Peripheral nerves serve as pain's first messengers, firing action potentials as far as three feet to the spinal cord, where they alert the next nerve en route to the brain.

Tissue damage and inflammation can lower nociceptor thresholds and increase neuronal excitability. The result is heightened pain sensitivity, a protective device, which resolves when the tissue heals.

But if something physically damages the peripheral nerve, the message is much bigger and more complex, with a flurry of activity at the site of injury, in the dorsal root ganglia--where the nerve's cell body is and in the dorsal horn of the spinal cord--where the first synapse is located.

Retrograde signals from the site of injury to the cell body affect transcription and alter expression of nociceptors and ion channels in peripheral nerves.

Secondary pain transmission neurons in the spinal cord react to increased peripheral nerve activity with changes in transcription and expression of neurotransmitters and receptors.

System-wide, the balance tips toward pain hypersensitivity and stays there. (end quote)