PMID- 22928864
OWN - NLM
STAT- MEDLINE
DCOM- 20130702
LR  - 20220129
IS  - 1476-5381 (Electronic)
IS  - 0007-1188 (Print)
IS  - 0007-1188 (Linking)
VI  - 168
IP  - 3
DP  - 2013 Feb
TI  - 4alpha-phorbol 12,13-didecanoate activates cultured mouse dorsal root ganglia neurons 
      independently of TRPV4.
PG  - 761-72
LID - 10.1111/j.1476-5381.2012.02186.x [doi]
AB  - BACKGROUND AND PURPOSE: The Ca(2+) -permeable cation channel TRPV4 is activated 
      by mechanical disturbance of the cell membrane and is implicated in mechanical 
      hyperalgesia. Nerve growth factor (NGF) is increased during inflammation and 
      causes mechanical hyperalgesia. 4alpha-phorbol 12,13-didecanoate (4alphaPDD) has been 
      described as a selective TRPV4 agonist. We investigated NGF-induced hyperalgesia 
      in TRPV4 wild-type (+/+) and knockout (-/-) mice, and the increases in [Ca(2+) 
      ](i) produced by 4alphaPDD in cultured mouse dorsal root ganglia neurons following 
      exposure to NGF. EXPERIMENTAL APPROACH: Withdrawal thresholds to heat, von Frey 
      hairs and pressure were measured in mice before and after systemic administration 
      of NGF. Changes in intracellular Ca(2+) concentration were measured by 
      ratiometric imaging with Fura-2 in cultured DRG and trigeminal ganglia (TG) 
      neurons during perfusion of TRPV4 agonists. KEY RESULTS: Administration of NGF 
      caused a significant sensitization to heat and von Frey stimuli in TRPV4 +/+ and 
      -/- mice, but only TRPV4 +/+ mice showed sensitization to noxious pressure. 4alphaPDD 
      stimulated a dose-dependent increase in [Ca(2+) ](i) in neurons from +/+ and -/- 
      mice, with the proportion of responding neurons and magnitude of increase 
      unaffected by the genotype. In contrast, the selective TRPV4 agonist GSK1016790A 
      failed to stimulate an increase in intracellular Ca(2+) in cultured neurons. 
      Responses to 4alphaPDD were unaffected by pretreatment with NGF. CONCLUSIONS AND 
      IMPLICATIONS: TRPV4 contributes to mechanosensation in vivo, but there is little 
      evidence for functional TRPV4 in cultured DRG and TG neurons. We conclude that 
      4alphaPDD activates these neurons independently of TRPV4, so it is not appropriate to 
      refer to 4alphaPDD as a selective TRPV4 agonist.
CI  - (c) 2012 The Authors. British Journal of Pharmacology (c) 2012 The British 
      Pharmacological Society.
FAU - Alexander, R
AU  - Alexander R
AD  - Wolfson Centre for Age-Related Diseases, King's College London, London, UK.
FAU - Kerby, A
AU  - Kerby A
FAU - Aubdool, A A
AU  - Aubdool AA
FAU - Power, A R
AU  - Power AR
FAU - Grover, S
AU  - Grover S
FAU - Gentry, C
AU  - Gentry C
FAU - Grant, A D
AU  - Grant AD
LA  - eng
GR  - BB/E527098/1/BB_/Biotechnology and Biological Sciences Research Council/United 
      Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Br J Pharmacol
JT  - British journal of pharmacology
JID - 7502536
RN  - 0 (Phorbol Esters)
RN  - 0 (TRPV Cation Channels)
RN  - 0 (Trpv4 protein, mouse)
RN  - 24928-17-4 (phorbol-12,13-didecanoate)
RN  - 9061-61-4 (Nerve Growth Factor)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Animals
MH  - Calcium/physiology
MH  - Cell Line
MH  - Cells, Cultured
MH  - Female
MH  - Ganglia, Spinal/cytology
MH  - Humans
MH  - Hyperalgesia/*physiopathology
MH  - Male
MH  - Mice
MH  - Mice, Knockout
MH  - Nerve Growth Factor/pharmacology
MH  - Neurons/*drug effects/physiology
MH  - Phorbol Esters/*pharmacology
MH  - TRPV Cation Channels/*physiology
MH  - Trigeminal Ganglion/cytology
PMC - PMC3579293
EDAT- 2012/08/30 06:00
MHDA- 2013/07/03 06:00
PMCR- 2014/02/01
CRDT- 2012/08/30 06:00
PHST- 2012/03/21 00:00 [received]
PHST- 2012/07/22 00:00 [revised]
PHST- 2012/08/15 00:00 [accepted]
PHST- 2012/08/30 06:00 [entrez]
PHST- 2012/08/30 06:00 [pubmed]
PHST- 2013/07/03 06:00 [medline]
PHST- 2014/02/01 00:00 [pmc-release]
AID - 10.1111/j.1476-5381.2012.02186.x [doi]
PST - ppublish
SO  - Br J Pharmacol. 2013 Feb;168(3):761-72. doi: 10.1111/j.1476-5381.2012.02186.x.