Pain mediator cytokines

The COX-2 enzyme, however, seems to be produced primarily in injured cells that is, other chemical mediators (cytokines, growth factors) induce the injured cell to synthesize the COX-2 enzyme, and this enzyme then produces prostaglandins that mediate pain and other aspects of the inflammatory response.19,61,84 There is also considerable evidence that the COX-2 form is responsible for producing prostaglandins in other pathological conditions such as colorectal cancer.62,100... 

MUligan ED, O Connor KA et al (2001) Intrathecal HlV-1 envelope glycoprotein gpl20 induces enhanced pain states mediated by spinal cord proinflammatory cytokines. J Neurosd 21(8) 2808-2819... 

Cross A, Asher L, Seguin M, Yuan L, Kelly N, Hammack C (1995) The importance of a hpopoly-sacchaiide-initiated, cytokine-mediated host defense mechanism in mice against extraintesti-nally invasive escheiichia coh. J Clin Invest 96(2) 676-686 Dahan A, van Dorp E, Smith T, Yassen A (2008) Morphine-6-glucuronide (M6G) for postoperative pain relief. Eur J Pain 12(4) 403-411... 

Nearly all cells express kinin receptors that mediate the activities of both bradykinin and kallidin. The activation of these G-protein coupled receptors causes relaxation of venular smooth muscle and hypotension, increased vascular permeability, contraction of smooth muscle of the gut and airway leading to increased airway resistance, stimulation of sensory neurons, alteration of ion secretion of epithelial cells, production of nitric oxide, release of cytokines from leukocytes, and the production of eicosanoids from various cell types [11,12]. Because of this broad spectrum of activity, kinins have been implicated as an important mediator in many pathophysiologies including pain, sepsis, asthma, rheumatoid arthritis, pancreatitis, and a wide variety of other inflammatory diseases. Moreover, a recent report demonstrated that bradykinin B2 receptors on the surface of human fibroblasts were upregulated three-fold beyond normal in patients with Alzheimer s disease, implicating bradykinin as a participant in the peripheral inflammatory processes associated with that disease [13]. 

There is some evidence that adenosine also participates in modulating peripheral somatosensory function through A3 receptors on immune cells. A predominant response to the activation of A3 receptors is degranulation of mast cells causing the release of multiple proinflammatory mediators (IL-6/IL-10/IL-12). Further involvement of A3 receptors in pain and inflammation may be a result of adenosine-mediated inhibition of the release of tumor necrosis factor a (TNF-a), a proinflammatory cytokine produced by monocytes and macrophages. 

Many mediators of inflammation have been identified— cytokines IL-6, tumor necrosis factor alpha cell adhesion molecules intracellular adhesion molecule-1 (ICAM-I), P-selectin and acute phase reactants CR.R fibrinogen, serum amyloid A, and soluble CD40 (Fig. I) (3). Myeloperoxidase is an enzyme secreted from monocytes, neutrophils, and macrophages. A single measurement taken from patient with chest pain in the emergency department predicted the early risk of myocardial infarction and the risk of major cardiac of ends in the next 30 days to six months (15). 

Holguin, A., O sConnor, K. A., Biedenkapp, J., Campisi, J., Wieseler-Frank, J., Milligan, E. D., Hansen, M. K., Spataro, L., Maksimova, E., Bravmann, C., Martin, D., Fleshner, M., et al. (2004). HIV-1 gpl20 stimulates proinflammatory cytokine-mediated pain facilitation via activation of nitric oxide synthase-I (nNOS). Pain 110, 517—530. 

Watkins, L. R., Milligan, E. D., and Maier, S. F. (2003). Glial proinflammatory cytokines mediate exaggerated pain states Implications for clinical pain. Ada. Exp. Med. Biol. 521, 1-21. 

Ledeboer, A., Gamanos, M., Lai, W., Martin, D., Maier, S. F., Watkins, L. R., and Quan, N. (2005). Involvement of spinal cord nuclear factor kappaB activation in rat models of proinflammatory cytokine-mediated pain facilitation. Eur.J. Neurosci. 22, 1977-1986. 

Inflammation A protective tissue response to injury that serves to destroy, dilute, or wall off both the injurious agent and the injured tissue. It is characterized by symptoms such as pain, heat, and redness and is the result of the combined effects of numerous inflammatory mediators (e.g., prostaglandins, histamine, cytokines, etc.). 

Milligan, E.D., Twining, C., Chacur, M. et al. (2003). Spinal glia and proinfiammatory cytokines mediate mirror-image neuropathic pain in rats. J. Neurosci. 23 1026-40. 

Cytokine Production/Cellular Activation TNFa and IFNy mediate the induction of other cytokines (IL-1 and IL-6) and the activation of phagocytes. It has been suggested that particle-induced expression of MIP-2 and cytokine-induced neutrophil chemoattractant CKs in the rat lung are mediated at least in part by production of TNFa. TNF is involved in control of monocyte-mediated regulation of cytokine production by T cells. Preincubation of monocytes with rTNF enhanced their ability to induce IFNy production, and TNF synthesis inhibitors decreased this induction. However, Th2 cells are stimulated in the relative absence of monocyte co-stimulatory signal(s), probably IL-6. Concerning pain responsivity, TNFa produces dose-dependent hyperalgesia mediated via the induced release of IL-lp. ... 

The production of pro-inflammatory substances is an important step during chronic painful inflammatory diseases and its inhibition is a target of novel analgesics. The resin of Protium kleinii is used in folk medicine for inflammatory skin conditions. Its effects seem to be mediated by several pentacyclic triterpenes such as amyrin and brein [92], The topical and systemic administration of the extract of P. kleinii and some of its triterpenes has antinociceptive and anti-inflammatory actions, accompanied by reduced neutrophil infiltration and cytokine... 

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