Nociceptive sensitization by the secretory protein Bv8

1 The small protein Bv8, isolated from amphibian skin, belongs to a novel family of secretory proteins (Bv8-Prokineticin family, SWISS-PROT: Q9PW66) whose orthologues have been conserved throughout evolution, from invertebrates to humans. 2 When injected intravenously or subcutaneously (from 0.06 to 500 pmol kg(-1)) or intrathecally (from 6 fmol to 250 pmol) in rats, Bv8 produced an intense systemic nociceptive sensitization to mechanical and thermal stimuli applied to the tail and paws. 3 Topically delivered into one rat paw, 50 fmol of Bv8 decreased by 50% the nociceptive threshold to pressure in the injected paw without affecting the threshold in the contralateral paw. 4 The two G-protein coupled prokineticin receptors, PK-R1 and PK-R2, were expressed in rat dorsal root ganglia (DRG) and in dorsal quadrants of spinal cord (DSC) and bound Bv8 and the mammalian orthologue, EG-VEGF, with high affinity. In DSC, PK-R1 was more abundant than PK-R2, whereas both receptors were equally expressed in DRG. IC50 of Bv8 and EG-VEGF to inhibit [I-125]-Bv8 binding to rat DRG and DSC were 4.1 +/- 0.4 nM Bv8 and 76.4 +/- 7.6 nm EG-VEGF, in DRG; 7.3 +/- 0.9 nm Bv8 and 330 +/- 41 nm EG-VEGF, in DSC. 5 In the small diameter neurons (< 30 pm) of rat DRG cultures, Bv8 concentrations, ranging from 0.2 to 10 nM, raised [Ca2+] in a dose-dependent manner. 6 These data suggest that Bv8, through binding to PK receptors of DSC and primary sensitive neurons, results in intense sensitization of peripheral nociceptors to thermal and mechanical stimuli.