Introduction to Pain Flashcards by Aliya Hussain

What is pain?

Unpleasant sensory and emotional experience, assoc. with actual tissue damage or described in terms of such damage (may arise spontaneously)

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3 classifications of pain?

Nociceptive pain (adpative - there is a biological purpose)
Inflammatory pain (adaptive and protective) - caused by activation of the immune system in injury/infection
Pathological pain (maladaptive - has outlived its biological purpose)

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What are nociceptors?

Specific peripheral primary sensory afferent neurons; they are FIRST ORDER neurons that relay info to second order neuron (in the CNS) by chemical synaptic transmission

Normalyl activated by INTENSE stimuli, e.g: thermal, mechanical, chemical, that are NOXIOUS

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Structure of nociceptor nerve ending?

Free nerve ending, in the periphery, has no surrounding structure, allowing sensory function

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Steps in nociceptor transmission?

Depolarization due to noxious stimulus elicits action potentials that propagate to the CNS

a.p arrives at central terminal in the CNS, which releases neurotransmitters that excite second order neurons

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Function of nociceptor pain?

Warning system to detect and minimise contact with noxious events, i.e: pain is felt and there is an autonomic response allowing the withdrawal reflex

It is HIGH THRESHOLD and so only provoked by intense stimuli

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Other consequences of nociceptor pain?

Initiates a withdrawal reflex

Unpleasant

Engages adverse emotional components

Inscribes memories, allowing avoidance of harm in the future

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How does inflammatory pain occur?

Peripheral inflammation means that there are inflammatory cells and tissue damage

These cause spontaneous pain and pain hypersensitivity

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Consequences of inflammatory pain?

Pain hypersensitivity (to noxious stimuli)
Allodynia (innocuous stimuli elicit pain)
Assists in healing of a damaged body part, i.e: tenderness discourages physical contact and movement

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Why does inflammatory pain require treatment?

Even though it is adaptive, suffering must be alleviated, e.g: in rheumatoid arthritis

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Cause of pathological pain?

Abnormal nervous system function, either neuropathic or dysfunctional

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How does neuropathic pain occur?

Neural lesion produces peripheral nerve damage, e.g: a stroke

Abnormal central processing causes spontaneous pain & pain hypersensitivity

There is maladaptive, low-threshold pain

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How does dysfunctional pain occur?

There is no neural lesion nor any inflammation and so the peripheral tissue and nerves are normal

But, there is still abnormal central processing and so the end result is the same as for neuropathic pain

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Differences between neuropathic and inflammatory pain?

Inflammatory pain is longer-lasting and can be provoked by moderate stimuli (not just intense)

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Describe the 3 types of pain using a fire alarm analogy

Nociceptive pain - system is working as intended and is only activated by intense heat

Inflammatory pain – system is activated by warm temps

Pathological pain – system is malfunctioning and sounding false alarms

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Condition where there is an absence of pain?

Congenital insensitivity to pain (CIP) - loss of function mutations that encode a part. voltage-activated Na+ channel, which is highly expressed in nociceptive neurons

Consequences of CIP?

Gross bodily damage:
• Lip and tongue injury
• Bruises and cuts
• Multiple scars
• Bone fractures
• Joint deformity
• Premature mortality due to multiple injuries/infections

2 types of nociceptors and the differences between them?

Aδ- fibres:
• Thinly MYELINATED
• Respond to noxius MECHANICAL/THERMAL stimuli
• Mediate FAST/first pain, i.e: stabbing/pricking sensations

C-fibres:
• UNMYELINATED
• Collectively respond to ALL noxious stimuli
• Mediate SLOW/second pain, i.e: burn/throb/cramp/ache sensations

How do mechanical stimuli activate nociceptors?

Activate mechano-receptors

Receptors/channels remain uncertain but Piezo 2 may contribute

How do thermal stimuli activate nociceptors?

Activate hot/cold sensitive receptors; these are members of the transient receptor potential (TRP) family, esp. TRPV1
Na+/Ca2+ influx
Depolarised membrane (graded)
Voltage-gated Na+ channel activation
Action potential to CNS

How do chemical stimuli activate nociceptors?

H+ activates acid-sensing ion channels (ASICs)
ATP activates P2X and P2Y receptors
Bradykinin activates B2 receptors

How do sensory neuron terminals transduce a stimulus, e.g: mechanical/chemical/thermal, into electrical activity?

Stimulus opens cation-selective ion channels in the nerve terminal; this elicits a depolarising receptor potential (amplitude is GRADED and proportional the intensity of the stimulus)

Local current triggers all-or-none a.p at a frequency proportional to amplitude of the receptor potential

Describe the graph of stimulus strength (x-axis) and amplitude of observed receptor potential (%)

Non-linear relationship with a greater sensitivty to change at low stimulus strength

Eventually, saturation of nerve fibre firing occurs

PICTURE 32

Describe the nociceptive pathway

Noxious stimulation at the free nerve ending, either C-polymodal or Aδ-, travels down the axon of the nociceptor (first order neuron) and into the dorsal horn of the spinal cord at that level

This signal crosses the spinal cord and enters the second order neuron, before travelling to higher brain centre via the:
Spinothalamic tract
Spinoreticulothamamic tract

Differences and similarities between Aδ- fibres of nociceptors?

Both sense mechanical and thermal stimuli but Type II has a lower temperature threshold (43 C) than Type I (53 C)

What are peptidergic polymodal nociceptors?

Subset of C-fibres that have afferent and efferent functions

Functions of peptidergic polymodal nociceptors?

Afferent: transmit nociceptive info to CNS via release of glutamate and peptides (substance P, neurokinin A) within the dorsal horn Efferent: release pro-inflammatory mediators, e.g: calcitonin gene-related peptide (CGRP), substance P, from peripheral terminals This contributes to NEUROGENIC INFLAMMATION

Consequences of long-term afferent peptidergic polymodal nociceptor stimulation?

Noxious stimulation in the long-term increases spinal excitability contributing to hyperalgesia and allodynia

How does neurogenic inflammation occur?

1. Peptides (SP and CGRP) released from free nerve ending of peptidergic nociceptor, due to tissue damage or inflammatory mediators 2. SP causes: (i) Vasodilation and extravasation of plasma proteins (promotes formation of bradykinin and prostaglandins) (ii) Release of histamine from mast cells (iii) Sensitizes surrounding nociceptors 3. CGRP induces vasodilatation 4. Primary and secondary hyperalgesia and allodynia ensue

Steps in neurotransmission between the primary afferent and 2nd order neurone (in the dorsal horn)?

1. a.p in the primary afferent causes opening of voltage-activated Ca2+ channels and Ca2+ influx occurs 2. GLUTAMATE is released into the synaptic cleft 3. These bind to glutamate receptors of the 2nd order neuron, causing membrane depolarisation 4. Opening of voltage-activated Na+ channels and a.p stimulation

What receptors does glutamate (primary transmitter) bind to?

Produces a FAST e.p.s.p. and neuronal excitation by activating post-synaptic AMPA receptors, with NMDA receptor participation

Describe the involvement of peptides (substance P and CGRP)

Participate mostly during high frequency stimulation, stimulating a SLOW and PROLONGED e.p.s.p. that facilitates activation of NMDA receptors, by relieving voltage-dependent block by Mg2+

Where does axon termination occur, for input to the spinal cord?

Centrally in the dorsal horn of the spinal cord, in various LAMINAE OF REXED

Where do nociceptive C- and Aδ- fibres terminate?

Mostly in the superficial Laminae I and II Aδ- also terminate in Lamina V

What are Wide Dynamic Range (WDR) neurons?

Receive input from all 3 types of fibre and so respond to a wide range of stimuli

How do 2nd order neurons ascend the spinal cord?

Spinothalamic tract (STT) Spinoreticular tract (SRT)

2 pathways of the STT and requirements for pain perception?

* Projection neurones originating from lamina I (fast fibre Aδ pain) terminate in posterior nucleus of the thalamus * Projection neurones originating from lamina V (WDR neurones) terminate in posterior and ventroposterior nucleus of the thalamus Pain perception (location, intensity) requires simultaneous firing in both pathways

Functions of the SRT?

Transmits slow C-fibre pain Makes extensive connections with reticular nuclei in the brainstem Also, inv. with autonomic responses to pain, arousal, emotional responses and fear of pain