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The Decade of Pain Control and Research (DPCR) legislation passed by the 106th Congress helped promulgate an extraordinary number of scientific inquiries into the mechanisms and treatment of pain. In the decade before Senator Hatch introduced the Bill, a PubMed search of the term “pathophysiology of pain” retrieved 53 articles. In the DPCR, the same search yielded 32,283 articles. In the ten years since the publication of the second edition of this textbook in 2004, nearly 48,000 articles have been published. The accelerated rate of publications has begun to slow; but it was hoped that such research growth would continue for three reasons: (1) For humane considerations, we simply need more effective and safer medications for better pain management. (2) The cost of pain to society is colossal–nearly $55 billion per year by one estimate. (3) Improved scientific and technological knowledge about pain pathways drives pain drug discovery research and development to meet demand.1 However, by the end of the DPCR, many impediments to using evidence-based pain management methods still remained, and federal economic support was waning.2,3

Acute pain results from the complex convergence of many signals traveling up and down the neuraxis and serves to warn us of potential impending harm. For example, noxious stimuli activate nociceptors in the periphery. The signal travels 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. The pain response can also 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 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.

Woolf describes a classification system that separates pain into two major divisions: adaptive and maladaptive. The former serves to protect the organism, but the latter can lead to pathological pain maintained as a disease state. Woolf's framework then distinguishes four different types of pain: nociceptive, inflammatory, neuropathic, and functional (abnormal central processing). Investigators have delineated some, but far from all, of the many mechanisms operative in the generation of these types of pain and the etiologies that cause them.4

Considerable knowledge has accrued, which has given some insight into the mechanisms responsible for the development of acute and chronic pain. Understanding the changes that follow injury at a cellular and molecular level may help lead to new therapeutic interventions. This chapter highlights, rather than exhaustively chronicles, some of these findings. The peripheral sensitization changes seen in inflammatory pain are described first, then the central mechanisms of sensitization, followed by the role of neurotrophic factors, the effects on neuronal ionic channels, higher neural mechanisms, central pain, and genetics. The chapter concludes with some remarks.

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