Role of thalamic phospholipase C[beta]4 mediated by metabotropic glutamate receptor type 1 in inflammatory pain.
Phospholipase C (PLC) beta4, one of the four isoforms of PLCbetas, is the sole isoform expressed in the mouse ventral posterolateral thalamic nucleus (VPL), a key station in pain processing. The mouse thalamus also has been shown to express a high level of metabotropic glutamate receptor type 1 (mGluR1), which stimulates PLCbetas through activation of Galphaq/11 protein. It is therefore expected that the thalamic mGluR1-PLCbeta4 cascade may play a functional role in nociceptive transmission. To test this hypothesis, we first studied behavioral responses to various nociceptive stimuli in PLCbeta4 knock-out mice. We performed the formalin test and found no difference in the pain behavior in the first phase of the formalin test, which is attributed to acute nociception, between PLCbeta4 knock-out and wild-type mice. Consistent with this result, acute pain responses in the hot plate and tail flick tests were also unaffected in the PLCbeta4 knock-out mice. However, the nociceptive behavior in the second phase of the formalin test, resulting from the tissue inflammation, was attenuated in PLCbeta4 knock-out mice. In the dorsal horn of the spinal cord where PLCbeta1 and PLCbeta4 mRNAs are expressed, no difference was found between the wild-type and knock-out mice in the number of Fos-like immunoreactive neurons, which represent neuronal activity in the second phase in the formalin test. Thus, it is unlikely that spinal PLCbeta4 is involved in the formalin-induced inflammatory pain. Next, we found that pretreatment with PLC inhibitors, mGluR1 antagonists, or both, by either intracerebroventricular or intrathalamic injection, attenuated the formalin-induced pain behavior in the second phase in wild-type mice. Furthermore, activation of mGluR1 at the VPL enhanced pain behavior in the second phase in the wild-type mice. In contrast, PLCbeta4 knock-out mice did not show such enhancement, indicating that mGluR1 is connected to PLCbeta4 in the VPL. Finally, in parallel with the behavioral results, we showed in an electrophysiological study that the time course of firing discharges in VPL corresponds well to that of pain behavior in the formalin test in both wild-type and PLCbeta4 knock-out mice. These findings indicate that the thalamic mGluR1-PLCbeta4 cascade is indispensable for the formalin-induced inflammatory pain by regulating the response of VPL neurons.
Miyata
Mariko
M
Department of Information Physiology, National Institute for Physiological Sciences, Myodaiji, Okazaki 444-8585, Japan. mmiyata@nips.ac.jp
Kashiwadani
Hideki
H
Fukaya
Masahiro
M
Hayashi
Takayuki
T
Wu
Dianqing
D
Suzuki
Tutomu
T
Watanabe
Masahiko
M
Kawakami
Yoriko
Y
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001522:Behavior, Animal; D004333:Drug Administration Routes; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005557:Formaldehyde; D007249:Inflammation / Q000139:chemically induced / Q000503:physiopathology*; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D010146:Pain / Q000139:chemically induced / Q000503:physiopathology*; D010147:Pain Measurement / Q000187:drug effects; D054799:Phospholipase C beta; D020671:Posterior Horn Cells / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D012333:RNA, Messenger / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020651:Ventral Thalamic Nuclei / Q000187:drug effects / Q000378:metabolism*
D004791:Enzyme Inhibitors; D007527:Isoenzymes; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1; D005557:Formaldehyde; D010738:Type C Phospholipases; D054799:Phospholipase C beta; C518043:Plcb4 protein, mouse