ABSTRACT
Title
Prokineticin receptor antagonists: novel antihyperalgesic and antiinflammatory drugs
Authors
R. Lattanzi1, D. Maftei 1, G. Balboni 2, S. Salvadori 3, L.Negri 1
1 Department of Physiology and Pharmacology “Vittorio Erspamer”, “Sapienza” University of Rome, Italy; 2 Department of Toxicology, University of Cagliari, Cagliari, Italy; 3Department of Pharmaceutical Sciences, University of Ferrara, Ferrara, Italy.
Abstract
Bv8, prokineticin 1 (PK1) and prokineticin 2 (PK2)make up a new family of chemokines, characterized by the presence of five disulfide bridges, that lowers pain threshold and modulates immune responses. They activate two G-protein linked PKR receptors (PKR1 and PKR2) in the central nervous system, dorsal root ganglia and in cells participating to immuno and inflammatory responsesIn rodents, exogenous administration of Bv8/PK2 reduces the nociceptive threshold to thermal and mechanical stimuli acting on PKRs on primary sensitive nerves and in spinal cord.
The endogenous mammalian homolog of Bv8 (PK2) is constitutively expressed, at very low levels, in bone marrow, spleen and in peripheral blood cells but is strongly up-regulated in inflamed tissues.In an animal model of CFA-induced paw inflammation, we brought evidence that the granulocyte-derived Bv8/PK2 is a major determinant in triggering inflammatory pain and PKRs may represent a therapeutic target for the development of novel peripherally acting antinociceptive drugs. For this reason we synthesized a non-peptide molecule (a triazine derivative) named PC1 that act as a prokineticin receptor antagonist. PC1 selectively antagonizes Bv8-induced nociceptor sensitization and also antagonizes capsain-induced hyperalgesia suggesting that PC1 blocks the positive interaction between PKR1 and the non selective cation channel TRPV1. Moreover, PC1abolishes the inflammation-induced hyperalgesia (1).
These promising results suggest that blocking Bv8/PK system might be a winning strategy to treat pain in other pathologies which usually develop from early neutrophil infiltration and flow into a chronic pain perception.
We evaluated the effect of PC1 chronically injected (150 µg/kg, s.c. twice a day for four days) in a mouse model of neuropathic pain (the sciatic nerve chronic constriction injury (CCI)) and of inflammatory pain (Complete Freund’s Adijvant (CFA) injection into the paw). One group of CCI-mice received PC1 starting at day three after surgery, when thermal hyperalgesia (Plantar test)peaks. PC1 treatment completely reverted thermal hyperalgesia during the four days treatment bringing the nociceptive threshold of injuried paw (9.8 ± 0.9 sec.) toward that of contralateral non-injuried paw (10.2 ± 1.2 sec.). At PC1 withdrawal, from day 5 to 30, thermal hyperalgesia slowly reappeard. Interestingly, in this mouse model allodynia (Von frey filaments)never develops. In Another group of CCI-mice received PC1 in therapeutic schedule starting at day seventeen after ligation when allodynia is already established. PC1 treatment completely reverted allodynia. Thermal hyperalgesia was abolished during the four days treatment but reappeared, at PC1 withdrawal, even if less intense than in control mice. In CFA-treated mice, the chronic administration of PC1 accelerates the recovery to normal paw volumes (Plethismometer). Thermal hyperalgesia disappears in two days and allodynia in three days. Appropriate changes in the molecule of PC1 let us to obtain other triazine derivatives. Some of them acting as PKRs antagonists display an anti-hyperalgesic effectfrom 10 to 100 fold more efficacious than PC1. So, PKRs antagonists merit development as innovative drugs to combat pain and reduce inflammation.
1) Giannini E., Lattanzi R., Nicotra A., Campese A.F., Grazioli P., Screpanti P., Balboni G., Salvadori S., Sacerdote P. and Negri L. (2009). PNAS, 106, 14646-14651.
The endogenous mammalian homolog of Bv8 (PK2) is constitutively expressed, at very low levels, in bone marrow, spleen and in peripheral blood cells but is strongly up-regulated in inflamed tissues.In an animal model of CFA-induced paw inflammation, we brought evidence that the granulocyte-derived Bv8/PK2 is a major determinant in triggering inflammatory pain and PKRs may represent a therapeutic target for the development of novel peripherally acting antinociceptive drugs. For this reason we synthesized a non-peptide molecule (a triazine derivative) named PC1 that act as a prokineticin receptor antagonist. PC1 selectively antagonizes Bv8-induced nociceptor sensitization and also antagonizes capsain-induced hyperalgesia suggesting that PC1 blocks the positive interaction between PKR1 and the non selective cation channel TRPV1. Moreover, PC1abolishes the inflammation-induced hyperalgesia (1).
These promising results suggest that blocking Bv8/PK system might be a winning strategy to treat pain in other pathologies which usually develop from early neutrophil infiltration and flow into a chronic pain perception.
We evaluated the effect of PC1 chronically injected (150 µg/kg, s.c. twice a day for four days) in a mouse model of neuropathic pain (the sciatic nerve chronic constriction injury (CCI)) and of inflammatory pain (Complete Freund’s Adijvant (CFA) injection into the paw). One group of CCI-mice received PC1 starting at day three after surgery, when thermal hyperalgesia (Plantar test)peaks. PC1 treatment completely reverted thermal hyperalgesia during the four days treatment bringing the nociceptive threshold of injuried paw (9.8 ± 0.9 sec.) toward that of contralateral non-injuried paw (10.2 ± 1.2 sec.). At PC1 withdrawal, from day 5 to 30, thermal hyperalgesia slowly reappeard. Interestingly, in this mouse model allodynia (Von frey filaments)never develops. In Another group of CCI-mice received PC1 in therapeutic schedule starting at day seventeen after ligation when allodynia is already established. PC1 treatment completely reverted allodynia. Thermal hyperalgesia was abolished during the four days treatment but reappeared, at PC1 withdrawal, even if less intense than in control mice. In CFA-treated mice, the chronic administration of PC1 accelerates the recovery to normal paw volumes (Plethismometer). Thermal hyperalgesia disappears in two days and allodynia in three days. Appropriate changes in the molecule of PC1 let us to obtain other triazine derivatives. Some of them acting as PKRs antagonists display an anti-hyperalgesic effectfrom 10 to 100 fold more efficacious than PC1. So, PKRs antagonists merit development as innovative drugs to combat pain and reduce inflammation.
1) Giannini E., Lattanzi R., Nicotra A., Campese A.F., Grazioli P., Screpanti P., Balboni G., Salvadori S., Sacerdote P. and Negri L. (2009). PNAS, 106, 14646-14651.