Figure 1.

Mechanism of peripheral versus central sensitization.

Notes: (A) Peripheral sensitization and (B) central sensitization. Activation of peripheral nociceptors on the skin in response to stimuli, such as heat, injury or mechanical pressure, initiates the release of chemical mediators at the site of injury (peripheral sensitization). Persistent pain or inflammation causes activation and repetitive firing in afferent C-fiber nociceptors, which triggers the release of excitatory neurotransmitter glutamate in the synapse of the dorsal horn (central sensitization). This is accompanied by the release of substance P, BDNF and neurokinins, which causes persistent depolarization of the cell membrane. Additionally, activation of AMPA or NMDA receptors by glutamate stimulates the microglia and subsequently induces the release of cyclooxygenase enzymes 1 and 2, nitric oxide and other proinflammatory mediators (TNF-α, IL-1, IL-6).

Abbreviations: AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; ATP, adenosine triphosphate; ASIC, acid-sensing ion channels; BDNF, brain-derived neurotropic factor; 5-HT, 5-hydroxytryptamine; IL, interleukin; NMDA, N-methyl-d-aspartate receptor; NGF, nerve growth factor; PG, prostaglandin; NK₁, neurokinin-1; TNF, tumor necrosis factor; TrkB, tyrosine receptor kinase B; TRPV, transient receptor potential vanilloid receptor.