Detection and Central Processing and Treatment of Pain

Question 1

what are phantom limbs?

Answer 1

Occur when nerve that would normally innervate the missing limb are abnormally stimulated and cause the pain perception
Sensation that the missing limb is twisted, permanently contracted etc
May be due to damaged nociceptor endings or somatosensory cortical reorganisation

Question 2

what is pain?

Answer 2

Unpleasant sensory or emotional experience associated with actual or perceived tissue damage. The perception of pain is individual.
can be ignored in some settings
We need pain - it’s protective. But it can be unuseful.
We know where pain is coming from.
Pain also produces learned responses so that we don’t do behaviours that hurt

Question 3

what causes congenital insensitivity to pain?

Answer 3

Mutation in voltage-gated sodium channel, essential for action potentials to travel up afferent fibres.
Information about noxious stimuli isn’t transmitted to the brain.

Nociceptive neurons don’t develop properly.
People have mutations in the nerve growth factor tyrosine kinase receptor.
Don’t have the pathways.

Express too many opioids - brain’s natural pain anesthetist.
Can be treated with naloxone, a MU receptor antagonist.
Opioids can be in the body but don’t get to bind to the receptor and dampen pain.

Sensation of touch is usually normal - evidence for pain and touch pathways being separate.

Question 4

what are the properties of Aα sensory fibres?

Answer 4

13-20µm
myelinated
80-120m/s conduction velocity
associated with muscle spindle primary receptors and golgi tendon organ sensory receptors

Question 5

what are the properties of Aß sensory fibres?

Answer 5

6-12µm
myelinated
33-75 m/s conduction velocity
associated with secondary receptors of muscle spindles and all cutaneous mechanoreceptors

Question 6

What are the properties of A∂ sensory fibres?

Answer 6

1-5µm
thin layer of myelin
3-30m/s conduction velocity
associated with free nerved endings of touch and pressure; nociceptors of neospinothalamic tract; cold thermoreceptors?

Question 7

what are the properties of c-firbes?

Answer 7

0.2-1.5µm
unmyelinated
0.5-2 m/s conduction velocity
associated with nociceptors of paleospinothalamic tract and warmth receptors

Question 8

what are nociceptors?

Answer 8

Sensory receptors that respond to dangerously intense stimuli that will damage the body
Very high thresholds of stimulation
Free nerve endings which branch to span a wide area so have large RFs - more important to detect pain itself then to know where it came from
A∂ mechanosensitive nociceptors - respond to dangerously intense mechanical stimulation
A∂ mechanothermal nociceptors respond to dangerously intense thermal stimulation.
C fibres - polymodal receptors which have lots of receptors on them that bind to lots of different ligands which are produced during tissue injury. Report back using EPSPs from different ligands present.

Question 9

What neurotransmitter do A∂ fibres release at the first synapse in the substantia gelatinosa of the spinal cord.

Answer 9

glutamate

Question 10

What neurotransmitter do C-fibres release at the first synapse in the substantia gelatinosa of the spinal cord.

Answer 10

Glutamate
Substance P
(neuropeptide - so doesn’t have an obvious clearance mechanism so last longer than Glu so can cause prolonged depolarisation when they bind to NM1 receptor)

Question 11

What is meant by the ‘first pain’?

Answer 11

initial sharp, brief, localised pain
First pain is due to ∂ fibre stimulation
pharmacologically inhibit the A∂ fibre - lose the peak from the first pain

Question 12

What is the second pain?

Answer 12

later, dull, poorly localised, longer-lasting pain that has a burning quality.
Second pain is due to c-fibre stimulation
Selective blocking of c-fibres removes second longer lasting peak

Question 13

what is the difference between nociceptors and thermoreceptors for touch?

Answer 13

Nonnococeptor thermal receptor: as stimulus increases, number of action potentials increase, intensity is encoded in the frequency of action potentials. At 45 step increase - already responding at maximum rates.
Nociceptor - high threshold of activation. Doesn’t start producing action potentials until 45’ - the temperature that will start to cause damage to the skin. Starts to increase frequency of action potentials so that the intensity of stimulus is reflected in the frequency of action potentials.

Question 14

How is pain localised?

Answer 14

Dermatomes stripes in the body which are very orderly and somatotopically mapped that come into the spinal cord at very specific points. 31 pairs of nerves.
In these nerves, pain information is sent within their respective fibres which is a separate pathway.

Question 15

What is the spinothalamic pathway

Answer 15

Nociceptors send action potentials into the spinal cord into the substantia gelatinosa
Decussates immediately and comes down into the anterior lateral quadrant
Sends information up, on the opposite side to where it entered the spinal cord
Makes second synapse in the hypothalamus
Sends information somatotopically mapped into the primary somatosensory cortex.
Different pathway to touch

Question 16

what is referred pain?

Answer 16

e.g heart attack
Pain in chest area and down their arm rather than heart
Nociceptors from several locations both synapse on the same neuron (dermatome) that is normally stimulated by the skin rather than the heart and so it’s interpreted as coming from the skin.
To diagnose someone with these conditions can take reported area of pain and diagnose the associated source organ, in this example the heart.

Question 17

What is brown-sequard hemipelgia

Answer 17

Physiological example that sensations are carried by different anatomical routes
Caused by lateral hemisection of spinal cord (one half of the spinal cord injured) caused by spinal cord injury, tumour, ischaemia
Loss of motor function and numbness to touch on the same side as injury
Loss of pain sensation of the opposite side of the injury
Touch is carried on the same side as its detected whereas pain information crosses over and is carried on the opposite side of the body

Question 18

What is the pain matrix?

Answer 18

fMRI of individuals who’ve been given pain stimuli indicate that many areas of the brain light up - the pain matrix
Required for evolutionary protection and is important to an organisms is detected by lots of different areas in the brain.

Question 19

What are the main ascending pathways for pain?

Answer 19

Spinothalamic tract - important in localisation of painful or thermal stimuli. Principle ascending pathway.
Spinoreticular tract - causes alertness in response to painful stimuli.
Spinotectal tract - orientate head and eyes towards painful stimuli - connections in the spinal tectral tract.3 neuron relays with 2 synapses

Question 20

What are the main descending pathways?

Answer 20

Spinomesencepahlic - important in descending modulation

More complicated perception of pain

Question 21

What is hyperaglesia??

Answer 21

when polymodal C-fibres do not adapt to stimuli
Become more sensitised to pain
Pain intensity reported reflects stimulus intensity

Question 22

what is allondynia?

Answer 22

experiencing pain from normal touch e.g putting clothes on

Question 23

What is the mechanism for hyperalgesia?

Answer 23

Free nerve ending coming into first synapse to relay neuron

Substance P and calcitonin gene regulated protein (CGRP) is released at nerve endings.

Glu also released at first synapse

Acts on mast cells to produce histamine which acts on blood vessels to increase blood flow to tissue damaged areas - redness
also makes them leaky so they swell
Brings white blood cells to fight infection and clear up damage

Send action potentials up into the spinal cord

Question 24

what is the mechanism for central hyperalgesia?

Answer 24

Neuronal plasticity - wind up response
Nerve ending, EPSP stimulate action potential causing release of neurotransmitter onto substantia gelatinosa
Under low levels of stimulation glutamate binds to the ampa receptors on postsynaptic membrane, signalling pain
NMDA and NK-1 receptors
Magnesium blocks pore of NMDA receptor under conditions of repetitive stimulation the C-fibres fire repeatedly causing the core release of Glu and Substance P
Substance P binsd to NK-1 receptor and causes slow chronic depolarisation
Glu binds to AMPA receptors
NMDA receptors (coincidence receptors - need both Glu to bind and for the membrane to be depolarised to remove the magnesium block which is inside them) open in prolonged stimulation.
This causes an influx of Na+ and Ca2+
Ca2+ activated calmodulin kinase and protein kinase c
Both result in the phosphorylation or transcription of additional AMPA receptors
Or phosphorylated ampa receptors already there
For a give pulse of Glu, AMPA receptors are conducting more ions
NK-1 causing slow depolarisation as a result of substance P
NMDA receptors will remain open and allow Ca2+ in to promote neuroplasticity which will increase more AMPA receptors.

Question 25

How can hyperalgesia be treated?

Answer 25

Chronic pain could be prevented by giving NK-1 receptors antagonists or NMDA and AMPA antagonists. However this results in memory loss so can't be used.

Question 26

what is nociception?

Answer 26

the detection of the firing of nociceptors and the processing through the three neuron relay with the two synapses.

Question 27

What pain medication is available?

Answer 27

``` Nonsteroidal antiinflammatories (NSAIDS) e.g aspirin COX 1 and COX 2 inhibitors, reduce prostaglandin synthesis. C-fibres are polymodal, the prostaglandin is one type of receptor producing ESPS Local anesthetics - lidocaine blocks voltage-gated sodium channels in the primary afferent fibre, the nociceptor. If action potentials don’t travel up to the spinal cord, they can’t proceed into the brain itself and be perceived. Can do things which can reduce the transmission of the pain information so that we don’t perceive it well. Opiates - pharmacological molecules that are similar to the body’s natural opioids. Morphine causes hyperpolarisation at the primary afferent by binding to µ receptors which open potassium channels which cause an IPSP or close calcium channels which will reduce the amount of neurotransmitter that’s released. ```

Question 28

what alternative pain medications and therapies can be used?

Answer 28

``` Acupuncture TENS machines - provide vibratory stimulus Hypnosis Distraction therapy CBT Deep brain stimulation Low dose antidepressants ```

Question 29

How does acupuncture work to alleviate pain?

Answer 29

mall needles are inserted just below the skin used to relieve pain adenosine as the pain relieving molecule produced in response to acupuncture

Question 30

How does TENS alleviate pain?

Answer 30

transcutaneous electrical nerve stimulation Deliver mild electric current creating impulses in Aß fibres in touch Believe there is a connection between Aß fibres and pain fibres which reduce the sensation of pain Pain and touch pathway are anatomically separate but there are situations within the spinal cord within the substantia gelatinosa where interneurons can be used to connect the two pathways. This strong vibratory stimulus helps with phantom limb pain in amputees Causes production of natural endorphins that reduce pain

Question 31

How can natural endorphins reduce pain?

Answer 31

opioids relieve high levels of endogenous pain released naturally in response to competitive situations and explains the placebo effect ``` examples of natural opiods: leucine-enkephalin methionine-enkephalin ß-Endorphin Dynorphin α- neoendorphin ```

Question 32

what effect can opioids have on descending pathways controlling pain?

Answer 32

reduce the firing of the nociceptive afferent neuron Can operate within the dorsal horn of the spinal cord, the substantia gelatinosa where they can cause an IPSP and prevent transmission. Can act to inhibit NRPG Can stimulate the PAG by inhibiting an interneuron which normally inhibits the PAG which then causes inhibition at the dorsal horn Opiate drugs can do the same thing When they bind to µ receptors they can open potassium channels and cause a hyperpolarisation or close voltage gated calcium channels and reduce the amount of neurotransmitter produced

Question 33

What collateral projections off the main pain pathway can modulate pain?

Answer 33

Periaqueductal grey (PAG) can be stimulated or inhibited by the cortex depending on the emotional state of the person. Can stimulate the nucleus raphe magnus (NRM) - note can also be stimulated by the NRPG Release the neurotransmitter serotonin and enkephalin through the lateral funiculus into the dorsal horn Reduce the transmission of pain up the relay neuron The locus cerelius (LC) - produced noradrenaline which also inhibits transmission in the dorsal horn

Question 34

How does deep brain stimulation alleviate pain?

Answer 34

Can stimulate areas in the brain identified as PAG, thalamus, cingulate cortex with neurostimulator electrodes - artificial pacemaker Highly invasive - relies on electrodes being put deep into the brain Some experiments have shown that they are though to increase the level of natural opioids Others show they cause the release of adenosine Others suggest that they modify the brain circuits to reduce the transmission of pain By stimulating descending pathways we can prevent ascending information about pain reaching the brain

Question 35

What is the nocebo effect?

Answer 35

If you expect a stimulus to be painful, it will be. Psychological basis to our pain The predictions about how painful the stimulus is, is likely to exert a dominant effect on the amount of pain that we actually perceive. found that the PAG can inhibit pain but can also facilitate it.

Question 36

What is pain gating?

Answer 36

If gates open, the spinal cord and substantia gelatinosa, we perceive pain. If closed, we don’t. ``` Conditions that close gates Mechanosensitive stimulation Emotional support Distraction Placebo Anti-inflammatory medication Opiates Environmental danger Learned danger signals Hypnotic suggestion Deep brain stimulation Acupuncture Low dose antidepressants ``` ``` Conditions that open gates Infection Inflammation Depression Anxiety Learned safety signals Learned sickness signals Nocebo effect ```