Reduced pain behaviors and extracellular signal-related protein kinase activation in primary sensory neurons by peripheral tissue injury in mice lacking platelet-activating factor receptor.
Peripheral tissue injury causes the release of various mediators from damaged and inflammatory cells, which in turn activates and sensitizes primary sensory neurons and thereby produces persistent pain. The present study investigated the role of platelet-activating factor (PAF), a phospholipid mediator, in pain signaling using mice lacking PAF receptor (pafr-/- mice). Here we show that pafr-/- mice displayed almost normal responses to thermal and mechanical stimuli but exhibit attenuated persistent pain behaviors resulting from tissue injury by locally injecting formalin at the periphery as well as capsaicin pain and visceral inflammatory pain without any alteration in cytoarchitectural or neurochemical properties in dorsal root ganglion (DRG) neurons and a defect in motor function. However, pafr-/- mice showed no alterations in spinal pain behaviors caused by intrathecally administering agonists for N-methyl-d-aspartate (NMDA) and neurokinin(1) receptors. A PAFR agonist evoked an intracellular Ca(2+) response predominantly in capsaicin-sensitive DRG neurons, an effect was not observed in pafr-/- mice. By contrast, the PAFR agonist did not affect C- or Adelta-evoked excitatory post-synaptic currents in substantia gelatinosa neurons in the dorsal horn. Interestingly, mice lacking PAFR showed reduced phosphorylation of extracellular signal-related protein kinase (ERK), an important kinase for the sensitization of primary sensory neurons, in their DRG neurons after formalin injection. Furthermore, U0126, a specific inhibitor of the ERK pathway suppressed the persistent pain by formalin. Thus, PAFR may play an important role in both persistent pain and the sensitization of primary sensory neurons after tissue injury.
Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, Maidashi, Higashi-ku, Fukuoka, JapanDepartment of Biochemistry and Molecular Biology, Faculty of Medicine, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo, JapanPrecursory Research for Embryonic Science and Technology (PRESTO) of Japan Science and Technology Agency, Hongo, Bunkyo-ku, Tokyo, JapanDepartment of Integrative Physiology, Graduate School of Medical Sciences, Kyushu University, Maidashi, Higashi-ku, Fukuoka, JapanDepartment of Pharmacology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Shimokato, Chuo, Yamanashi, Japan.
Makoto
M
Tsuda
Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, Maidashi, Higashi-ku, Fukuoka, JapanDepartment of Biochemistry and Molecular Biology, Faculty of Medicine, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo, JapanPrecursory Research for Embryonic Science and Technology (PRESTO) of Japan Science and Technology Agency, Hongo, Bunkyo-ku, Tokyo, JapanDepartment of Integrative Physiology, Graduate School of Medical Sciences, Kyushu University, Maidashi, Higashi-ku, Fukuoka, JapanDepartment of Pharmacology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Shimokato, Chuo, Yamanashi, Japan.
Satoshi
S
Ishii
Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, Maidashi, Higashi-ku, Fukuoka, JapanDepartment of Biochemistry and Molecular Biology, Faculty of Medicine, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo, JapanPrecursory Research for Embryonic Science and Technology (PRESTO) of Japan Science and Technology Agency, Hongo, Bunkyo-ku, Tokyo, JapanDepartment of Integrative Physiology, Graduate School of Medical Sciences, Kyushu University, Maidashi, Higashi-ku, Fukuoka, JapanDepartment of Pharmacology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Shimokato, Chuo, Yamanashi, Japan.
Takahiro
T
Masuda
Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, Maidashi, Higashi-ku, Fukuoka, JapanDepartment of Biochemistry and Molecular Biology, Faculty of Medicine, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo, JapanPrecursory Research for Embryonic Science and Technology (PRESTO) of Japan Science and Technology Agency, Hongo, Bunkyo-ku, Tokyo, JapanDepartment of Integrative Physiology, Graduate School of Medical Sciences, Kyushu University, Maidashi, Higashi-ku, Fukuoka, JapanDepartment of Pharmacology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Shimokato, Chuo, Yamanashi, Japan.
Shigeo
S
Hasegawa
Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, Maidashi, Higashi-ku, Fukuoka, JapanDepartment of Biochemistry and Molecular Biology, Faculty of Medicine, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo, JapanPrecursory Research for Embryonic Science and Technology (PRESTO) of Japan Science and Technology Agency, Hongo, Bunkyo-ku, Tokyo, JapanDepartment of Integrative Physiology, Graduate School of Medical Sciences, Kyushu University, Maidashi, Higashi-ku, Fukuoka, JapanDepartment of Pharmacology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Shimokato, Chuo, Yamanashi, Japan.
Koji
K
Nakamura
Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, Maidashi, Higashi-ku, Fukuoka, JapanDepartment of Biochemistry and Molecular Biology, Faculty of Medicine, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo, JapanPrecursory Research for Embryonic Science and Technology (PRESTO) of Japan Science and Technology Agency, Hongo, Bunkyo-ku, Tokyo, JapanDepartment of Integrative Physiology, Graduate School of Medical Sciences, Kyushu University, Maidashi, Higashi-ku, Fukuoka, JapanDepartment of Pharmacology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Shimokato, Chuo, Yamanashi, Japan.
Kenichiro
K
Nagata
Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, Maidashi, Higashi-ku, Fukuoka, JapanDepartment of Biochemistry and Molecular Biology, Faculty of Medicine, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo, JapanPrecursory Research for Embryonic Science and Technology (PRESTO) of Japan Science and Technology Agency, Hongo, Bunkyo-ku, Tokyo, JapanDepartment of Integrative Physiology, Graduate School of Medical Sciences, Kyushu University, Maidashi, Higashi-ku, Fukuoka, JapanDepartment of Pharmacology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Shimokato, Chuo, Yamanashi, Japan.
Tomohiro
T
Yamashita
Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, Maidashi, Higashi-ku, Fukuoka, JapanDepartment of Biochemistry and Molecular Biology, Faculty of Medicine, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo, JapanPrecursory Research for Embryonic Science and Technology (PRESTO) of Japan Science and Technology Agency, Hongo, Bunkyo-ku, Tokyo, JapanDepartment of Integrative Physiology, Graduate School of Medical Sciences, Kyushu University, Maidashi, Higashi-ku, Fukuoka, JapanDepartment of Pharmacology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Shimokato, Chuo, Yamanashi, Japan.
Hidemasa
H
Furue
Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, Maidashi, Higashi-ku, Fukuoka, JapanDepartment of Biochemistry and Molecular Biology, Faculty of Medicine, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo, JapanPrecursory Research for Embryonic Science and Technology (PRESTO) of Japan Science and Technology Agency, Hongo, Bunkyo-ku, Tokyo, JapanDepartment of Integrative Physiology, Graduate School of Medical Sciences, Kyushu University, Maidashi, Higashi-ku, Fukuoka, JapanDepartment of Pharmacology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Shimokato, Chuo, Yamanashi, Japan.
Hidetoshi
H
Tozaki-Saitoh
Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, Maidashi, Higashi-ku, Fukuoka, JapanDepartment of Biochemistry and Molecular Biology, Faculty of Medicine, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo, JapanPrecursory Research for Embryonic Science and Technology (PRESTO) of Japan Science and Technology Agency, Hongo, Bunkyo-ku, Tokyo, JapanDepartment of Integrative Physiology, Graduate School of Medical Sciences, Kyushu University, Maidashi, Higashi-ku, Fukuoka, JapanDepartment of Pharmacology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Shimokato, Chuo, Yamanashi, Japan.
Megumu
M
Yoshimura
Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, Maidashi, Higashi-ku, Fukuoka, JapanDepartment of Biochemistry and Molecular Biology, Faculty of Medicine, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo, JapanPrecursory Research for Embryonic Science and Technology (PRESTO) of Japan Science and Technology Agency, Hongo, Bunkyo-ku, Tokyo, JapanDepartment of Integrative Physiology, Graduate School of Medical Sciences, Kyushu University, Maidashi, Higashi-ku, Fukuoka, JapanDepartment of Pharmacology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Shimokato, Chuo, Yamanashi, Japan.
Schuichi
S
Koizumi
Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, Maidashi, Higashi-ku, Fukuoka, JapanDepartment of Biochemistry and Molecular Biology, Faculty of Medicine, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo, JapanPrecursory Research for Embryonic Science and Technology (PRESTO) of Japan Science and Technology Agency, Hongo, Bunkyo-ku, Tokyo, JapanDepartment of Integrative Physiology, Graduate School of Medical Sciences, Kyushu University, Maidashi, Higashi-ku, Fukuoka, JapanDepartment of Pharmacology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Shimokato, Chuo, Yamanashi, Japan.
Takao
T
Shimizu
Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, Maidashi, Higashi-ku, Fukuoka, JapanDepartment of Biochemistry and Molecular Biology, Faculty of Medicine, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo, JapanPrecursory Research for Embryonic Science and Technology (PRESTO) of Japan Science and Technology Agency, Hongo, Bunkyo-ku, Tokyo, JapanDepartment of Integrative Physiology, Graduate School of Medical Sciences, Kyushu University, Maidashi, Higashi-ku, Fukuoka, JapanDepartment of Pharmacology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Shimokato, Chuo, Yamanashi, Japan.
Kazuhide
K
Inoue
D000818:Animals; D001522:Behavior, Animal; D002211:Capsaicin / Q000494:pharmacology; D002452:Cell Count / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005557:Formaldehyde / Q000009:adverse effects; D005727:Ganglia, Spinal / Q000473:pathology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009475:Neurons, Afferent / Q000201:enzymology* / Q000473:pathology; D010146:Pain / Q000201:enzymology* / Q000209:etiology / Q000473:pathology*; D010147:Pain Measurement / Q000379:methods; D018408:Patch-Clamp Techniques / Q000379:methods; D010523:Peripheral Nervous System Diseases / Q000150:complications; D010812:Physical Stimulation / Q000379:methods; D010980:Platelet Membrane Glycoproteins / Q000172:deficiency*; D011930:Reaction Time / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000172:deficiency*
D004791:Enzyme Inhibitors; D010980:Platelet Membrane Glycoproteins; D043562:Receptors, G-Protein-Coupled; C039351:platelet activating factor receptor; D005557:Formaldehyde; D048049:Extracellular Signal-Regulated MAP Kinases; D002211:Capsaicin