W7: Nociception and Pain - Peripheral and central mechanisms Flashcards

1
Q

We have sensory receptors that are specialised torespond to changes in both the internal and external environment/ These receptors can be classified according to the type of stimulus that activates them. List and describe some examples

A

Mechanoreceptors – generate nerve impulses when they, or surrounding tissues are deformed by mechanical stress – touch, pressure (including blood pressure), vibration and stretch (also involved in special senses of hearing and balance)*
Thermoreceptors – sensitive to temperature changes – warm and cold
Photoreceptors – in the retina of the eye –sensitive to light energy
Chemoreceptors – respond to chemicals in solution – control respiratory and cardiovascular function – also involved in our senses of smell and taste
Nociceptors – respond to stimuli that can potentially damage the body’s tissues

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2
Q

Does everyone feel the same sensation and have the same perception of that sensation?

A

Pain perception varies between individuals
Our survival depends not only on the brain being made aware of changes that are happening (sensation), but also on our conscious interpretation of these events –perception. Receptors recieve same stimulus.
Perception determines how we will respond to stimuli – there may also be a learning component as well

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3
Q

What is the difference between Pain and Nociception?

A

Pain: cortical awareness
Before cortex = Nociception
The actual signal sent in the nociceptive nerves is known as a nociceptive signal - regarding some noxious stimulation. The nociceptive signal is then interpreted by the brain as a sensation of pain

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4
Q

Pain involves Receptors, Processing in central pathways and Conscious perception. Explain how a stimulus is recieved by the receptor.

A

A particular type of stimulus (modality) will stimulate a specific sensory receptor – specificity (ex. distinguish between pressure and feel/type)
The energy of the stimulus is converted into a graded electrical response within the receptor = receptor potential, may be excitatory or inhibitory

The stimulus must be within the area that a particular sensory receptor is monitoring – receptive field

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5
Q

Describe ‘generator potentials’

A

Membrane depolarizations that summate, and may lead to action potentials are referred to as generator potentials
ie. A generator potential must reach threshold in order to generate an action potential through the opening of voltage-gated Na+ ion channels

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6
Q

How is severity of a stimulus distinguished?

A

Information about the stimulus is encoded in the frequency of the nerve firing – the greater the frequency of firing, the more intense the stimulus

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7
Q

Explain sensory receptor adaptation

A

Many sensory receptors undergo adaptation –there is a change in their sensitivity (and rate of firing) in response to a constant stimulus –as a result, they respond more to what is new, or what is changing
= PHASIC RECEPTORS

Ex. When sitting you are only aware of the pressure when you sit down or stand up. Not when you are sitting down (no continuous signals)

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8
Q

Describe the difference between tonic and phasic receptors

A

Phasic receptors: Receptors that rapidly adapt to stimuli – give bursts of impulses at the beginning and the end of a stimulus

Tonic receptors: Receptors that give a sustained response to a stimulus, with little, or no, adaptation Ex. most proprioceptors and nociceptors - normally become more sensitive to noxious stimuli

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9
Q

Explain the sensory pathway of the pressure of holding a pen

A

Low threshold mechanoreceptor pathway, Primary afferent neurons (sensory neurons) cell body in dorsal root ganglion enter dorsal horn of spinal chord (white matter tracts ie. dorsal columns) -> medulla -> cross over in thalamus -> cerebral/ cortical representation

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10
Q

Explain the processing that happens at the spinal chord level

A

Information recieved at appropriate level of neuroaxis (vertebral level) through primary sensory nerve (first-order neuron). Processes enter the dorsal horn of the spinal cord.

Some branches of these primary nerves may be involved in local, or spinal, reflexes. Others synapse with second-order sensory nerves associated with the ascending sensory pathways that run to the thalamus.

Third-order neurons, whose cell bodies reside in the thalamus, conduct impulses to the somatosensory cortex

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11
Q

List the three somatosensory pathways (ascending pathways in the spinal cord)

A
  1. Non-specific pathways (anterolateral – anterior and lateral spinothalamic tracts
  2. Specific pathway (medial lemniscal)
  3. Spinocerebellar tracts
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12
Q

Describe the Spinal Thalamic - anterolateral tract pathway

A

Non-specific pathway (anterolateral – anterior and lateral spinothalamic tracts)
Noxious information conveyed centrally: pain, temperature and course-touch– sensations we have difficulty in precisely localising –involved in emotional aspects of perception

Synapse spinal cord, synapse in thalamus, third neuron up to cortex
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13
Q

Desctibe the medial lemniscal dorsal column pathway

A

Specific pathway - low threshold
mediates precise information from a single type of sensory receptor that can be precisely localised on the body surface – from the thalamus, impulses are relayed to specific areas of the somatosensory cortex

synapse in medulla, second to thalamus third to cortex
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14
Q

Describe the Spinocerebellar tract pathway

A

convey information about muscle or tendon stretch, as well as proprioceptive information –these pathways do not contribute to conscious sensation – information used to coordinate skeletal muscle activity

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15
Q

Where does interpretation of sensory information occur? What does this rely on?

A

Interpretation of sensory information occurs in the cerebral cortex

Relies on where the signal came from, not from the signal itself – one actionpotential is just like another. For example the nature of the nerve that sent the signal tells us what the message is about e.g. pain,touch, warmth, taste etc.

Differs from person to person

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16
Q

What is the major sensory relay station in the brain?

A

The thalamus
gateway of the cortex - recieved info from all sensory inputs. Sorts edits and packages information for the appropriate area of the sensory cortex
Crude recognition of sensation happens at the thalamus - pleasent or unpleasent

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17
Q

Provide the defintion of pain, distinguishing acute vs chronic

A

Pain: An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.

Pain is commonly described as acute/nociceptive/physiological pain, or chronic when it lasts for longer periods.
Chronic Pain as pain without apparent biological value that has persisted beyond the normal tissue healing time (usually taken to be 3 months).

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18
Q

Describe the type of nerve involved in pain

A

Only sensory (afferent) nerves of clinical interest are those involved in generating sensations of painnociceptive nerves

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19
Q

Information regarding pain is transmitted in two types of nerves…Describe.

A

C-fibres - fine, slow conducting non-myelinated nerves (polymodal nociceptors) - dull, burning pain
Aδ fibres - fine, myelinated fibres - conduct more rapidly, but respond to same stimuli - sharp, well localised pain
Both involved in conveying nociception information centrally
Plus Ax and AB fibres - low threshold mechanoreceptors for proprioception and touch

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20
Q

Explain the biopsychosocial model of health

A

Pain is multifactorial.
The amount of pain felt in response to a given noxious stimulus varies between individuals* But also varies within an individual – it is particularly dependent on circumstance and mood (subjective sensation)

21
Q

What two factors impact conduction velocity?

A

Degree of Myelination and diameter

22
Q

Desribe the different afferent fibre modalities involved when injury occurs Ex. stubbing a toe

A

Ad fibre – conduction velocity ~ 20 m/sec – less than 0.1seconds (first pain)
C-fibres – conduction velocity ~ 0.5 m/sec – between 3 and 4 seconds (second pain)
stimulus delivered at same time, difference in perception due to different conduction velocity in the fibres

23
Q

Primary afferent nociceptive nerves have a peripheral terminal, cell body and central terminal. Describe the significance of this with regards to pathologic conditions.

Peripheral vs central release

A

CONCEPT OF NEUROGENIC INFLAMMATION - nerve generated/mediated inflammation
Normally The direction of AP’s: stimulus = transduction of info towards CNS (dorsal horn of grey matter) (orthodromic direction) - seen in white picture
BUT
Nothing to stop AP from travelling in either direction when some sort of stimulus initiates ie. toward peripheral terminal (antidromic direction). Glutamate, CGRP ect. release = vasodilation and swelling
= seen in chronic pain conditionsas seen in yellow picture

Happens as there is no difference between peripheral and central terminals

24
Q

List the N.T’s released by nociceptive nerves

A

Glutamate = fast N.T
Peptide N.T’s (substance P, neurokinin A, Calcitonin Gene Related Peptide (CGRP)) = second, more robust stimulus required for release

25
Q

Describe the difference between C and Aδ Nociceptive Nerves

A

Whilst the C and Ad fibres basically respond to the same types of nociceptive stimuli, they have slightly different characteristics and distributions…

Aδ fibres:
- mainly innervate the skin (not normally associated with deeper structures)
- give rise to pain associated with needle prick, cut, acute burn AND important role in reflex responses aimed at limiting or preventing tissue damage eg withdrawal reflex
- small diameters, their myelin sheath enables higher speed conductivity of action potentials
- sensitive to inhibition by pressure, but are relatively insensitive to low doses of local anaesthetics

C-fibres
- associated with skin, but also innervate deep tissue and organ systems
- nauseous, chronic pain associated with tissue damage and destruction
- relatively insensitive to inhibition by pressure, but are sensitive to low doses of local anaesthetics

26
Q

Explain the concept of polymodal nociception and give an example of a polymodal receptor.

A

Pain may be associated with a whole variety of stimuli- mechanical, chemical, thermal - hence “polymodal nociceptor.” The only common factor is that the stimulus is sufficiently intense to cause tissue damage –hence these nerves normally have a high threshold for stimulation

TRPV1 is a high threshold receptor only located on pain sensing neurons in the periphery (nociceptive N’s). Polymodal receptor activiated by Capsaicin (chemical - chilli), Temperature, H+, Lipids, Mechanical stimuli
potential therapy: TRPV1 antagonists, blocking pain (not motor or autonomic activity)

27
Q

What is the main ion that contributes to Activation of Nociceptive Nerves

A

Ca2+ - opening leads to depolarisation
excessive Ca2+ = apoptosis

28
Q

Where do local anesthetics bind?

A

Intracellular epitope of voltage gated Na+ channels

29
Q

Define sensitisation

A

Increase in responsiveness of nociceptive neurons to their normal input, and/ or recruitment of a response to normally subthreshold inputs.
Clinically: symptoms of hyperalgesia and allodynia

Central: contributes to chronic pain states
Periphral: bee sting/burn ect.

30
Q

Describe peripheral sensitisation

A

Freq of AP and thermal threshold for activation is increased post sensitisation. ie. Easier to activate
DUE TO
* cell bodies producing more receptors (increase in dentistry of voltage gated Na or TRPV channels)
* intracellular messengers (protein kinases) change the function of proteins/receptors - post translational modification
* in periphery inflammation impacts receptors…

31
Q

How is neurogenic inflammation linked to peripheral sensitisation

A

Glutamate, substance P, CRGP released at the peripheral terminal = vasodilation and increased permeability = infiltration of immune cells/mediators releasing cytokines and signals = change in pH and release of ATP = TRVP1 and acid senscing respond/activate = changes to sensitivity of receptor, more readily excited, easier to activate fibres

32
Q

How is peripheral sensitisation linked to dentistry

A

Peripheral sensitisation key to many dental pain conditions
short term changes in response to pulp or odontoblast fibres

33
Q

Define Hyperalgesia,
Primary and Secondary…

A

Increased amount of pain associated with a mild noxious stimulus
Primary = Peripheral
Secondary = Central component

34
Q

What leads to central sensitization? ie. causes

A

Causes:
* Activate both A and C fibres consistently (longer) at high frequency = Ectopic firing = WIND UP ie. sustained enhanced responses
* Nerve degeneration (Wallerian)
* Phenotypic changes in AB (pathologic - sprout into new teritory)

35
Q

Define Allodynia
give examples

A

Pain evoked by a non-noxious stimulus- may also get spontaneous pain spasms - no precipitating stimulus
Example:
- Sprain ankle
- Try to walk - painful due to weight on injured ioint
- Not a pathological pain state

36
Q

Describe the etiology of central sensitisation, the contributing factors and syndromes that result

A
37
Q

Define Neuropathic Pain

A

Diseases that affect sensory nerve pathways may produce severe, chronic pain
* Neuropathic pain is unrelated to any peripheral tissue injury - occurs with stroke, multiple sclerosis, mechanical damage, diabetes and herpes zoster infections (shingles)
* ONE mechanism associated with this - damaged nerve terminals express a-adrenergic receptors - become sensitive to noradrenaline

38
Q

Describe the N.T’s and mechanisms of central sensitization

A

NT involved:
* Glutamate release - binds to glutamate receptors.
* AMPA, kainite, mGLUR…
* NMDA receptors - these are normally quiet at resting membrane potentials and have a Mg+ block

Mechanism: At the synapse of second-order neurons, this increased responsiveness can involve changes in calcium permeability, receptor overexpression, and synapse location
* De novo gene exp.
* Alterations in protein actions
* Decreased desending inhibitory drive

increased responsiveness of nociceptive neurons in the central nervous system to their normal or subthreshold afferent input

39
Q

Compare peripheral and central sensitisation in terms of time and neurons involved

A

PERIPHERAL:
* Primary afferent
* short term
* Inflammatory or peripheral nerve changes usually at the peripheral ends
* Mechanisms: Post-translational modification, protein upregulation…
Example: heat sensitivity after sunburn.

CENTRAL:
* Second or third order (secondary is medullary dorsal horn for orofacial pain)
* longer term
* Increase in excitability in CNS - may involve protein upregulation, de novo protein expression (not normally produced)…

40
Q

Recount the endogenous pain suppression systems ie. Desending inhibitory drive

A

Pathways travelling down the spinal cord from brain…
1. Periaqueductal Gray (midbrain) -> projects to rostral ventral medulla (raphe nuclei) which RELEASES serotonin and projects to dorsal horn
2. Locus Coeruleus releases noradrenaline (acts on Alpha 2 receptors Gi/Go coupled - inhibit adenylate cyclase) and projects to dorsal horn
3. Rostroventral Medulla

Decrease pain transmission from the cord to the brain releasing…
noradrenaline and serotonin and endorphins (enkephalins)
If you can cause pain somewhere, the pathway activated (not specific), therefore pain elsewear is dimished as a result!

41
Q

Describe the factors/areas involved in pain modulation

A

Neurons in the substantia gelatinosa can either potentiate inhibit nociceptive (pain)
transmission
* Nociceptive signals (C and AS fibres) cause the substantia gelatinosa to further potentiate pain transmission
* Signals from mechanoreceptors (AB fibres) and the descending
inhibitory pathways
will cause the substantia gelatinosa to inhibit
pain transmission

Interneurons inhibitory or excitatory can impact the output from that level of the spinal cord (medullary dorsal horn) - PAIN GATE MECHANISM

42
Q

Why is Pre-emptive analgesia Impt.

A

Pre-emptive analgesia blocks input that causes central sensitisation

43
Q

Describe “Gate Theory” and how it contributes to pressure anaesthesia

A

Sometimes C fibre activation = strong activation and excitatory input
BUT If AB fibres activated = activation of inhibitory interneurons = release of GABA = Cl influx = hyperpolarisation of membrane = dimish potenital/response

44
Q

Describe some adjunct therapies that are used for pain inhibition which are associated with the descending inhibitory pathways

A

High levels of endophorus opioid peptides and their receptors are found in the PAG, rostral ventral medulla and primarily at the dorsal horn + act locally direclty on peripheral neurons
Part of morphine’s (and other opioid analgesic effects are mediated via these pathways

45
Q

Define referred pain, why does it occur?

A

A patient may often feel pain in a part of their body that is quite remote from the tissue that is causing the pain
occurs because there is convergence of the signals from visceral nociceptive nerves with those from the cutaneous nociceptors - within the spinal cord there appears to be mixing of this information

46
Q

Why does visceral pain occur? Why is it important to diagnose?

A
  • In general, the main sensory nerves associated with the viscera are nociceptors
  • Very localised damage to a viscera seldom causes severe pain, but conversely any diffuse stimulus is likely to cause severe pain (e.g. ischaemia)
    Identification of visceral pain is important in clinical diagnosis - way of picking up on inflammation and infection in the viscera
47
Q

What are the main causes of visceral pain?

A
  • Ischaemia - presumably through build up of acidic and metabolic by products
  • Chemical stimuli - leakage through a ruptured gastric or duodenal ulcer
  • Muscle spasms in a hollow viscus - probably due to mechanical stimulation of the nerve endings, although ischaemia can also develop due to reduced blood flow
  • Overdistension of a hollow viscus - again probably due to mechanical forces and possibly ischaemia
48
Q

Why do muscle spasms/pain occur?

A

Result of direct mechanical stimulation of nociceptive nerves, although may also occur as a result of secondary ischaemia
Spasms of the muscles in the head and neck are one of the common causes of headaches