Peripheral sensitization

Fig. 4.1 Hypothetical model of pathogenesis of pain in DSP. (1) Injury of peripheral nerve fibers due to multifocal inflammation and secreted macrophage activation products results in abnormal spontaneous activity of neighboring uninjured nociceptive fibers ( peripheral sensitization ). (2) Furthermore, the aberrant inflammatory response in DRG leads to alterations in neuronal sodium and calcium channel expression and ectopic impulse generation. (3) This results in central remodeling within the dorsal horn due to A-fiber sprouting and synaptic formation with pain fibers in lamina 11, and maintenance of neuropathic pain ( central sensitization ). Reproduced with permission from (Keswani et al. 2002)...

Two current foci in pain management are to identify the mechanisms that are responsible for pain hypersensitivity and to prevent this initial hypersensitivity. Therefore, the goal of pain therapy is to reduce peripheral sensitization and subsequent central stimulation and amplification associated with wind-up, spread, and central sensitization.17... 

Inflammatory pain results from changes both in primary sensory and dorsal horn neurons 933 Peripheral sensitization lowers nociceptor activation threshold 933... 

Inflammatory pain results from changes both in primary sensory and dorsal horn neurons. The alterations in primary sensory neurons fall into two broad categories (a) a reduction in threshold and an increase in the response of the peripheral terminals of nociceptors (peripheral sensitization), and (b) an alteration in transmitter content modifying synaptic input to the spinal cord. In the dorsal horn, peripheral inflammation results in an increase in membrane excitability and synaptic efficacy, which is the phenomenon of central sensitization [12]. 

NGF, in addition to its direct sensitizing action in the peripheral terminal, is retrogradely transported to the cell body, where, via the ERK MAPK and CREB pathways, it increases expression of substance P (sub P), CGRP, BDNF, ASIC and Navl-8, and produces an increase in TRPV1 translation. Navl-8, ASIC and TRPV1 are shipped to the periphery, where their increased levels further augment peripheral sensitivity. After peripheral inflammation, substance P and BDNF are expressed in low threshold... 

Peripheral inflammation increases prostanoid levels at the site of inflammation and this contributes directly to inflammation and peripheral sensitization (prostanoids and inflammation are discussed in Ch. 33). Peripheral inflammation also increases central prostanoid levels as a result of the central induction of COX-2, to mediate widespread changes in pain sensitivity as well as fever, anorexia, altered mood and sleep patterns [19]. 

Pain is thought to originate from myofascial factors and peripheral sensitization of nociceptors. Central mechanisms are also involved. Mental stress, nonphysiologic motor stress, a local myofascial release of irritants, or a combination of these may be the initiating stimulus. In predisposed individuals, chronic, tension-type headache can evolve. 

Even the most severe acute pain (that lasting hours to days) can usually be well controlled—with significant but tolerable adverse effects—with currently available analgesics, especially the opioids. Chronic pain (lasting weeks to months), however, is not very satisfactorily managed with opioids. It is now known that in chronic pain, presynaptic receptors on sensory nerve terminals in the periphery contribute to increased excitability of sensory nerve endings (peripheral sensitization). 

Penz M, Kornek GV, Raderer M, Ulrich-Pur H, Fiebiger W, Scheithauer W. Subcutaneous administration of amifostine a promising therapeutic option in patients with oxaliplatin-related peripheral sensitive neuropathy. Ann Oncol 2001 12(3) 421-2. 

Because of the lipase deficiency, fat-soluble vitamin (A, D, E, and K) deficiencies may occur. Whether lipase activity or bile acids (e.g., in micelle formation) are involved in fat-soluble vitamin absorption with steatorrhea is unclear. Vitamin and zinc deficiencies also may occur as aresult of pancreatic enzyme deficiency. Although pancreatic involvement is predominantly exocrine in nature, insulin deficiency with glucose intolerance also occurs in CF patients, especially as they advance in age. Carbohydrate intolerance is characterized by low insulin concentrations and enhanced peripheral sensitivity to insulin but not by the presence of islet cell or anti-insulin antibodies. Carbohydrate intolerance in CF is not usually associated with the ketosis as commonly occurs in type 1 diabetes. This complication involves an increase in the number of insulin receptors with decreased affinity for insulin. Despite a concomitant increase in tissue affinity for insulin, 8% of CF children over 12 years of age require insulin therapy. 

Given that insects possess differential peripheral sensitivity to cues from potential resources and differential responsiveness mediated by the CNS (see StUdler and Mustaparta, Chapters 1 and 2), we turn to how these abilities are... 

Hyperalgesia describes a state of increased pain sensitivity and enhanced perception following acute injury which is related to peripheral release of intracellular or humoral noxious mediators [7,9-11]. Primary hyperalgesia (peripheral sensitization) describes an altered state of sensibility in which the intensity of painful sensation induced by noxious and non-noxious... 

Hyperalgesia is defined by the International Association for the Study of Pain (lASP) as an increased response to a stimulus which is normally painful . Primary hyperalgesia or peripheral sensitization reflects the activation and sensitization of nociceptive A delta and polymodal C-fiber terminal endings within the injured area. Secondary hyperalgesia, or central sensitization, involves spinal neuroplasticity and facilitation... 

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