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.