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. IC(50) of Bv8 and EG-VEGF to inhibit [(125)I]-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 microm) of rat DRG cultures, Bv8 concentrations, ranging from 0.2 to 10 nM, raised [Ca(2+)](i) 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.
Negri
Lucia
L
Department of Human Physiology and Pharmacology V. Erspamer, University La Sapienza, 00185 Rome, Italy. lucia.negri@uniroma1.it
Lattanzi
Roberta
R
Giannini
Elisa
E
Metere
Alessio
A
Colucci
Mariantonella
M
Barra
Donatella
D
Kreil
Günther
G
Melchiorri
Pietro
P
D029845:Amphibian Proteins; D000818:Animals; D001001:Anura; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009479:Neuropeptides; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D017288:Pain Threshold / Q000187:drug effects* / Q000502:physiology; D011506:Proteins / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled; D018000:Receptors, Peptide / Q000378:metabolism
D029845:Amphibian Proteins; C121344:Bv8 protein, Bombina variegata; D009479:Neuropeptides; C470837:PROKR1 protein, human; C470838:PROKR2 protein, human; D011506:Proteins; D043562:Receptors, G-Protein-Coupled; D018000:Receptors, Peptide; D002118:Calcium