2016A13 Outline the physiological mechanisms of progression from acute to chronic pain
and how drugs may alter this progression.

 

List:

·       Intro: chronic pain

·       Peripheral sensitization

·       Dorsal horn sensitization

·       Higher processing

 

Intro: chronic pain

Definition

·  Chronic pain: > 3 months

·  Initial insult resolved

Features

·  Hyperalgaesia: hurts more than should

·  Allodynia: hurts when shouldn’t

·  Neuropathic pain: hurts due to nerve damage

·  Phantom pain: hurts after body part removed

Risk factors

·  Surgical: nerve injury e.g. amputation, breast, thoracotomy -> ↑dorsal horn activation

·  Patient: depression, psychosocial stressors -> altered cortical processing

·  Pain character: neuropathic, phantom -> ↑dorsal horn activation

 

Peripheral sensitization:

Inflammation -> nociception

·  Inflamed tissue and WBC release NGF, neurturin etc

·  ↑nociceptive receptor activation and expression

Nociception -> inflammation

·  Nociceptor releases substance P, VIP etc

·  Mast cell degranulation

·  Vasodilatation, capillary leak

·  WBC chemotaxis, differentiation

·  *note vicious cycle*

Nerve injury -> nociception

·  Spontaneous abnormal discharge -> neuropathic pain

·  ? Altered receptor function

Prevention

·  Anti-inflammation: NSAID

·  Inhibit bradykinin-sensitive nociceptors: paracetamol

(both less effective in chronic pain)

·  Nerve injury: no effective peripheral agent exists yet

 

Dorsal horn sensitization:

Gain of function WDR neurons

·  Inflamed tissue, injured nerve -> ↑ NMDA activation

·  Brief: ↑receptor irritability -> “wind-up”

·  Persistent: synaptic reinforcement -> “long term potentiation”

·  Mechanism: NMDA -> 2nd messenger and altered gene expression

o  Early: ↑c-Fos, COX-2

o  Late: ↑NK1, TrkB

Gain of function of excitatory neurons

·  Inhibition of VDKC -> ↑excitability

Loss of function of inhibitory neurons

·  (Don’t know the cause)

Abnormal new connections

·  e.g. Aβ 1° afferents -> nociceptive specific 2° afferents

·  Touch becomes painful

Effects on chronic pain

·  Hyperalgaesia

·  Allodynia

·  Expansion of receptive field

Prevention

·  Regional anaesthetic: inhibit pre-synaptic VDNaC

·  Neuraxial anaesthetic: inhibit VDNaC at dorsal horn, spinal nerve root (very effective)

·  Monoamine reuptake inhibitors: ↓pre-synaptic activity

·  NMDA antagonists: ↓ post-synaptic activity, sensitisation, reinforcement (very effective)

·  Antagonists at pre-synaptic VdCC α2δ subunit: ↓pre-synaptic activity

·  Opioids: inhibit 1° afferent (less effective for chronic pain)

 

Higher processing:

Thalamus

·  ↑Production of CCL21 -> ↑PGE2 production by microglia -> sensitisation
-> hyperalgaesia, allodyania

Cerebral cortex

·  Psychiatric illness increases risk of chronic pain

·  Mechanism poorly understood

·  Anti-depressants may help (e.g. SSRI – fluoxetine)