What are the three ways in which a signal is terminated at a synapse?
Reuptake
Enzymatic breakdown
Negative feedback via autoreceptors on the presynaptic membrane
Positive feedback via autoreceptors on the presynaptic membrane
Depolarisation
Hyperpolarisation
What are some examples of anxiolytics?
Benzodiazepines
Barbiturates
Alcohol
Monoamine oxidase inhibitors
SSRI's
What are some examples of anti-depressants?
Tricyclic
Selective serotonin reuptake inhibitors
What are some examples of anti-psychotics?
Typical neuroleptics
Atypical neuroleptics
How do anxiolytics work?
They bind to a different site to GABA and increase the affinity of the receptor for GABA, causing increased inhibition and the user to feel drowsy.
They inhibit the neurotransmission at a synaptic junction which creates fewer excitatory signals in the post-synaptic membrane.
Novel anxiolytics that block peripheral receptors instead of central ones relieve sedative symptoms.
Depression is thought to be caused by monoaminergic synaptic hyperactivity.
What do MAOI's do?
Inhibit the reuptake of serotonin and noradrenaline into the pre-synaptic knob.
Inhibit the monoamine oxidase enzyme that breaks down serotonin and noradrenaline neurotransmitters.
What do TCA and SSRI's do?
They inhibit the re-uptake of serotonin and noradrenaline from the synaptic cleft.
They inhibit monoamine oxidase which breaks serotonin and noradrenaline down.
TCA's are much more selective than SSRI's at blocking serotonin rather than noradrenaline at monoaminergic synapses.
Typical neuroleptics are more selective at blocking dopamine receptors.
Psychosis is thought to be caused by dopaminergic hyperactivity.
Why can anti-psychotics sometimes cause parkinsonian?
Anti-psychotics reduce the activity at dopaminergic synapses. This can be so extreme that motor function is impaired and parkinson like symptoms are experienced.
Anti-psychotics increase the activity at dopaminergic synapses. This can be so extreme that motor function is impaired and parkinson like symptoms are experienced.
Anti-psychotics reduce the activity at monoaminergic synapses. This can be so extreme that motor function is impaired and parkinson like symptoms are experienced.
Anti-psychotics increase the activity at monoaminergic synapses. This can be so extreme that motor function is impaired and parkinson like symptoms are experienced.
As well as parkinsonian, what other motor symptoms can anti-psychotics produce? (CLOZAPINE DOES NOT PRODUCE THIS)
Tardive dyskinesia
Duchene muscular dystrophy
Ataxia
Which three areas of the brain are affected by anti-psychotics?
Mesolimbal
Mesocortical
Nigrostriatal
Lateral hypothalamic area
Primary gustatory cortex
What do mechanical nociceptors respond to? What is an example?
A-delta fibres
C fibres
Sharp cuts or Blunt force
Damaging heat
What do polymodal nociceptors respond to? What is an example?
Many modalities
Only a few modalities
Myelination tends to reflect upon what property of a primary sensory neurone?
That is transmits a fast, sharp pain.
That it transmits a slow, dull pain.
Frequency coding states what?
The greater the pain stimulus is, the higher the frequency of action potentials fired from the periphery to the CNS.
The lower the pain stimulus is, the higher the frequency of action potentials fired from the periphery to the CNS.
The laminar order in which primary sensory neurones synapse in the spinal cord means that each "sheet" in the spinal cord receives input from a particular part of the body (somatotopic)
When a painful stimulus is detected and an action potential is propagated to the spinal cord, how is the pain then transmitted up to the brain?
Excitatory neurotransmitters are released from the a-delta/c fibre and this causes pain signals to be carried to the brain.
Excitatory neurotransmitter are released from the a-delta/c fibre which stimulate an inhibitory interneurone to inhibit the GATEKEEPER. This inhibits the inhibitory GATEKEEPER and weakens the inhibition that the GATEKEEPER provides to the ascending pain signal. This allows pain signals to carry up to the brain.
Rubbing your knee activates a-beta mechanoreceptor fibres which cause excitatory neurotransmitter release to the GATEKEEPER which then releases more inhibitory signals to block pain signals going to the brain.
The GATEKEEPER sends out excitatory signals to aid pain signals passing up to the brain.
Where is pain perceived?
Subcortically (before the cortex)
At the cortex
Where is pain localised?
The cortex
The emotional (psychogenic) element of pain means that it is not just a single part of the brain that takes part in pain signal processing, but many different regions that co-ordinate together.
Descending pathways that release endogenous opioids act where?
The GATEKEEPER to enhance inhibition of pain signals ascending to the brain.
The GATEKEEPER to enhance pain signals ascending to the brain.
Primary hyperalgesia occurs where?
CNS
Peripheral nervous system
Secondary hyperalgesia occurs where?
Primary hyperalgesia occurs due to what process?
Noxious stimulus occurs after initial injury -> AXON REFLEX -> SP and CGRP release -> vasodilatation + immune cell activation -> Bradykinin, PG etc "inflammatory soup"
Noxious stimulus occurs after initial injury -> AXON REFLEX -> Bradykinin and CGRP release -> vasodilatation + immune cell activation -> SP, PG etc "inflammatory soup"
Noxious stimulus occurs after initial injury -> AXON REFLEX -> SP and Bradykinin release -> vasodilatation + immune cell activation -> CGRP, PG etc "inflammatory soup"
Which receptor does substance P act?
NK-1
AMPA
NMDA
Which receptor does Glutamate act at?
Glutamate is usually released during normal, acute pain, rather than Substance P.
Why does binding of Substance P and Glutamate cause secondary hyperalgesia?
Binding of Substance P and Glutamate activate the NK-1 and AMPA receptors respectively. This causes sufficient depolarisation in order to repel the magnesium dependent block out of the VG Ca2+ channel. Calcium entry causes 2ndry messenger activation and increased neurone responsiveness. This increases the rate of AP firing and explains why pain is more intense in secondary hyperalgesia.
Binding of Substance P and Glutamate activate the AMPA and NK-1 receptors respectively. This causes sufficient depolarisation in order to repel the magnesium dependent block out of the VG Ca2+ channel. Calcium entry causes 2ndry messenger activation and increased neurone responsiveness. This increases the rate of AP firing and explains why pain is more intense in secondary hyperalgesia.
Binding of Substance P and Glutamate activate the NK-1 and AMPA receptors respectively. This causes sufficient depolarisation in order to repel the calcium dependent block out of the VG Ca2+ channel. Calcium entry causes 2ndry messenger activation and increased neurone responsiveness. This increases the rate of AP firing and explains why pain is more intense in secondary hyperalgesia.
Neuropathic pain is the overall sensation of pain; the physiological factor and the psychogenic factor.
Name two types of endogenous opioids
Enkephalins
Beta-endorphins
Naloxone
Pethidine
Name two types of therapeutic agent opioids
Heroin
Codeine
Methadone
Fentanyl
Name four types of synthetic agent opioids
Buprenorphine (partial agonist)
Fluoxetine
Opioids are usually administered parenterally as the GIT does not absorb opioids well.
What are the three sites of action for opioids?
Inhibition of primary sensory neurones synapsing to second order neurones in the spinal cord
Excitation of the nucleus raphe magnus which causes inhibition of pain signals at the spinal cord level
Excitation of the nucleus reticularis which causes inhibition of pain signals at the spinal cord level
Decreased excitability of peripheral nociceptor neurones
What does label 2 show?
Activation of the G-protein
Less opening of Ca2+ channels - less neurotransmitter release
More opening of K+ channels - leading to hyperpolarisation
What does label 3 show?
Activation of G-protein
What does label 4 show?
Opioids inhibit adenylyl cyclase which leads to increased cAMP levels.
What effects occur due to opioid action?
Analgesia
Constriction of smooth muscle at all sites
Nausea
Relaxation of smooth muscle at all sites
Euphoria at all sites
What are two problems with prolonged opioid use?
Tolerance - due to increased adenylyl cyclase expression
Dependence - withdrawal symptoms
NSAIDS are cyclo-oxygenase inhibitors.
Aspirin is a competitive inhibitor of COX.
COX enzymes catalyse the reaction that turns arachidonic acid into prostaglandins. Inhibition of COX therefore reduces prostaglandin production and thus inflammation.
As a result of the action of NSAIDs, what effects are produced?
Anti-pyretic - decreases the temp set point in the hypothalamus
Anti-inflammatory - dec PG = dec vasodilation
Analgesia - dec PG = decrease sensitivity of nerves to inflammatory pain
Anti-inflammatory - dec PG = inc vasodilation
Anti-pyretic - decreases the temp set point in the basal ganglia
Prostaglandins help to produce the mucus lining of the stomach, therefore NSAIDs can cause increased risk of peptic ulcers.
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