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4α‐phorbol 12,13‐didecanoate activates cultured mouse dorsal root ganglia neurons independently of TRPV4
Author(s) -
Alexander R,
Kerby A,
Aubdool AA,
Power AR,
Grover S,
Gentry C,
Grant AD
Publication year - 2013
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2012.02186.x
Subject(s) - trpv4 , hyperalgesia , agonist , sensitization , chemistry , dorsal root ganglion , nociceptor , endocrinology , medicine , nociception , pharmacology , neuroscience , transient receptor potential channel , anatomy , biology , dorsum , biochemistry , receptor
Background and Purpose The C a 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. 4α‐phorbol 12,13‐didecanoate (4α PDD ) has been described as a selective TRPV4 agonist. We investigated NGF ‐induced hyperalgesia in TRPV4 wild‐type (+/+) and knockout (–/–) mice, and the increases in [ C a 2+ ] i produced by 4α PDD in cultured mouse dorsal root ganglia neurons following exposure to NGF . Experimental Approach Withdrawal thresholds to heat, von F rey hairs and pressure were measured in mice before and after systemic administration of NGF . Changes in intracellular C a 2+ concentration were measured by ratiometric imaging with F ura‐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. 4α PDD stimulated a dose‐dependent increase in [ C a 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 C a 2+ in cultured neurons. Responses to 4α PDD 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 4α PDD activates these neurons independently of TRPV4 , so it is not appropriate to refer to 4α PDD as a selective TRPV4 agonist.