Activity-dependent central sensitization (CS)

Adjunto:

• Central sensitization

1. Glutamate
   1. NMDR
      1. Induction
         1. antagonists

            Nota:

            • blocking NMDRs by non-competitive/ competitive anta>> prevents and reverses hyperexcitability of nociceptive neurons
         2. subunit deletion

            Nota:

            • abolishes NMDA synaptic inputs and acute activity-dependent central sensitization
      2. Maintenance

         Nota:

         •    o   SP and CGRP>> remove the Mg block by depolarisation o   Glutamate>> generates an inward Ca current  o   >> activates intracellular pathways>> Contributes to maintenance of CS   
   2. mGluRs
      1. Group I

         Nota:

         • mGluR1 and 5) are coupled with Gαq-proteins (whose activation causes an increase of [Ca2+]
         1. Induction
      2. Group II

         Nota:

         • mGluR 2 and 3
         1. blocks induction
      3. Group III

         Nota:

         • mGluR4, 6, 7 and 8) are coupled with Gαi/o-proteins
      4. Lamina

         Nota:

         • There is a lamina-specific pattern of expression has been characterized for mGluR1α (lamina V), mGluR5 (laminas I-II), mGluR2/3 (lamina II inner),suggesting precise and distinct physiological roles for the different subtypes
   3. Kainate (KA)
   4. AMPAR
2. NMDR
3. Substance P (SP)
   1. Neurokinin 1 (NK1)
      1. Induction

         Nota:

         • Ablation of NK1-positive neurons in the spinal cord leads to a reduction in capsaicin-evoked central sensitization   
4. CGRP

   Nota:

   • Calcitonin gene-related peptide  Enhances the release of BDNF
   2. CGRP1 receptor

      Nota:

      • participates in central sensitization through postsynaptic CGRP1 receptors, which activate PKA and PKC

   3. Nota:

      • potentiates the effects of SP
5. BDNF

   Nota:

   • brain-derived neurotrophic factor  may contribute to its involvement in migraine and other primary headaches
   • release in enhanced by CGRP
   1. trkB receptor

      1. Nota:

         • BDNF enhances NMDAR-mediated C-fiber–evoked responses and causes activation of several signaling pathways in spinothalamic track neurons, including ERK,and PKC
6. Signalling pathways
   1. Induction

      Adjunto:

      • Central sensitization
      1. Role for Ca
         1. NMDAR Phosphorylation (P)
         2. AMPAR (P)
         3. activates PKC/ CAMKII
   2. Maintenance

      Adjunto:

      • Central sensitization
   3. multiple pathways

      Adjunto:

      • Central sensitization
7. NO

1. Homosynaptic
2. Heterosynaptic

1. Inflammatory
2. Neuropathic

1. Early
2. Late

1. Induced by short latency (seconds)
2. intense, repeated, or sustained nociceptor inputs
3. Long-lasting
4. Multiple pathways for induction

   Adjunto:

   • Central sensitization
   1. NMDAR
   2. AMPAR
   3. Why?
      1. Interaction needed
      2. Parallel inputs