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Review
. 2009 Dec;32(12):611-8.
doi: 10.1016/j.tins.2009.07.007. Epub 2009 Sep 24.

Critical role of nociceptor plasticity in chronic pain

David B Reichling  1 , Jon D Levine
Affiliations
Review

Critical role of nociceptor plasticity in chronic pain

David B Reichling et al. Trends Neurosci. 2009 Dec.

Abstract

The transition from acute to chronic pain states might be the most important challenge in research to improve clinical treatment of debilitating pain. We describe a recently identified mechanism of neuronal plasticity in primary afferent nociceptive nerve fibers (nociceptors) by which an acute inflammatory insult or environmental stressor can trigger long-lasting hypersensitivity of nociceptors to inflammatory cytokines. This phenomenon, "hyperalgesic priming," depends on the epsilon isoform of protein kinase C (PKCepsilon) and a switch in intracellular signaling pathways that mediate cytokine-induced nociceptor hyperexcitability. We discuss the impact of this discovery on our understanding of, and ultimately our ability to treat, a variety of enigmatic and debilitating pain conditions, including those associated with repetitive injury, and generalized pain conditions, such as fibromyalgia.

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Figures

Figure 1
Figure 1. Chronic hyperalgesia associated with inflammation-induced hyperalgesic priming
(A) In the normal (unprimed) paw, a small intradermal injection of prostaglandin E2 (PGE2) causes an episode of acute hyperalgesia (decreased threshold for paw withdrawal from a pressure stimulus) lasting less than 4 hours. (B) Injection of the inflammogen, carrageenen, causes an episode of hyperalgesia that lasts less than 4 days (gray-filled curve). After carrageenan-induced hyperalgesia is no longer present, the paw remains in a latent state of hyperalgesic priming. In this state, an injection of PGE2, which would cause only acute hyperalgesia in the normal (unprimed) paw, now induces an additional chronic hyperalgesia. In comparison to the unprimed paw, this hyperalgesia is greater in magnitude and is greatly prolonged, lasting at least 3 weeks.
Figure 2
Figure 2. PKCε-dependence of hyperalgesia in the primed state demonstrated by antagonism antisense oligonucleotide
PKCε is synthesized in cell bodies of sensory neurons in the dorsal root ganglia (purple dot) and transported along the sensory nerve axons (purple line) to nerve endings in the paw where it plays a role in nociception. To reduce expression of PKCε in the sensory nerve, oligonucleotide antisense to PKCε (blue) is injected into the intrathecal space of the spinal cord where it is taken up by dorsal root ganglion neurons. The resultant reduction in PKCε transported to the sensory nerve ending eliminates the priming-induced enhancement of hyperalgesia induced by PGE2 (red) in the paw.
Figure 3
Figure 3. Priming-induced switch in second messenger pathways of cytokine hyperalgesia
This simple schematic illustrates the switch in hyperalgesia induced by prostaglandin E2 (PGE2) acting on a prostaglandin E receptor (EP-R) on the surface of a nociceptive primary afferent nerve ending (purple). In the normal (unprimed) paw PGE2-induced hyperalgesia is mediated by Gs G-protein activation of protein kinase (PKA) activity which ultimately causes an acute episode of hyperalgesia (green-filled curve) by presumed modulation of ion channels (sinusoidal arrow). In the primed paw, PGE2 acts on the same EP-R receptors, but in addition to the normal PKA-mediated pathway to acute hyperalgesia, an additional pathway involving Gi/o G-protein activation of PKCε, leading to an amplified and prolonged chronic hyperalgesia (red-filled curve) in addition to the PKA-mediated acute hyperalgesia.
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References

    1. International Association for the Study of Pain Task Force on Taxonomy: Classification of Chronic Pain Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms. 1994. p. 222. - PubMed
    1. Magni G. On the relationship between chronic pain and depression when there is no organic lesion. Pain. 1987;31:1–21. - PubMed
    1. Croft P, et al. The prevalence of chronic widespread pain in the general population. J Rheumatol. 1993;20:710–713. - PubMed
    1. Brekke M, et al. Severity of musculoskeletal pain: relations to socioeconomic inequality. Soc Sci Med. 2002;54:221–228. - PubMed
    1. Casey C. Young, et al. Transition from acute to chronic pain and disability: A model including cognitive, affective, and trauma factors. Pain. 2007 - PubMed