title: Pharmacological activity of a Bv8 analogue modified in position 24.
abstract: OBJECTIVE
  The amphibian peptide Bv8 induces potent nociceptive sensitization in rodents. Its mammalian homologue, prokineticin 2 (PROK2), is strongly up-regulated in inflamed tissues and is a major determinant in triggering inflammatory pain. Bv8 and PROK2 activate two closely related GPCRs, PK(1) and PK(2) , in a relatively non-selective fashion. To characterize better the roles of the two receptors in hyperalgesia and to obtain ligands whose binding affinity and efficacy differed for the two receptors, we modified the Bv8 molecule in regions essential for receptor recognition and activation.
  
  
  METHODS
  We modified the Bv8 molecule by substituting Trp in position 24 with Ala (A-24) and compared it with Bv8 for binding and activating PK(1) and PK(2) receptors in cell preparations and in affecting nociceptive thresholds in rodents.
  
  
  RESULTS
  A-24 preferentially bound to PK(2) receptors and activated them with a lower potency (5-fold) than Bv8. When systemically injected, A-24 induced Bv8-like hyperalgesia in rats and in mice, at doses 100 times higher than Bv8. Locally and systemically injected at inactive doses, A-24 antagonized Bv8-induced hyperalgesia. In rat and mouse models of inflammatory and post-surgical pain, A-24 showed potent and long-lasting anti-hyperalgesic activity. Unlike Bv8, A-24 increased β-endorphin levels in mouse brain.
  
  
  CONCLUSIONS
  A-24 induced its anti-hyperalgesic effect in rodents by directly blocking nociceptor PK(1) receptors and by activating the central opioid system and the descending pain control pathway through brain PK(2) receptors.
authors: Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy.
authors: R
authors: R
authors: Lattanzi
authors: P
authors: P
authors: Sacerdote
authors: S
authors: S
authors: Franchi
authors: M
authors: M
authors: Canestrelli
authors: R
authors: R
authors: Miele
authors: D
authors: D
authors: Barra
authors: S
authors: S
authors: Visentin
authors: C
authors: C
authors: DeNuccio
authors: F
authors: F
authors: Porreca
authors: M
authors: M
authors: De Felice
authors: F
authors: F
authors: Guida
authors: L
authors: L
authors: Luongo
authors: V
authors: V
authors: de Novellis
authors: S
authors: S
authors: Maione
authors: L
authors: L
authors: Negri
mesh_terms: D000409:Alanine / Q000737:chemistry; D019943:Amino Acid Substitution; D029845:Amphibian Proteins / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D000700:Analgesics / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D016466:CHO Cells; D002633:Chemotaxis / Q000187:drug effects; D006224:Cricetinae; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000188:drug therapy; D006930:Hyperalgesia / Q000188:drug therapy / Q000378:metabolism; D008024:Ligands; D008264:Macrophages / Q000166:cytology / Q000187:drug effects; D008297:Male; D051379:Mice; D009479:Neuropeptides / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D010149:Postoperative Pain / Q000188:drug therapy / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D018000:Receptors, Peptide / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014162:Transfection; D014364:Tryptophan / Q000737:chemistry
chemical_list: D029845:Amphibian Proteins; D000700:Analgesics; C121344:Bv8 protein, Bombina variegata; D008024:Ligands; D009479:Neuropeptides; C470837:PROKR1 protein, human; C470838:PROKR2 protein, human; D043562:Receptors, G-Protein-Coupled; D018000:Receptors, Peptide; D014364:Tryptophan; D000409:Alanine