Modulators of pain: Bv8 and prokineticins

Bv8 is a small protein secreted by frog skin. Mammalian homologues of Bv8, the prokineticins PK1 and PK2, and their G-protein coupled receptors PKR1 and PKR2 have been identified and linked to several biological effects. Bv8 elicits a dose-dependent reduction in nociceptive threshold to thermal and mechanical stimuli applied to the skin of tail and paw of rats and mice and increases the sensitivity to nociceptive mediators as capsaicin and prostaglandins. The receptors for Bv8/PKs are present in a fraction of peptidergic population of C-fibre neurons, and in a fraction of A myelinated-fibre neurons. In mouse and rat dorsal root ganglia, PKR-expressing neurons also express TRPV1 and the activation of PKRs sensitises TPRV1 to the action of capsaicin. Mice lacking PKR1 gene exhibit impaired Bv8-induced hyperalgesia, develop deficient responses to noxious heat, capsaicin and protons and show reduced thermal and mechanical hypersensitivity to paw inflammation, indicating a requirement for PKR1 signalling associated with activation and sensitisation of primary afferent fibres. PKs are highly expressed by neutrophils and other inflammatory cells and must be considered as new pronociceptive mediators in inflammatory tissues. Bv8-like hyperalgesic activity was demonstrated in extracts of rat inflammatory granulocytes. Bv8 stimulate macrophage and T lymphocyte to differentiate between an inflammatory and Th1 profile indicating that Bv8/PK proteins play a role in immuno-inflammatory responses. Blockade of PKRs may represent a novel therapeutic strategy in acute and inflammatory pain conditions.