Pain in the older person 02/04

Question 1

Define nocioception

Answer 1

The physiological response of nervous tissue to perceived or actual tissue damage

Question 2

Which nerve fibre types conduct high intensity noxious stimuli and what is their morphology?

Answer 2

A-delta - thinly myelinated, intermediate diameter, intermediate conducting speed. C fibres - unmyelinated, thin diameter, slow conducting speed

Question 3

What types of sensations do a-delta fibres transmit?

Answer 3

Sharp, immediate, and relatively short lasting. Highly localised pain. They respond to weaker stimuli, which can be temperature-induced, mechanical, and chemical.

Question 4

What types of sensations do C fibres transmit?

Answer 4

Slow, dull aching. Poorly localised pain. Considered to be polymodal, responding to a wide range of stimuli. However there may be different types of C-fibres which have different modalities but can of themselves be only uni-modal.

Question 5

Onto which rexed lamina do adelta fibres synapse in the dorsal horn?

Answer 5

I, II and onto wide dynamic range neurons in lamina V.

Topographical organisation of input to the spinal cord –enables retention of primary afferent encoding of stimulus modality, intensity, location and duration

Question 6

Onto which rexed lamina do C-fibres synapse in the dorsal horn?

Answer 6

Peptidergic c-fibres (substance p expressing) synapse primarily onto NK1R expressing projection neurons in lamina I and II.

Non-peptidergic c-fibres synapse onto vertical cells in lamina II.

Topographical organisation of input to the spinal cord –enables retention of primary afferent encoding of stimulus modality, intensity, location and duration

Question 7

What are the ascending pathways of pain transmission?

Answer 7

Spino-parabrachial - Spinal cord, brainstem, hypothalamus/amygdala

Lateral Spinothalamic tract - spinal cord, thalamus, somatosensory cortex Both decussate in the spinal cord

Question 8

What is the descending pathway of pain modulation?

Answer 8

Amgydala/hypothalamus -> Periaqueductal grey -> rostroventral medulla -> dorsal horn

• PAG is a brain region dense in opioid receptors

Question 9

How does the descending pathway inhibit pain transmission?

Answer 9

Activated neurons in the RVM release endogenous opioids (enkephalins) and 5HT onto the dorsal horn to inhibit transmission

Question 10

How is primary transmission of pain mediated?

Answer 10

Primary pain afferents (sensory) e.g. c-fibres synapse onto second order nocioceptive neurones or WDR neurons (L-V) in the dorsal horn and release glutamate. At high firing frequencies substance P may also be co-transmitted. Often many AP must be summated in order to overcome inhibitory controls and reach threshold for WDR depolarisation.

• Glutamate: activates AMPA receptors evoking fast excitatory post-synaptic potentials (NMDA receptor is blocked)
• Neuropeptides: mainly Substance P which acts via NK1 receptor to elicit slow excitatory post-synaptic potentials enhancing glutamate response

Question 11

What are the molecular mediators of inhibitory control of primary pain transmission?

Answer 11

local spinal networks and descending networks from supraspinal sites.

• GABA: Receptors: GABA-A, GABA-B
• Opioids: μ(MOR) δ(DOR) κ(KOR)
• 5-HT: various receptors
• cannabinoids: CB1 CB2
• Norepinephrin (A2?)

These bind to inhibitory receptors either on the primary afferent or on the projection neuron to cause hyperpolarasation and prevent neurotransmission at the primary synpase

Question 12

Define allodynia

Answer 12

Allodynia can lead to the triggering of a pain response from stimuli which do not normally provoke pain. It is associated with central sensitization which manifests as:

1) ⇓ in the threshold for activation
2) ⇑ receptive field size and recruitment of novel input
3) ⇑ spontaneous background activity of neurones

Question 13

Define hyperalgesia

Answer 13

An increased sensitivity to noxious stimulu which may be caused by damage to nociceptors or peripheral nerves.

Sensitisation in the periphery is primary hyperalgesia. Involves activation and sensitisation of peripheral nociceptors by locally produced inflammatory mediators decreasing the threshold for activation by further stimuli.

Primary hyperalgesia can also trigger central sensitization

Question 14

What is the mechanism underpinning central sensitization?

Answer 14

Increased input from primary afferents results in depolarisation of projection neurons. Kinases are activated and phosphorylate the NMDA receptor, removing Mg2+ block of NMDA channels and leading to enchanced calcium tranmission. If projection neurons continue to be activated then sustained intracellular ca2+ increases will lead to activation of kinases (e.g. PKC), activation of transcription factors and long term changes in gene expression will occur.
This can lead to input:output of primary afferent activation:projection neuron activation exceeding a 1:1 activation

This may lead to hyperalgesia, allodynia or spontaneous pain signal transmission

AB-fibre mediated tactile allodynia. AB fibres can begin to express substance P - therefore DH neurons become activated by non-noxious stimuli.

Question 15

What is the role of microglia in hyperalgesia?

Answer 15

They normally dormantly survey the parenchyma of the spinal cord.
After peripheral nerve injury, they become activtated

Morphological changes -> Become large, dense and retract protrusions

Increased afferent stimulation causes P2X₄ receptor activation.
This causes activaition of BDNF and Fraktalkine pathway which results in inflammation and hyperexcitablity of pain processing pathways

Question 16

Three age related changes in pain systems

Answer 16

Sensitivity in the somatosensory systems decreases with advancing age due in part to diminished numbers of specialised peripheral receptors combined with a deterioration of supporting tissue

1. Peripheral nerves show a reduction in unmyelinated and myelinated fibres
2. Decreased number and size of sensory neurons in dorsal root ganglia
3. Change in NT expression. E.g., decreased labelling of substance P in the dorsal horn, loss of serotoninergic and noradrenergic terminals=reduced descending modulatory pathways

Question 17

What is the effect of Alzheimer’s disease on pain processing?

Answer 17

AD patients may have decreased pain processing. This is supported by clinical data showing AD patients have low frequencies of painkiller prescriptions.

It’s unclear if this relates to reduced chronic pain conditions, or reduced ability to communicate pain.

AD brains show widespread atrophy and neuronal degradation, including areas related to pain processing.

AD mice models show increased endogenous enkephalin expression and reduced thermal sensitivity.

Increased opioid-mediated inhibition may be responsible for the reduced thermal sensitivity associated with AD-related pathology

Question 18

What are the patterns of chronic pain across age.

Answer 18

It is complex, with no overall pattern emerging. It is quite condition specific.

Question 19

How are microglia altered in aging?

Answer 19

Microglia have two states M1, and M2

M1 is associated with neurotoxic effects. They secrete pro-inflammatory agents, induced oxidative stress and immune stimualtion.

M2 is associated with neuroprotection. They promote phagocytotic clearance of debri, release of trophic factors and resolution of immune response.

Aging brain has been shown to preferentially adopt the M1 state even in the presence of factors that would normally stimulate their transition to M2.

Alongside this, they show abnormal morphologies, and cellular death by non-apoptotic pathways.

Question 20

Onto which rexed lamina do AB (low threshold mechanoreceptors) synapse?

Answer 20

They send projections to both excitatory and inhibitory neurons in lamina II and III. They also contact NK1R projection neurons in lamina III, and if they begin to express substance P then this can result in tactile allodynia.

They send projections to lamina IV and V also.