Impaired Nociception and Inflammatory Pain Sensation in Mice Lacking the Prokineticin Receptor PKR1: Focus on Interaction between PKR1 and the Capsaicin Receptor TRPV1 in Pain Behavior

Abstract

Bv8, prokineticin-1 or EG-VEGF (endocrine gland-derived vascular endothelial growth factor), and prokineticin-2, are naturally occurring peptide agonists of two G-protein-coupled receptors (GPCRs), prokineticin receptor 1 (PKR1) and PKR2. PKRs are expressed in neurons in the CNS and peripheral nervous system and many dorsal root ganglion (DRG) cells expressing PKRs also express transient receptor potential vanilloid receptor-1 (TRPV1). Mice lacking the pkr1 gene were generated to explore the role of the PKR1 receptor in nociceptive signaling and in nociceptor sensitization. When compared with wild-type littermates, mice lacking the pkr1 gene showed impaired responsiveness to noxious heat, mechanical stimuli, capsaicin, and protons. In wild-type mice, activation of PKRs by the PKR agonist Bv8 caused hyperalgesia and sensitized to the actions of capsaicin. pkr1-null mice exhibited impaired responses to Bv8 but showed normal hyperalgesic responses to bradykinin and PGE2 (prostaglandin E2). Conversely, trpv1-null mice showed a reduced pronociceptive response to Bv8. Additionally, pkr1-null mice showed diminished thermal hyperalgesia after acute inflammation elicited by mustard oil and reduced pain behavior after chronic inflammation produced by complete Freund's adjuvant. The number of neurons that responded with a [Ca 2ϩ ] i increase to Bv8 exposure was five times lower in pkr1-null DRG cultures than in wild-type cultures. Furthermore, Bv8-responsive neurons from pkr1-null mice showed a significant reduction in the [Ca 2ϩ ] i response to capsaicin. These findings indicate a modulatory role of PKR1 in acute nociception and inflammatory pain and disclose a pharmacological interaction between PKR1 and TRPV1 in nociceptor activation and sensitization.

The chemokine Bv8/prokineticin 2 is up-regulated in inflammatory granulocytes and modulates inflammatory pain

“…In WT mice CFA-induced inflammation reduced paw withdrawal latency to the noxious thermal stimulus and greatly up-regulated PK2 mRNA with respect to noninflamed paw (saline). In comparison with WT-mice, pkr1 (15) or pkr2 gene disruption significantly reduced CFA-induced inflammatory hypersensitivity, but only the pkr1 gene disruption reduced inflammatory PK2 mRNA up-regulation. Indeed, PK2 transcript levels 12 h after CFA injection were 15-fold lower in pkr1-null mice than in WT mice, whereas PK2 transcript levels in pkr2-null mice were similar to those in WT mice.…”

“…This increase in nociceptor excitability resulted from functional cooperation between PKR1 and TRPV1, the two receptors being coexpressed in small sensory neurons of DRG (14)(15)(16).…”

“…Inflammatory stimuli activate the release of the cytokine G-CSF that stimulates the synthesis and release of the chemokine PK2 by neutrophils, and this chemokine, in turn, stimulates macrophage chemotaxis and cytokine release by recruited macrophages. Although other leukocyte-derived chemokines are known to produce hypernociception in rats and mice (2,29,30) their pronociceptive activity and potency in activating G protein-coupled receptors is Ϸ100-500 times lower than that of PK2, and their receptors are far less abundant than PKRs in the primary sensory neurons under basal conditions (15,16,31,32).…”

“…Later on, the human orthologues of this highly conserved protein (PK1 or EG-VEGF and PK2 or mammalian Bv8) were shown to promote angiogenesis and modulate neurogenesis, circadian rhythms, hematopoiesis, and immune response (13). Activation of PKRs in primary afferent C fibers sensitizes nociceptors to thermal, mechanical, and chemical stimuli (14)(15)(16). In neutrophils, macrophages, and dendritic cells it promotes chemotaxis and cytokine release (17)(18)(19)(20), and in capillary endothelial cells it stimulates angiogenesis (21).…”

“…Testis, peripheral blood leukocytes, and macrophages express two mRNA transcripts of PK2, one coding for the canonical PK2 and the other for an elongated form containing additional 21 basic amino acids between Lys-47 and Val-48 of the mature PK2 protein, named PK2L (6,19,22). In inflamed tissues both PK2 and PK2L mRNA transcripts are overexpressed (15), but the mature proteins have not yet been isolated from inflammatory cells nor tested for their biological activity.…”