CENTRAL SENSITIZATION (CS)

Annotations:

• Def-   Enhanced responsiveness of nociceptive neurons in the CNS to their normal afferent input   

1. Discovery
   1. Woolf, 1980's

      Annotations:

      • brief (∼10–20 s), low frequency (1–10 Hz) burst of action potentials into the CNS generated by electrical stimulation or natural activation of nociceptors increased synaptic efficacy in nociceptive neurons in the dorsal horn of the spinal cord and this lasted for tens of minutes after the end of the conditioning stimulus
2. Maintenance

   Annotations:

   • of CS
   1. activity-dependent synaptic plasticity
   2. microglia
   3. gap junctions
   4. membrane excitability
   5. gene transcription
3. CNS is plastic

   Annotations:

   • it demonstrates the plasticity of the CNS
   1. Changes in pain
      1. Duration
      2. Degree
      3. Sensation

         Annotations:

         • the sensation we feel no longer represents the stimulus, but the functional state of circuits in the CNS

1. LaMotte (1991)

   Annotations:

   • using capsaicin injection (activates TRPV1 receptors) >> intense localised pain lasting minutes at the injection site, >> followed by three-zone hyperalgesia
2. La Motte and Torebjork (1992)

   Annotations:

   • intradermal injection of capsaicin to induce an area of tactile allodynia that lasted for 2 h
   •   Nerve block experiments revealed that while the capsaicin and heat pain was carried by C fibers, the mechanical allodynia was transferred to the CNS by low threshold myelinated fibers.   
   • electrical intraneural stimulation of single Aβ mechanoreceptive fibers that elicited a non-painful tactile sensation before the capsaicin injection, began to produce pain if the fibers’ receptive field fell within the zone of secondary mechanical hyperalgesia
3. Koltzenburg and Torebjork (1994)

   Annotations:

   •    using mustard oil (which activates TRPA1) as the pain conditioning stimulus, together again with differential nerve blocks, confirmed that brush-evoked mechanical allodynia was mediated by low threshold Aβ fibers that normally encode non-painful tactile sensations  
   • evoked tactile allodynia required an ongoing low level input from C-nociceptors to sustain it
   •    >> indicating that different sensory fibers may have  different central actions, some short and others long lasting  
4. Sang et al (1996)

   Annotations:

   •   intradermal capsaicin model in volunteers together with radial or ulnar nerve blocks to clearly identify individual nerve territory >> found that diagnosing CNS damage can be done using peripheral methods   
5. Schulte et al (2004)

   Annotations:

   •    skin hyperaemia induced by a skin burn injury and the skin blood flow changes induced by the injury disappear by the time secondary mechanical hyperalgesia peaks o   the two were not correlated in time or space, supporting the conclusion that peripheral mechanisms do not contribute to secondary hyperalgesia.   
6. Shenker et al (2008)

   Annotations:

   • intradermal capsaicin induces contralateral hyperalgesia and allodynia that are delayed in their manifestation and reduced in extent compared to the ipsilateral secondary hyperalgesia, but present in a majority of subjects  >> a form perhaps of “tertiary hyperalgesia” that cannot be peripheral in origin.   
7. Witting et al (2000)

   Annotations:

   • Repeated capsaicin injection- response to intradermal injection of capsaicin is dependent on the time and distance between injections. The lack of significant relation between capsaicin pain intensity and area of allodynia and punctate hyperalgesia suggests that the two phenomena are mediated by different central mechanisms
8. Limitations

   Annotations:

   • Experimental studies in human volunteers are necessarily restricted to use non-injurious conditioning inputs, and therefore are limited to studying only the activity-dependent components of pain hypersensitivity elicited by sensory inputs, and not those transcription-dependent and structural changes that manifest after inflammation or nerve injury, which may have different mechanisms, time courses and presentations 

1. intradermal injection in man

   Annotations:

   • Capsaicin or mustard oil >> skin conditioning stimuli hypertonic saline injections >>experimental muscle pain
   1. Coupled with nerve damage/block

      Annotations:

      • tests whether peripheral and central mechanisms are connected
2. Electrical stimulation
   1. C-fibres (noci)
   2. Ad-fibres(noci/LTM)
   3. Ab-fibres (LTM)
3. behavioural changes
   1. withdrawal reflexes
4. Imaging

   Annotations:

   • in response to a painful stimulus
   1. MEG
   2. fMRI
   3. magnetic fields

      Annotations:

      • measuring a magnetic field in neurons evoked by a pain stimulus
   4. PET
5. Nociceptor activation
   1. electrical stimulation
   2. capsaicin
   3. mustard oil
   4. heat/ UV burn
   5. hypertonic saline

1. Drug trials

   Annotations:

   •    ·         Because central sensitization can be induced in almost all subjects and detected using subjective and objective outcome measures and is sensitive to pharmacological interventions, it is a useful tool for determining the activity of drugs on centrally driven pain hypersensitivity.   
2. Pain syndromes

   Annotations:

   • The induction of use-dependent central facilitation in nociceptive central pathways increases pain sensitivity indicates contribution to pain syndromes
3. Homo/heterosynaptic
4. Fast induction, long-lasting, reversible

   Annotations:

   •    ·         Generally this activity-dependent plasticity manifests immediately, but its effects persist for many hours beyond the inducing conditioning stimulus, eventually returning, however, back to baseline, indicating its usual full reversibility.   
5. elicited by conditioning:
   1. skin
   2. muscle
   3. visceral organs
6. Manifests as:
   1. Hypersensitivity
      1. Allodynia
      2. Hyperalgesia
   2. Enhanced pressure
   3. Thermal sensitivity
7. Sites of action
   1. Primary

      Annotations:

      • conditioning site 
   2. Secondary

      Annotations:

      • neighbouring areas
   3. Tertiary

      Annotations:

      • remote regions e.g. referred pain/ contralateral 
      1. Referred
      2. Contralateral
8. LTP
9. NMDA
10. Wind-up
    1. Woolf (1996)

1. Rheumatoid arthritis (RA)
2. Osteoarthritis (OA)
3. Temporomandibular disorders (TMD)
4. Fibromyalgia (FM)
5. Miscellaneous musculoskeletal disorders
6. Headache
7. Neuropathic pain
8. Complex regional pain syndrome (CRPS)
9. Post-surgical pain