In peripheral non-neuronal tissues, the response to tissue damage involves the synthesis of a number of inflammatory mediators including prostaglandins from damaged cells or immune cells that invade the injury site. Prostaglandins induce nociceptor sensitisation by binding to prostaglandin receptors on nerve terminal which modulate the activity of ion channels in the cell membrane. Following tissue damage, the inducible isoform of cox-2 is upregulated and prostaglandin synthesis is markedly increased.

Molecular, biochemical and immunocytochemical studies have shown that cox enzymes are expressed in peripheral and central neurones. Cox-1 is expressed in subsets of small diameter dorsal root ganglion neurones suggesting that it is preferentially expressed in primary afferent nociceptors. The role of cox enzymes in these neurones has not been fully determined but there is good evidence that they have an important role in relaying signals from Gq coupled GPCRs to ion channels that regulate the excitability and/or firing pattern of these neurones.

Almost 10 years ago it was demonstrated that NSAIDs have a pronounced spinal action which occurs in addition to the established peripheral effects. Since these original studies were performed, several groups have shown that both cox-1 and cox-2 isoforms are expressed in the spinal cord neurones and there is now good evidence that spinal cox-2 gene expression is upregulated in animal models of peripheral inflammatory pain. Recent evidence from neuroanatomical, immunocytochemical and electrophysiological studies have provided good evidence that prostaglandins have a role as neuromodulators in spinal nociceptive pathways.

In summary, non-neuronally derived, and neuronally derived prostaglandins have an important role in regulating the excitability of primary afferent neurones as well as synaptic transmission within the spinal cord. NSAIDs have actions at several sites which individually contribute to the overall analgesic actions of this important group of drugs.