Pain. Author manuscript; available in PMC 2012 Mar 1.
Published in final edited form as:
Pain. 2011 Mar; 152(3 Suppl): S2–15.
Published online 2010 Oct 18. doi: 10.1016/j.pain.2010.09.030
PMCID: PMC3268359
NIHMSID: NIHMS249521
PMID: 20961685
Clifford J Woolf
Abstract
Nociceptor inputs can trigger a prolonged but reversible increase in the excitability and synaptic efficacy of neurons in central nociceptive pathways, the phenomenon of central sensitization. Central sensitization manifests as pain hypersensitivity, particularly dynamic tactile allodynia, secondary punctate or pressure hyperalgesia, aftersensations, and enhanced temporal summation. It can be readily and rapidly elicited in human volunteers by diverse experimental noxious conditioning stimuli to skin, muscles or viscera, and in addition to producing pain hypersensitivity, results in secondary changes in brain activity that can be detected by electrophysiological or imaging techniques. Studies in clinical cohorts reveal changes in pain sensitivity that have been interpreted as revealing an important contribution of central sensitization to the pain phenotype in patients with fibromyalgia, osteoarthritis, musculoskeletal disorders with generalized pain hypersensitivity, headache, temporomandibular joint disorders, dental pain, neuropathic pain, visceral pain hypersensitivity disorders and postsurgical pain. The comorbidity of those pain hypersensitivity syndromes that present in the absence of inflammation or a neural lesion, their similar pattern of clinical presentation and response to centrally acting analgesics, may reflect a commonality of central sensitization to their pathophysiology. An important question that still needs to be determined is whether there are individuals with a higher inherited propensity for developing central sensitization than others, and if so, whether this conveys an increased risk both of developing conditions with pain hypersensitivity, and their chronification. Diagnostic criteria to establish the presence of central sensitization in patients will greatly assist the phenotyping of patients for choosing treatments that produce analgesia by normalizing hyperexcitable central neural activity. We have certainly come a long way since the first discovery of activity-dependent synaptic plasticity in the spinal cord and the revelation that it occurs and produces pain hypersensitivity in patients. Nevertheless, discovering the genetic and environmental contributors to and objective biomarkers of central sensitization will be highly beneficial, as will additional treatment options to prevent or reduce this prevalent and promiscuous form of pain plasticity.
From the article:
Finally, it seems that also metabolic factors may be related to central pain processing. There is growing evidence in favor of low-carbohydrate or ketogenic diets in order to diminish hyperexcitability of the CNS in case of seizures or chronic pain. It is indeed known that metabolism influences brain activity [92]. A ketogenic diet is very high in fat, with sufficient protein and restricted carbohydrates. It alters metabolism so that ketones are burned instead of glucose.
First, it has long been known that reducing glucose metabolism influences pain. There is an overall increase in pain thresholds (and thus reduced pain) when glycolytic enzymes are inhibited [93]. This effect is mediated centrally [94] and might involve increased brain/spinal cord inhibition by adenosine [95,96]. Inversely, glucose toxicity on local site of the spinal cord can contribute to the development of spinally mediated hyperalgesia [97]. The high concentration of glucose results in pain hypersensitivity probably by disrupting the functions of cell mitochondria and subsequent generation of reactive oxygen species and oxidative stress [98] and activating microglia [99]. Up to now the use of ketogenic diets has only been established as a successful anticonvulsant therapy. But based on overlap between mechanisms postulated to underlie pain and mechanisms postulated to underlie therapeutic effects of ketogenic diets, recent studies have explored the ability for ketogenic diets to reduce pain. [100]
Although it is known that ketogenic diets reduce central excitability [101], theories are divided as to whether these effects are produced directly by ketones and/or low glucose, fatty acids, or downstream metabolic effects [102-104]. A number of inhibitory mechanisms are hypothesized to underlie the efficacy of the ketogenic diet: for example, activation of K1 channels, adenosine A1 receptors or gamma aminobutyric acid receptors, all causing hypoalgesia [105-107].