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The Journal of Neuroscience, September 3, 2003, 23(22):8098-8108

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Role of Thalamic Phospholipase C4 Mediated by Metabotropic Glutamate Receptor Type 1 in Inflammatory Pain

Mariko Miyata,^1,2 Hideki Kashiwadani,² Masahiro Fukaya,³ Takayuki Hayashi,² Dianqing Wu,⁴ Tutomu Suzuki,⁵ Masahiko Watanabe,³ and Yoriko Kawakami²

¹Department of Information Physiology, National Institute for Physiological Sciences, Okazaki 444-8585, Japan, ²Department of Physiology, Tokyo Women's Medical University, Tokyo 162-8666, Japan, ³Department of Anatomy, Hokkaido University, School of Medicine, Hokkaido 060-8638, Japan, ⁴Department of Genetics and Developmental Biology, University of Connecticut, Farmington, Connecticut 06030, and ⁵Department of Toxicology, Faculty of Pharmaceutical Science, Hoshi University, Tokyo 142-8501, Japan

Phospholipase C (PLC) 4, one of the four isoforms of PLCs, 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 PLCs through activation of Gq/11 protein. It is therefore expected that the thalamic mGluR1-PLC4 cascade may play a functional role in nociceptive transmission. To test this hypothesis, we first studied behavioral responses to various nociceptive stimuli in PLC4 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 PLC4 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 PLC4 knock-out mice. However, the nociceptive behavior in the second phase of the formalin test, resulting from the tissue inflammation, was attenuated in PLC4 knock-out mice. In the dorsal horn of the spinal cord where PLC1 and PLC4 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 PLC4 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, PLC4 knock-out mice did not show such enhancement, indicating that mGluR1 is connected to PLC4 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 PLC4 knock-out mice. These findings indicate that the thalamic mGluR1-PLC4 cascade is indispensable for the formalin-induced inflammatory pain by regulating the response of VPL neurons.

Key words: thalamus; phospholipase C4; metabotropic glutamate receptor type 1; formalin test; inflammatory pain; knock-out mouse; electrophysiology

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Received March 27, 2003; revised June 13, 2003; accepted June 20, 2003.

This article has been cited by other articles:

				M. Miyata and K. Imoto Different composition of glutamate receptors in corticothalamic and lemniscal synaptic responses and their roles in the firing responses of ventrobasal thalamic neurons in juvenile mice J. Physiol., August 15, 2006; 575(1): 161 - 174. [Abstract] [Full Text] [PDF]

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