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The Journal of Neuroscience, June 21, 2006, 26(25):6716-6727; doi:10.1523/JNEUROSCI.5403-05.2006
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Behavioral/Systems/Cognitive
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
Lucia Negri,1
Roberta Lattanzi,1
Elisa Giannini,1
Mariantonella Colucci,1
Federica Margheriti,1
Pietro Melchiorri,1
Vittorio Vellani,2
Hui Tian,3
Milena De Felice,1,4 and
Frank Porreca4
1Department of Human Physiology and Pharmacology "Vittorio Erspamer", University of Roma "La Sapienza", 00185 Roma, Italy, 2Department of Biomedical Sciences, University of Modena and Reggio Emilia, 41100 Modena, Italy, 3Amgen, South San Francisco, California 94080, and 4University of Arizona, Tucson, Arizona 58274
Correspondence should be addressed to Lucia Negri, Department of Human Physiology and Pharmacology, University of Roma "La Sapienza", Piazzale Aldo Moro 5, 00185 Rome, Italy. Email: lucia.negri{at}uniroma1.it
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.
Key words: PKR1; TRPV1; prokineticins; Bv8; nociception; inflammation
Received Dec. 19, 2005;
revised May 13, 2006;
accepted May 13, 2006.
Correspondence should be addressed to Lucia Negri, Department of Human Physiology and Pharmacology, University of Roma "La Sapienza", Piazzale Aldo Moro 5, 00185 Rome, Italy. Email: lucia.negri{at}uniroma1.it
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