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How do we define pain?

Nociception: activation of nociceptive primary afferents; cutaneous and internal, the physiological aspect of detecting pain-causing stimuli

Pain: conscious, affective unpleasant somaesthetic percept localised to the body

Hyperalgesia: increased sensitivity to noxious stimuli


What is an experimental demonstration that nociception involves specialised neurons?

- insert a small electrode/recorder into skin to a pain receptor
- use heat (doesn't stimulate other nerve fibres i.e. touch mechanoreceptors)
- map receptor field of a single nociceptor fibre
- they have a very high threshold for activation
- they don't respond until things get quite high energies
- the non-nociceptive thermoreceptor is sensitive early on but plateaus after a certain point (~42ºC) while the nociceptor only begins firing at this temperature and increases firing with increased heat


What are the different types of nociceptor afferents?

- nociceptors are the thinnest nerve fibres in the periphery
- they are either unmyelinated (C fibre) - myelin would actually slow down the conduction of the impulse in a fibre this small; very slow conduction (less than walking speed)
- A-delta fibres: thinly myelinated, ~5µ, faster, tend to signal different aspects of noxious stimuli, high-threshold mechanoreceptors

- fast, sharp pain sensation (A-delta)
- C fiber - diffuse or duller burning pain

- most C fibers don't respond to just one stimulus
- noxious mechanical injury, chemical, high acid [H+], various other inflammatory mediators


What is the association between axon size, conduction velocity and somatosensory modality?

- big (13-20µ), fast (80-120m/sec), highly myelinated
- proprioreceptors of skeletal muscle

- myelinated
- 6-12µm
-35-75 m/sec
- mechanoreceptors of skin

- 1-5µm
- 5-30 m/sec
- pain, temperature

- 0.2-1.5 µm
- 0.5-2 m/sec
- temperature, pain, itch

- there's more C fibres than anything else, every tissue in the body has innervation from C fibres
- massive, broad innervation so need small diameter


What activates nocireceptors?

- heat
- H+ concentration
- chemicals such as capsaicin (found in chiles), lipid soluble molecule that diffuses through the membrane and acts on an internal part of the receptor
- a lot of these act at a single molecular place in these nerve membranes
- VR-1 receptors
- also mechanical gated channels
- these agents lead to depolarisation of the neuron (cation channels)


What is the pathway of a nociceptive afferent?

- cell body in dorsal root ganglion
- nociceptors invariably do their transmitting locally
- within a segment or two of entering the spinal cord they find their postsynaptic cell
- the postsynaptic cell is usually sitting in the very superficial part of the dorsal horn
- this first synapse is usually the first opportunity for things like drugs to work (not counting periphery)
- second neuron does long range projection up the spinal cord to brainstem and thalamus
- second neuron decussates
- travel in anterior and lateral part of the white matter
- aka Anterior Lateral System (ALS) aka spinothalamic tract
- second neuron has targets in the thalamus (also other places in the brain stem)


What happens in the superficial dorsal horn?

- nervous system organised in layered system
- C fibres invariably synapse in the superficial dorsal horn (directly or via interneurons to decussating neuron)
- A-delta fibre: synapses on superficial dorsal horn neurons (perhaps converging onto same neuron), also has some projection neurons in layer V (smaller proportion)

- we seem to get convergence of the specificity/differences of the peripheral nociceptors in the spinal cord, even converging on cells that get touch AND nociceptive information
- unclear how we get such a clear distinction between painful and non-painful stimuli etc


What different symptoms might you get in a lesion of the spine based on its location?

'Textbook lesion' - what would happen if half of your spinal cord was cut
- on the opposite side to the lesion you have reduced sensation of temperature and pain
- on the same side as the lesion you have reduced sensation of two-point discrimination,vibration, and proprioception

'harlequin sensory loss'
- you also have a zone of complete loss because there are a few segments where the nociceptors travel before they decussate


Where does the anterolateral system send information?

Different parts of the brainstem/forebrain
1. (major target) ventral posterior nucleus --> somatosensory cortex (S1, S2) – sensory-discriminative (location)
2. midline thalamic nuclei --> anterior cingulate cortex and insular cortex (affective-motivational) (pain is extremely motivational)

generating conscious experience of pain/what it is what it feels like (also the midline thalamic nuclei)
3. reticular formation
4. superior colliculus
5. periaquiductal grey
6. hypothalamus
7. amygdala (key structure in negative experience/emotions)


What is the cingulate cortex?

- 1cm - 1.5cm of cortex that sits above the corpus callosum
- right on the midline
- anterior: where a lot of the nocireceptor pathways seem to end/location of cortical targets (3rd neuron in path from thalamus to anterior cingulate)
- a lot of emotional states that we experience seem to require anterior cingulate cortex e.g. hunger, thirst, pain


What is the insula cortex?

- quite internal (if you cut out part of cortex just superior to sylvian fissure - underneath
- gets a lot of input from nociceptors, also visceral nociceptors (viscerotropic)
- also gets interoceptive input e.g. porcinian corpuscles in the peritoneal cavity
- mysterious
- might have something to do with how we localise that pain as our own
- 'my' body


What are pathways mediated discriminative aspects of pain/temperature for body and face?

- primary afferent containing pain and temperature information from lower body enters lumbar spinal cord
- cervical spinal cord for upper body excluding face
- second neuron (projection neuron in superficial layer of dorsal horn) decussates - anterolateral system
- travels through brainstem to thalamus (spinothalamic tract)
- third order neuron in thalamus that meets cortical targets

- for face: trigemino nucleus - pain and temperature info, spinal trigeminal tract (afferent axons) come down to caudal medullar to find a place to decussate, trigemino-thalamic tract


What activates the receptors on C fibres?

- think of things that are present when skin is damaged
- H+
- 5-HT
- Bradykinin
- ATP (extracellular)
- prostaglandin
- histamine (released by mast cell or neutrophil)


What happens when a C fibre is stimulated?

- apart from the action potential that travel to the spinal cord
- we have nerve impulses that after travelling retrogradely, travel anterogradely at branching points where they actually release compounds
- sensory and effector
- release small peptides e.g. substance P (stimulates mast cells or neutrophils) or CGRP (calcitonin gene related peptide) which acts on blood vessels
- these are inflammatory
- vasodilation, histamine release
- very short reflex


How can we think of pain as a homeostatic system?

- it's a mechanism of maintaining the integrity of tissue
- mechanism of detecting damage and of reversing damage (C fibres)
- have a homeostatic conscious mechanism - behavioural mechanisms


What are phantom limbs/phantom pain?

- amputation
- normal sensation of people after they lose the limb is that it still remains
- sometimes it is incomplete (only fingers)
- sometimes it might be telescoped (foot feels closer than it normally would have had it still been there)
- sometimes painful
- how can you feel limbs without nerves?:
-- mechnoreceptors in skin etc aren't to tell you that you have an arm, they are to tell you that some part of the external world is touching your arm
-- we don't have nerves that say 'this is your body' --> we somehow construct that out of all the inputs that we have, maybe very little reliant on mechanoreceptors
-- mechanoreceptors and proprioreceptors tell you the location and what it's doing and touching - modulate your sense of 'you'
- high level conscious perception that can exist without the sensory inputs coming from the arm
- pain is different because it tells us about the physiological state of our tissues: rare compared to phantom limb
- almost have to remove the cortex to remove phantom pain - very difficult to treat


What are the descending systems that modulate the transmission of ascending pain signals?

Somatic sensory cortex/prefrontal cortex (more important)
Activates structures that are associated with emotional experience and homeostasis (amygdala and hypothalamus)
Activation of structures in the brainstem
Brainstem projects right down through to the dorsal horn of spinal
Modulate activity through the first synapse
e.g. Excites an interneuron (locally) that is inhibitory (pre-synaptic inhibition), typically very small peptides (e.g. endorphins or ekephalins) as neurotransmitter, reduce activity through nociceptive pathways
Endogenous pain reductive system driven from the top of the hierarchy


Is the idea of a "pain pathway" an oversimplification?

- yes
- what we have learnt is most definitely oversimplified
- don't have a full understanding - lots of things that still confuse us about pain and its interconnectedness with somatosensory etc
- much more complex picture yet to emerge