What is hyperalgesia and what are the mechanisms underlying it?

Hyperalgesia is an increase in nociception in response to a nociceptive stimuli

which may be due to sensitization of peripheral nociceptive nerve terminals or central
facilitation of transmission in the dorsal horn and thalamus. Hyperalgesia at the site of
tissue damage is described as primary hyperalgesia and that in the surrounding
undamaged area as secondary hyperalgesia. Primary hyperalgesia is due to sensitization
of nociceptors whereas secondary hyperalgesia is due to sensitization of nociceptors with
diffuse collateral axons or sensitization of central nociceptor neurons in response to
sustained activation.

Hyperalgesia occur after tissue injury or inflammation because of the chemical

mediators released, such as bradykinin and prostaglandin which lower nociceptor
threshold. Bradykinin acts by binding to G-protein coupled receptors leading to activation
fo protein kinase C which results in phosphorylation of vanilloid receptor 1 (VR1). This
facilitates the opening of VR1, a major transducer of nociceptive stimuli including
temperatures above 45oC and pH below 5.5. Prostaglandins are synthesized during
inflammation and tissue ischaemia, and they sensitize nociceptive nerve terminals by
inhibiting K+ channels and facilitating the opening of cation channels. Our understanding
of the mechanisms underlying hyperalgesia provides the basis of the mechanism by
which analgesic drugs such as aspirin. Inhibitors of cyclooxygenases such as aspirin
prevent synthesis of prostaglandins and thus are effective at producing analgesic effects.

Hyperalgesia may also involve central facilitation of transmission which may be

due to neuroplasticity. Repeated noxious stimuli can cause a ‘wind-up’ phenomenon
whereby synaptic responses of dorsal horn neurons to nociceptive inputs increase. This
process is likely to involve glutamate, substance P and NO as this activity-dependent
facilitation has been shown to be blocked by antagonists of NMDA and substance P
receptors, and inhibitors of nitric oxide synthesis. Central facilitation of transmission may
also arise from the effects of nerve growth factor (NGF) which affect gene transcription
to increase electrical excitability, promote formation of synaptic contacts and
strengthening of synaptic transmission.