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After great pain, a formal feeling comes—

The Nerves sit ceremonious, like Tombs—

Emily Dickinson (1862)

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 injury.

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 ...

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