Hyperalgesic actions of cytokines on peripheral nerves

Abstract

The relationship between nerve injury and pain is pervasive in medicine, being both a simple, common experience and an important diagnostic tool. Acute trauma to a nerve is almost always painful and has been experienced by many people in association with sports and workplace activities. In these cases, injuries occur usually because of nerve stretching or compression, damaging sensory axons that will then degenerate and regenerate. If the nerve is not transected and the Schwann cell basal lamina of the nerve fiber is left intact, the prognosis for recovery is good since regenerating axons are appropriately guided to the original target tissue. If neuropathic pain states do not develop, acute pain will normally resolve during the period of axonal regeneration, which begins within about a week after nerve injury and the start of nerve fiber degeneration. Misguided regeneration that produces a neuroma in continuity or, more often, a neuroma at the severed end of the nerve bundle, can be persistently painful because of the sensitivity of the undifferentiated free nerve endings to mechanical pressure and chemical stimuli. Another example is the sub-chronic low back pain syndrome caused by nerve root compression and chemical irritation secondary to herniated spinal discs. This and other forms of subchronic nerve injury caused by repeated physical or chemical irritation become more problematic in terms of predicting the duration of pain. In these cases, there is often ongoing and intermixed degeneration and regeneration that not only produces acute pain but can also lead to facilitated central processing of peripheral nociceptive signals and chronic pain states. Chronic nerve injuries can be more painful still, but may also be so severe or widespread that nociceptive axons and first-order sensory neurons in the dorsal root ganglia are permanently damaged so that peripheral stimuli are not meaningfully transduced. Severe diabetic neuropathy fits this description if it progresses through states of paresthesia, hyperalgesia, hypoalgesia, and anesthesia. Other causes of complete nerve injury such as iatrogenic transection of peripheral nerves during limb amputation may lead to deafferentation syndromes in which phantom pain is prevalent, although some models of deafferentation imply that phantom pain may be associated with regeneration [1].