Bv8/PK2 and prokineticin receptors: a druggable pronociceptive system

Mammalian Bv8 (also called prokineticin 2) is a secreted protein that regulates diverse biological processes including pain perception. It belongs to a new family of chemokines, which activate two G-protein linked receptors (prokineticin receptor 1 and 2, PKR1 and PKR2) expressed in regions of the nervous system associated with pain and in cells participating to immuno-inflammatory responses. Primary sensitive neurons co-express PKRs and the transient potential receptor vanilloid 1, cooperating in nociceptor sensitization. Bv8, strongly upregulated in neutrophils and other inflammatory cells, is a main pronociceptive mediator in inflamed tissues, where it sensitizes peripheral nociceptors, stimulates neutrophil chemotaxis and modulates the release of inflammatory and pronociceptive cytokines. Availability of a nonpeptide PKR antagonist, leading to blockade of the Bv8/PKR system, ameliorates pain arising from tissue injury and reduces the time required for recovery from injury.

► Bv8 is a secreted protein that regulates diverse biological processes including pain. ► It belongs to a new family of chemokines strongly upregulated by inflammation. ► Bv8 is a main pronociceptive mediator in inflamed tissues. ► Blocking the Bv8 receptors (PKR1 and PKR2) ameliorates pain and speeds up tissue healing. ► Nonpeptide selective PKR antagonists constitute a novel therapeutic approach for the treatment of chronic pain.