After great pain, a formal feeling comes—
The Nerves sit ceremonious, like Tombs—
Acute, nociceptive pain results from the complex convergence
of many signals traveling up and down the neuraxis and serves to
warn us of impending harm. The painful sensations ultimately leave
the periphery and travel centrally, carried by the axons of the
primary sensory neurons, the dorsal root ganglia (DRG), which are
relatively quiescent unless specifically stimulated by sensory input.
Unlike the “tombs” that the Belle of Amherst describes,
however, if inflammation or injury damages the neural structures,
pain sensation (neuropathic pain) may continue long after the noxious
stimuli subside. The pain response can then harm rather than help
the individual. Injured DRG may become hyperexcitable and display
considerable spontaneous electrical activity. Such increased activity
results from the expression of a dramatically different constellation
of many cell-specific molecules in injured cells compared with normal
ones. Ultimately, the operation of complex neuronal circuits may
be markedly altered. Chronic pain sensation can result from such
Considerable advances have been made in the last decade, which
have given some insight into the mechanisms responsible for the
development of chronic pain. Understanding the changes that follow
injury at a cellular and molecular level may help lead to new therapeutic
interventions. In this chapter I focus on neuropathic pain and highlight,
rather than exhaustively chronicle, these findings. I first describe
peripheral sensitization changes seen in inflammatory pain, then
central mechanisms of sensitization, followed by the role of neurotrophic
factors, the effects on neuronal ionic channels, and higher neural
mechanisms, concluding with a brief word on central pain.
Unmyelinated C or thinly myelinated Aδ afferent
fibers convey pain sensation. Minor irritation of tissue in a neuron’s
receptive field results in the release of inflammatory mediators,
which is often accompanied by a reduction in the nociceptor threshold.
Such a change, called peripheral sensitization, renders the nerve
ending responsive to weak, normally nonpainful stimuli (allodynia).
Stronger stimuli typically provoke exaggerated pain (hyperalgesia).
Sensitization involves not only normal nociceptive fibers but also
the recruitment of so-called silent nociceptors, which are not usually
sensitive to painful stimuli or inflammatory substrates such as
prostaglandins or bradykinin.
Bradykinin can sensitize C and Aδ fibers to
prostaglandins, protons, serotonin, heat, and mechanical stimuli.1–4 Because
its algesic effect displays considerable tachyphylaxis, however,
bradykinin alone cannot account for the hyperalgesia seen in inflammation.3 Bradykinin
also appears to facilitate the production of prostaglandins.5 Similarly,
prostaglandins sensitize nerve afferents to bradykinin action.6 Blockade
of such sensitization accounts for the clinical efficacy of antiinflammatory
drugs such as aspirin and cyclooxygenase-1 and -2 inhibitors.
Some light has been shed on cellular transduction mechanisms
that may be involved in the development of this type of sensitization.
For example, the afterhyperpolarization of primary afferent fibers
decreases, which renders the cell more likely to fire ...