Involvement of lysophosphatidic acid in bone cancer pain by potentiation of TRPV1 via PKCε pathway in dorsal root ganglion neurons.
BACKGROUND
It has been demonstrated that lysophosphatidic acid (LPA) released from injury tissue and transient receptor potential vanilloid 1 (TRPV1) receptor are implicated in the induction of chronic pain. In the present study we examined whether an interaction between LPA receptor LPA(1) and TRPV1 in dorsal root ganglion (DRG) neurons contributes to the development of bone cancer pain.


RESULTS
Bone cancer was established by injection of mammary gland carcinoma cells into the rat tibia. Following the development of bone cancer pain, the TRPV1 expression and capsaicin-evoked currents were up-regulated in rat DRG neurons at L(4-6) segments. Immunohistochemistry staining revealed a high co-localization of LPA(1) with TRPV1 in DRG neurons. In isolated DRG neurons, whole-cell patch recording showed that capsaicin-induced currents were potentiated by LPA in a dose-dependent manner. The potentiation was blocked by either LPA(1) antagonist, protein kinase C (PKC) inhibitor or PKCε inhibitor, but not by protein kinase A (PKA) inhibitor or Rho inhibitor. In the behavioral tests, both mechanical allodynia and thermal hyperalgesia in bone cancer rats were attenuated by LPA(1) antagonist.


CONCLUSIONS
LPA potentiates TRPV1 current via a PKCε-dependent pathway in DRG neurons of rats with bone cancer, which may be a novel peripheral mechanism underlying the induction of bone cancer pain.
Institute of Neurobiology, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200032, China.
Hai-Li
HL
Pan
Yu-Qiu
YQ
Zhang
Zhi-Qi
ZQ
Zhao
D000818:Animals; D001859:Bone Neoplasms / Q000473:pathology*; D005727:Ganglia, Spinal / Q000473:pathology*; D006930:Hyperalgesia / Q000188:drug therapy; D007150:Immunohistochemistry; D008246:Lysophospholipids / Q000032:analysis* / Q000037:antagonists & inhibitors / Q000494:pharmacology; D009374:Neoplasms, Experimental; D009474:Neurons / Q000473:pathology; D010146:Pain / Q000209:etiology*; D051744:Protein Kinase C-epsilon / Q000378:metabolism*; D051381:Rats; D050916:TRPV Cation Channels / Q000032:analysis* / Q000378:metabolism
D008246:Lysophospholipids; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; D051744:Protein Kinase C-epsilon; C032881:lysophosphatidic acid