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SUMMARY:Why pain gets worse – molecular mechanisms of inflammatory heat 
 pain - Peter McNaughton\, Department of Pharmacology\, University of Cambr
 idge
DTSTART:20081119T163000Z
DTEND:20081119T173000Z
UID:TALK14005@talks.cam.ac.uk
CONTACT:Suzy Blows
DESCRIPTION:One of the distinguishing characteristics of the sensation of 
 pain is that it increases when a constant painful stimulus is applied. Thi
 s process\, known as sensitization or hyperalgesia\, is caused by the rele
 ase of pro-inflammatory mediators\, amongst which are prostaglandin E2\, b
 radykinin and nerve growth factor (NGF). Heat pain is promoted by all thre
 e of these mediators\, and also by a multitude of others (Huang et al.\, 2
 006). At least three different intracellular signalling mechanisms are imp
 ortant in mediating the effects of these inflammatory mediators on the hea
 t-sensitive ion channel\, TRPV1. Bradykinin and PGE2 enhance the probabili
 ty 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 ma
 in action of NGF is instead to increase the expression of TRPV1 channels i
 n the neuronal cell membrane by promoting trafficking from a subcellular v
 esicle store (Zhang et al.\, 2005). This process depends on phosphorylatio
 n of TRPV1 at a single tyrosine residue\, Y200\, by the non-receptor tyros
 ine kinase Src  (Zhang et al.\, 2005). \n\nIn more recent work we have fou
 nd that phosphorylation of TRPV1 by PKC and PKA is critically dependent on
  a scaffolding protein\, AKAP79\, which binds PKA and PKC into a signallin
 g complex together with TRPV1 (Zhang et al.\, 2008).  Preventing binding o
 f AKAP79 to TRPV1 completely ablates sensitization by pro-inflammatory med
 iators acting via PKA and PKC. AKAP79 is therefore a final common element 
 in heat hyperalgesia\, on which the effects of multiple proinflammatory me
 diators converge. The dependence of sensitization of TRPV1 on AKAP79 raise
 s the possibility that disrupting binding may reverse heat hyperalgesia in
  vivo. The binding site of AKAP79 to TRPV1 may therefore prove to be an at
 tractive target for the development of novel analgesics.\n\nBhave G\, Zhu 
 W\, Wang H\, Brasier DJ\, Oxford GS\, & Gereau RW (2002). Neuron 35\, 721-
 731.\nCesare P\, Dekker LV\, Sardini A\, Parker PJ\, & McNaughton PA (1999
 ). Neuron 23\, 617-624.\nCesare P & McNaughton PA (1996). Proc Natl Acad S
 ci U S A 93\, 15435-15439.\nHuang J\, Zhang X\, & McNaughton PA (2006). Cu
 rrent Neuropharmacology 4\, 197-206.\nZhang X\, Huang J\, & McNaughton PA 
 (2005). EMBO J 24\, 4211-4223.\nZhang X\, Li L\, & McNaughton PA (2008). N
 euron 59\, 450-461.\n\n
LOCATION:Lecture Theatre 1\, Department of Veterinary Medicine
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