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.
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 [Ca2+]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 [Ca2+]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.
Negri
Lucia
L
Department of Human Physiology and Pharmacology Vittorio Erspamer, University of Roma La Sapienza, 00185 Roma, Italy. lucia.negri@uniroma1.it
Lattanzi
Roberta
R
Giannini
Elisa
E
Colucci
Mariantonella
M
Margheriti
Federica
F
Melchiorri
Pietro
P
Vellani
Vittorio
V
Tian
Hui
H
De Felice
Milena
M
Porreca
Frank
F
D000818:Animals; D001522:Behavior, Animal; D001831:Body Temperature / Q000187:drug effects / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D002211:Capsaicin / Q000009:adverse effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005727:Ganglia, Spinal / Q000166:cytology; D005768:Gastrointestinal Hormones / Q000009:adverse effects; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006930:Hyperalgesia / Q000235:genetics / Q000503:physiopathology; D017403:In Situ Hybridization / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009475:Neurons, Afferent / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009479:Neuropeptides / Q000009:adverse effects; D009619:Nociceptors / Q000502:physiology*; D010146:Pain / Q000139:chemically induced / Q000235:genetics / Q000503:physiopathology*; D010147:Pain Measurement / Q000379:methods; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D010812:Physical Stimulation / Q000379:methods; D011930:Reaction Time / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D050916:TRPV Cation Channels / Q000378:metabolism*
D005768:Gastrointestinal Hormones; D009479:Neuropeptides; C486586:Prok2 protein, mouse; D043562:Receptors, G-Protein-Coupled; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D002211:Capsaicin; D002118:Calcium