Pain Flashcards
What is pain?
Subjective experience
Both sensory and emotional components
Which nerves carry pain information?
C fibre
Where does pain information travel in the spinal cord?
Lateral spinothalamic tract
Where does the information go to in the brain?
Nerve travelling in the lateral spinothalamic tract synapses in the thalamus
The thalamo cortical tracts send information to the sensory cortex
What are the three main targets for pain therapy?
Site of injury
C-fibre
Sensory cortex
Which drugs target the site of injury to reduce pain?
Anti-inflammatory drugs
Like COX inhibitors
Target bradykinin, prostaglandin, ATP and H+ build up
Which drugs target the C fibre to reduce pain?
Local anaesthetics
Like sodium channel blockers (cocaine)
Which drugs target the sensory cortex to reduce pain?
General anaesthetics
Like anaesthetic gases (NO, halothane)
What suggests there is an endogenous mechanism underlying pain?
Don’t feel pain during fight or flight
Could be as a result of the endogenous mechanism underlying response
What is the gate control theory of pain?
Explains how there are two pathways involved in pain sensation that antagonise each other
Painful stimuli travel through the a-delta and c fibre
Non-painful stimuli travel through the a-beta fibres
At the spinal cord, non painful inputs close the nerve gates to painful inputs
What stimuli travel through the a-delta and c fibres?
Painful stimuli
What stimuli travel through a-beta fibres?
Nonpainful stimuli
What is the action of the a-delta and c fibes?
Open the pain gate
Leads to transmission of pain
What is the action of a-beta fibres?
Close the pain gate
Blocks transmission of pain
What is different between c-fibres and a-delta fibres?
C-fibres are sensory neurons with no myelination, impulses travel very slowly
A-delta fibres are myelinated and work on a much more local way to transfer the stimuli faster
What happens when the pain fibres reach the dorsal horn of the spinal cord?
Synapse with the nerve going up the spinothalamic tract
Cross to go to the thalamus
Split either:
- into the sensory motor area for localisation
- limbic system for more emotional aspect of pain
What was the first sodium channel blocker developed to inhibit pain?
Cocaine - local pain reliever
What is the name of the main pain-relieving drugs?
Analgesics
What is the effect of analgesics?
Modify the transmission of pain
Modify the subjective perception of the painful stimulus
What are opioids?
Drugs derived from the milky fluid of unripe poppy seedpods (opium)
What is the active ingredient of opium?
Morphine
When was the structural formula of morphine identified?
1925
When was morphine first isolated from opium?
1804
How was morphine modified to make heroine?
Synthetic acetylation
What, apart from analgesia, are the effects of opioids?
Cough suppression - interacts with CNS causing cough
Pupil constriction
Constipation
Euphoria
Itching
Vomiting
Respiratory depression - respiratory center no longer sensitive to CO2
What are the two categories of opioid drugs?
Morphine and related compounds
Synthetic analogues of morphine
Examples of related compounds to morphine
Heroine
Codeine
Examples of synthetic analogues of morphine
Methadone
Fentanyl
Pethidine
How do opioids work?
Bind to opioid receptors
These are g-protein linked
Gi - decrease intracellular cAMP and increase activity of K+ channels
Inhibits presynaptic transmitter release and reduce postsynaptic excitability
What are the types of opioid receptors?
y (miu)
d
k
Most important in pain = miu
Where are opioid receptors found on the neurons of the dorsal horn?
Presynaptically
What are the effects of analgesics on opioid receptors?
Agonists
What are the endogenous opioids in the body?
Met-enkephalin
Leu-enkephalin
Dynorphin
Endorphin
How are the effects of analgesics reversed?
Some are structurally related to morphine and act as partial agonists with antagonist activity
Some are full antagonists
Which precursor do endogenous opioids derive from?
POMC
Expressed in tissues like the pituitary
Catalysed by peptidases
Which receptors does enkephalin work on?
Miu
Delta
Kappa
Which receptors does endorphin work on?
Miu
Delta
Which receptors does Dynorphin work on?
Kappa
What behaviour do opioid receptor knockouts experience?
Modulation of stress-induced nociception
Lack of social attachment
Non-alcohol dependent
Where are opidergic neurons mainly located?
Periaqueductal grey matter
In the brain stem - midbrain
Anterior to the ventricle
How do opidergic neurons inhibit pain?
Inhibit the neurons at the dorsal horn carrying the pain reception
Activates the descending pathways that inhibit pain transmission in the dorsal horn
Inhibit the activation of nociceptive afferents in the tissues
Why are opioids used in diarrhea?
Reduces peristalsis
Leading to constipation
Don’t want to prevent diarrhea for a long time, since we want to remove the agent causing the diarrhea
How do opidergic neurons inhibit the neurons in the dorsal horn carrying pain?
Through binding to pre-synaptic membrane of neurons carrying pain
This prevents the release of NT and inhibits neural transmission
How do opioids cause euphoria?
Bind to miu-receptors
These mediate well-being
Signs of opioid overdose
Unconscious
Respiratory depression
Pupillary constriction
What leads to death by opioid overdose?
Respiratory depression
What is tolerance?
Person’s diminished response to a drug
Occurs when a drug is used repeatedly
Body adapts to the continued presence of the drug
What are the two mechanisms of opioid tolerance?
Downregulation of surface receptors
Desensitisation of signalling pathways
How do opioids cause downregulation of surface receptors?
Causes a decreased efficacy of intracellular mechanisms controlling the movement of receptors
Remedy for opioid overdose
Naloxone
Opioid receptor antagonist
Which mechanisms have been developed to deal with opioid withdrawal?
Inhibiting pain through cox inhibitors
Local or general anaethesia
Endogenous anti-pain mechanisms
What causes the respiratory depression by opioids?
miu-receptors reduce the sensitivity of the respiratory center to CO2
What causes the nausea and vomiting by opioids?
Stimulation of the chemoreceptor trigger zone in the medulla
Which drug can be used to replace opioid addiction?
Methadone
What are the four stages of anaesthesia?
Analgesia - still conscious
Excitement - inhibition cortical inhibition
Surgical anaesthesia - reflexes disappear, respiratory depression
Medullary depression - respiratory arrest and cardiovascular collapse
What is the action of anaesthetics?
Analgesia - suppress pain inputs
Loss of consciousness - effect on spinothalamic tract
Short term amnesia - effect on hippocampus
What are the two main categories of anaesthetics?
Inhalation
Intravenous
How is the potency of inhalational anaesthetics expressed?
Minimum alveolar concentration required to produce surgical anaesthesia
Represents the dry dose required
The higher the MAC the less efficient the inhalational anaesthetic is
What is the MAC for NO?
100%
What is the MAC for halothane?
1%
When is NO used?
Pregnancy
Don’t want patient to be completely unconscious
What is the mechanism of action of inhalation anaesthetics?
Not known
Does not have a well-defined receptor
There is no clear structure-activity relationship
Known to potentiate inhibitory transmission through GABA receptors
What is the relationship between the lipid solubility of inhalatory agents and potency?
Potency is well correlated with lipid solubility
What is the blood-gas partition coefficient?
Describes the lipid solubility of a drug
The lower the coefficient the higher the solubility
The more rapid the effect
What results in the characteristic sustained CNS depression following anaesthesia?
In long surgical procedures, the inhalation agents are taken up into adipose tissue
Slow release from this leads to respiratory depression
Types of inhalation anaesthetic agents used today
Ether
Nitrous oxide
Halothane
Who are inhalational anaesthetics advised against?
Patients with heart conditions
Cause cardiovascular collapse due to inhibition of excitable tissues
How are intravenous anaesthetics different to inhalation anaesthetics?
Specifically target receptors
What are the two main receptor targets of intravenous anaesthetics?
GABA
NMDA
How do intravenous agents target GABA receptors?
Act as agonists
Bind to the chloride channels and hyperpolarises the membranes
Mimic the effects of GABA
Examples of IV anaesthetics targetting GABA
Barbituates
Profolol
How do IV anaesthetics target NMDA receptors?
Antagonists
Block the receptor for being excitatory
Example of an IV anaethetic that targets NMDA
Ketamine
Why is Ketamine not a very commonly used anaesthetic?
Causes dissociative anaesthesia
Does not always cause anaesthesia
So patients often have distant memories of what happened
When is ketamine used?
Children
Patients with heart conditions
Who discovered anaesthetics?
Ether Day
Ether vaporiser
Are anaesthetics often given singularly?
No
Other factors are given prior, after or during recovery following anaesthesia
Because anaesthesia is not ideal
What do local anaesthetics do?
Inhibit pain in a localised area of the body
Mechanism of action of local anaesthetics
Block voltage-gated Na+ channels in the cell membrane
What are the three states a sodium channel can be found in?
Resting
Activation
Inactivation
Which states of the sodium channel do local anaesthetics mostly act on?
Open or inactive
Which neurons do local anaesthetics mostly act on?
Small fibres are blocked more easily
Pain sensation is therefore blocked before other sensory inputs
Usually block large fibre diameters less effectively
Describe the specificity of local anaesthetics
It is not possible to achieve local anaesthesia without loss of other sensory modalities
What form does the drug have to be in to generate local anaesthesia?
Lipid-soluble, uncharged form
In order to cross through the cell membrane
What type of molecule are most local anaesthetics?
Weak bases
What was the first local anaesthetic developed?
Cocaine
Example of a modern anaesthetic
Lidocaine
Uses of local anaesthetics
Antidysrhythmics
Epilepsy
