**5.5 Progression of OA to chronicity**

Chronic pain (CP) is pain that persists for a month beyond the usual course of an acute disease or a reasonable time period for an injury to heal.

CP differs from the acute process not only in the duration of its course but also the different receptors involved in the mechanisms of action for acute pain and CP.

Those most involved in the acute process are a-amino-3-hydroxy- 5-methyl-isoxazole-4 propionic acid (AMPA) receptors, while those of primary importance in the sensation of CP are N-methyl- D-aspartate (NMDA) receptors. Activation of NMDA receptors causes the release of peptide neurotransmitter SP, which amplifies the pain by causing the spinal neurons carrying the pain to be easily stimulated.

Elevated levels of SP in spinal fluids have been documented in patients with OA and fibromyalgia. The progression of nociception from an acute to a chronic process has yet to be fully understood. However, recent evidence from animal experiments as well as human research suggests that peripheral mechanisms in acute pain and long-term potentiation (LTP) of neuronal sensitivity to nociceptive inputs in the dorsal horn of the spinal cord may underline the transition from acute to a chronic process.

LTP in spinal nociceptive systems has been suggested as one of the mechanisms underpinning the transition of acute pain to CP. It seems possible that LTP may underlie some forms of afferent induced hyperalgesia and that simultaneous activation of NMDA; SP neurokinin-I (NK-I) and glutamate receptors are required for the induction of spinal LTP. Therefore, it is likely that the conditioning stimuli that induce synaptic LTP in the superficial spinal dorsal horn are similar to those that trigger hyperalgesia. LTP is likely to occur in both the sensory and the affective pain pathways. Additionally, spinal LTP and injuryinduced hyperalgesia share signal transduction pathways, which make use-dependent LTP an attractive model of injury-induced central sensitisation and hyperalgesia.

### **Summary of progression to chronic pain state**

	- CaMKII phosphorylates AMPA receptors making them more permeable to the inflow of Na+ ions and thus increasing the sensitivity of the cell to depolarization.
	- In time CaMKII also increases the number of AMPA receptors at the synapse.
