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Pain: Moving from Symptom Control toward Mechanism-Specific Pharmacologic Management

Clifford J. Woolf, MD
[+] Article, Author, and Disclosure Information

From Neural Plasticity Research Group, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts.

Potential Financial Conflicts of Interest: None disclosed.

Requests for Single Reprints: Clifford J. Woolf, MD, Neural Plasticity Research Group, Department of Anesthesia and Critical Care, Massachusetts General Hospital and Harvard Medical School, 149 13th Street, Room 4309, Charlestown, MA 02129; e-mail, cwoolf@partners.org.

Ann Intern Med. 2004;140(6):441-451. doi:10.7326/0003-4819-140-8-200404200-00010
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Pain can be essentially divided into 2 broad categories: adaptive and maladaptive. Adaptive pain contributes to survival by protecting the organism from injury or promoting healing when injury has occurred. Maladaptive pain, in contrast, is an expression of the pathologic operation of the nervous system; it is pain as disease.



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Figure 2.
Contributions of primary sensory neurons to pain.

A. The peripheral terminal of a nociceptor sensory neuron. The different transducing receptor and ion channels that respond to thermal, mechanical, and chemical stimuli are shown. B.The mechanism of peripheral sensitization. Inflammatory mediators, such as prostaglandin E2 (PGE2), bradykinin (BK), and nerve growth factor (NGF), activate intracellular kinases in the peripheral terminal that phosphorylate transducer channels to reduce their threshold or sodium channels to increase excitability. C. Transcriptional changes in the dorsal root ganglion. Activity, growth factors, and inflammatory mediators act on sensory neurons to activate intracellular transduction cascades. These cascades control the transcription factors that modulate gene expression, leading to changes in the levels of receptors, ion channels, and other functional proteins. AA = archidonic acid; ASIC = acid-sensing ion channel; ATP = adenosine triphosphate; CaMKIV = camkinase IV; COX-2 = cyclooxygenase-2; ERK = extracellular signal-regulated kinase; EP = prostaglandin E receptor; JNK = jun kinase; mRNA = messenger RNA; PKA = protein kinase A; PKC = protein kinase C; TRP = transient receptor potential receptor.

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Figure 3.
Contributions of spinal cord dorsal horn neurons to pain.

A. Nociceptive transmission. B. The acute phase of central sensitization. C. The late phase of central sensitization. Some alterations in gene expression are activity-driven and restricted, such as dynorphin, whereas others are widespread and produce diverse changes in function, such as induction of cyclooxygenase-2 (COX-2) in central neurons after peripheral inflammation. D. Disinhibition. AA = arachidonic acid; AMPA = α-amino-3-hydroxy-5-methyl-4-isoxazole propionate; EP = prostaglandin E receptor; IL-1β = interleukin-1β; NK1 = neurokinin 1; NMDA = -methyl- -aspartic acid; PGE2 = prostaglandin E2; TrkB = tyrosine kinase B2.

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