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Why pain gets worse – molecular mechanisms of inflammatory heat pain

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One of the distinguishing characteristics of the sensation of pain is that it increases when a constant painful stimulus is applied. This process, known as sensitization or hyperalgesia, is caused by the release of pro-inflammatory mediators, amongst which are prostaglandin E2, bradykinin and nerve growth factor (NGF). Heat pain is promoted by all three of these mediators, and also by a multitude of others (Huang et al., 2006). At least three different intracellular signalling mechanisms are important in mediating the effects of these inflammatory mediators on the heat-sensitive ion channel, TRPV1 . Bradykinin and PGE2 enhance the probability that TRPV1 channels will be activated by a heat stimulus by promoting phosphorylation of TRPV1 by protein kinases C and A, respectively (Cesare & McNaughton, 1996; Cesare et al., 1999; Bhave et al., 2002). The main action of NGF is instead to increase the expression of TRPV1 channels in the neuronal cell membrane by promoting trafficking from a subcellular vesicle store (Zhang et al., 2005). This process depends on phosphorylation of TRPV1 at a single tyrosine residue, Y200 , by the non-receptor tyrosine kinase Src (Zhang et al., 2005).

In more recent work we have found that phosphorylation of TRPV1 by PKC and PKA is critically dependent on a scaffolding protein, AKAP79 , which binds PKA and PKC into a signalling complex together with TRPV1 (Zhang et al., 2008). Preventing binding of AKAP79 to TRPV1 completely ablates sensitization by pro-inflammatory mediators acting via PKA and PKC . AKAP79 is therefore a final common element in heat hyperalgesia, on which the effects of multiple proinflammatory mediators converge. The dependence of sensitization of TRPV1 on AKAP79 raises the possibility that disrupting binding may reverse heat hyperalgesia in vivo. The binding site of AKAP79 to TRPV1 may therefore prove to be an attractive target for the development of novel analgesics.

Bhave G, Zhu W, Wang H, Brasier DJ, Oxford GS, & Gereau RW (2002). Neuron 35, 721-731. Cesare P, Dekker LV, Sardini A, Parker PJ, & McNaughton PA (1999). Neuron 23, 617-624. Cesare P & McNaughton PA (1996). Proc Natl Acad Sci U S A 93 , 15435-15439. Huang J, Zhang X, & McNaughton PA (2006). Current Neuropharmacology 4, 197-206. Zhang X, Huang J, & McNaughton PA (2005). EMBO J 24 , 4211-4223. Zhang X, Li L, & McNaughton PA (2008). Neuron 59, 450-461.

This talk is part of the Departmental Seminar Programme, Department of Veterinary Medicine series.

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