrane potnetial
hyperpolarization-K+ channel remain open after potential reaches resting level
oubain
na/K+ atpase inhibitor
Reduces the size of the AP progressively until the membrane Na+ gradient is reduced to the point where the APs can be initiated but fail.
tetrodotoxin
blocks neuronal VGSC
abolishes AP
action potential refractory period is due to….
due to the inactivation of voltage gated na channels
during this period, another stimulus given to the neuron (no matter how strong) will not lead to a second action potential
Propagation of action potential along an axon. why propagation goes forward and not backwards
At rest the membrane is polarised.
Depolarization due to AP sets up local circuit currents in both directions.
In ‘backwards’ direction, Na+ channels are in refractory phase and another AP cannot be generated.
AP moves forward.
speed of conductance
regulated by
Temp
Axon diameter [thicker the axon, lower the longitudinal resistance, faster the conductance.]
[membranes have high capacitance= charge storage]
myelination
what is greater at increasing the speed of conductance myelination or increasing diameter
insulating the axon with myelin is a more efficient way to increasse AP conduction velocity than increasing diameter
Glia
Oligodendocytes wrap multiple CNS axons with myelin.
nn cells apply myelin to single peripheral axons.
saltory conductance
is the propagation of action potentials along myelinated axons from one node of Ranvier to the next node, increasing the conduction velocity of action potentials.
local anaesthetic
Block conduction of APs in sensory nerves by blocking VGSC from the inside.
Weak bases. (e.g lidocaine, bupivacaine)
Need to diffuse through axon membrane and must be uncharged at plasma pH.
Charged molecular species (ionised) cannot pass back through the membrane and is trapped.
Ionised drug binds to and blocks the VGSC.
different sensitivities to local anaesthetics
nerve bundles consist of multiple fibre types
myelinated and thicker axons are more difficult for LAs to treat than thin, unmyelinated axons
c fibres carrying pain singlans are easier to block than motor nerve fibres
Applications of LAs
Surface anaesthesia
Infiltration
- injection in tissues
- adrenaline added (vasoconstrictor to prevent diffusion away from site)
Intravenous regional
Nerve block
Spinal
Epidural
Pain
Unpleasant sensory and emotional experience associated with actual or potential tissue damage.
Duality. Has a physiological and psychological aspect
Nociception
Neural physiological process of encoding and processing noxious stimuli.
Nociceptor
Sensory neuron detecting noxious input.
Pseudounipolar neuron with a peripheral and central axon.
a protein involved in pain
nav1.7
Nociceptor nerve endings
Bare nerve ending.
Specialised to detect high threshold noxious stimuli (heat, cold, high threshold mechanical stimuli, capsacin)
Specific cation channels can detect these stimuli
TRPV 1
Receptor for capsaicin, protons.
Detects noxious heat.
6 transmembrane ion channel with a pore forming loop.
4 subunits form the channel.
Na+ and Ca2+ cation permeable.
Opening the channel leads to ion influx.
Depolarises the membrane.
Voltage-gated sodium channels
VGSC in the nociceptor
Generate action potential.
Tetrodotoxin sensitive + tetrodotoxin insensitive
Tetrodotoxin insensitive
Nav1.9, Nav 1.9
Nav1.8= highly expressed in nociceptors (nociceptor specific)
Role in acute noxious mechanical sensation
Important in acute cold sensation.
Doesn’t inactivate in low temp whereas all other Nav channnels do.
Sensory nerve and nerve fibres
- Nociception
A-delta fibres= Lightly myelinated, medium diameter
C fibres= unmyelinated, small diameter
- Proprioception, light touch
A-beta fibres= myelinated, large diameter
Nociceptor central terminal
Main excitatory transmitter= Glutamate
Substance P
VGCC= facilitate transmitter release
Various receptors on the presynaptic terminal modulate transmitter release= GABA, CB1, DOR, MOR
synaptic transmission. ampa receptor
AMPA receptors Glutamate released presynaptically binds to AMPA receptors at the postsynaptic neuron(second order neuron that is located at the dorsal horn). Ligand gated ion channels. Primarily Na+ gating and depolarising. Fast excitatory transmission.
Nociceptor connections in the spinal cord
-Projection neurons (direct connection to brain)
Nociceptor specific= only receive input from nociceptors (A-delta, C fibres)
Wide dynamic range= receive input from nociceptor (A-delta, C fibres) and non-nociceptors (A-beta)
-Various types of interneurons
Inhibitory= GABA
Excitatory= Glutamate
Modulation of nociceptor signalling: mu-opioid receptor
Localised presynaptically.
Central terminal.
Modulation of ion channel function.
Results in reduced synaptic transmission.
Acute MOP receptor function
Inhibition of adenylyl cyclase and reduction in cAMP.
Increase opening K+ channels and hyperpolarization.
Decrease opening of Ca2+ channels.
Reduced neuronal excitability.
Endogenous inhibitory controls: inside the dorsal horn
nhibitory interneurons in the dorsal horn: GABA transmission
GABA A receptor= ligand gated ion channel
Localised presynaptically of the nociceptor terminal
Agonism
Cl- gating, hyperpolarises the membrane and dampens excitation.
Acute nociceptive pain
threshold of activation and when activated
Pain= sensation of hurt
Nociception= detection of noxious stimuli
Leads to Reflex or Pain
Threshold of activation is high.
Under normal circumstances, the nociceptive system is not activated.
Warning device.
Protective mechanism (reflex, avoidance behaviour)
Hypersensitivity
Inflammation sensitizes the sensory system.
Innocuous stimuli elicit pain and the response to noxious stimuli is enhanced and prolonged.
Helps to protect and preserve by provoking avoidance of further contact with such stimuli.
Aids healing and repair.
Adaptive process.
hypersensitivity occur due to
Occur as a consequence of neuronal damage.
- Mechanical trauma
- Metabolic disease such as diabetes
- Neurotoxic chemicals= chemotherapy
- Infection
- Tumour invasion
- Spinal cord injury
- Stroke
Allodynia
Pain in response to normally innocuous stimulus
Hyperalgesia
Pain in response to a noxious stimuli with an exaggerated response
Classification of nociceptive, inflammatory and neuropathic pain
in terms of pain sensitivity (threshold) stimulus clinical setting function
Nociceptive pain= High threshold Noxious stimuli Acute trauma Protective
Inflammatory pain= Low threshold Inflammation Post operative pain, Arthritis Healing/ repair
Neuropathic pain= Low threshold Neural damage and ectopic firing PNS and CNS lesions, Diabetic neuropathy, Trigeminal neuralgia Pathological
changes in the nociceptive system can be what two types of sensitisation
peripheral
central
peripheral sensitisation
nociceptor activation threshold are lowered
the nociceptor starts firing more and more and this is experienced as pain
Central sensitisation
Spinal cord pain neurons are changed (anatomically, physiologically).
Show increased responsiveness to peripheral input
Tissue damage and inflammation
inflammation-associated changes in the chemical environment of the nerve fiber
Thus, tissue damage is often accompanied by the accumulation of endogenous factors released from activated nociceptors or non-neural cells that reside within or infiltrate into the injured area (including mast cells, basophils, platelets, macrophages, neutrophils, endothelial cells, keratinocytes, and fibroblasts).
how do these factors (inflammaotry soup)released from nociceptors during tissue damage work
Nociceptors express receptors that can recognise these factors.
Factors bind to the receptor.
Leads to depolarisation or alteration of the activation threshold.
Nociceptor excitation.
prostalgladin sensitisation pathway
Prostaglandins produced from arachidonic acid in several steps, including COX enzyme activity. Prostaglandin E2 binds to PGE2 receptor. Activates Gs G-protein Activates adenylyl cyclase. Converts ATP into cyclic AMP. Cyclic AMP activates protein kinase A. Facilitates voltage-gated sodium channels. Changes nociceptor excitability.
NGF altering gene expression
NGF(nerve growth factor) produced by mast cells and fibrolasts
alters gebe expressions of other receptors that can induce nociceptor excitability
receptor for NGF
TrkA
Protons activate ASICs. what are ASICs
ASICs (acid sensitive ion channels)
Family of 2T channel subunits.
Homo and heterotrimers.
Na+ gating and depolarising
ASICs and pain
activated by small changes in pH
ASIC3 can be inhibited by a peptide toxin from the venom of the sea anemone
snakes toxin inhibits pain axis
p2x and atp
p2x is a ligand gated ion channel that recognises ATp
cation gating and depolarization
direct excitation of nocieptor
p2x structure
heteromultimers of subunits consisting of 2T1P
Bradykinin sensitization pathway
Bradykinin binds to the Bradykinin receptor on nociceptor terminal.
Activates Gq G-protein
Activates phospholipase C-beta
Converts membrane phospholipid PIP2 into DAG and IP3.
DAG activates the Protein Kinase C-epsilon isoform.
Bradykinin increases the response of TRPV1 to heat.
Reduces the thermal activation threshold of TRPV1.
how do we get an increase in synaptic strength
increase of presynaptic e.g. calcium channels after nerve damage
loss of mu opioid receptors on presynaptic terminal after nerve damange
increase of postsynaptic signalling via nmda receptors
somatosensory cortex
location, duration and intensity
involved in the perception and modulation of pain
spinal cord. medulla, mid brain, thalamus. s1, s2
nociceptors
alpha delta
c fibres
non nociceptor
alpha beta
