Red nucleus glutamate facilitates neuropathic allodynia induced by spared nerve injury through non‐NMDA and metabotropic glutamate receptors

Abstract

Previous studies have demonstrated that glutamate plays an important role in the development of pathological pain. This study investigates the expression changes of glutamate and the roles of different types of glutamate receptors in the red nucleus (RN) in the development of neuropathic allodynia induced by spared nerve injury (SNI). Immunohistochemistry indicated that glutamate was constitutively expressed in the RN of normal rats. After SNI, the expression levels of glutamate were significantly increased in the RN at 1 week and reached the highest level at 2 weeks postinjury compared with sham-operated and normal rats. The RN glutamate was colocalized with neurons, oligodendrocytes, and astrocytes but not microglia under physiological and neuropathic pain conditions. To elucidate further the roles of the RN glutamate and different types of glutamate receptors in the development of neuropathic allodynia, antagonists to N-methyl-D-aspartate (NMDA), non-NMDA, or metabotropic glutamate receptors (mGluRs) were microinjected into the RN contralateral to the nerve-injury side of rats with SNI, and the paw withdrawal threshold (PWT) was dynamically assessed with von Frey filaments. Microinjection of the NMDA receptor antagonist MK-801 into the RN did not show any effect on SNI-induced mechanical allodynia. However, microinjection of the non-NMDA receptor antagonist 6,7-dinitroquinoxaline-2,3(1H,4H)-dione or the mGluR antagonist (±)-α-methyl-(4-carboxyphenyl) glycine into the RN significantly increased the PWT and alleviated SNI-induced mechanical allodynia. These findings suggest that RN glutamate is involved in regulating neuropathic pain and facilitates the development of SNI-induced neuropathic allodynia. The algesic effect of glutamate is transmitted by the non-NMDA glutamate receptor and mGluRs.

Red nucleus structure and function: from anatomy to clinical neurosciences

“…Probably, this antinociceptive response is regulated on a cellular level by the metabolic pathway of nitric oxide (NO): microinjections of l-arginine (a NO precursor) into RN have a strong antinociceptive effect, that is, in turn, prevented by the inhibition of the NO synthase (Kumar et al 1995). Since the inhibition of non-NMDA and metabotropic glutamate receptors has also an antinociceptive effect, it is likely that glutamate, the most important neurotransmitter in the RN, plays an opposite effect, by reducing the antinociceptive response (Yu et al 2015).…”

Defective functional connectivity between posterior hypothalamus and regions of the diencephalic-mesencephalic junction in chronic cluster headache

“…FC between the red nucleus and the hypothalamus has been reported in humans (44). In animals, chemical or electrical stimulation of the red nucleus has an analgesic effect (45); and it was shown that red nucleus activation occurs during CH attacks (11). Taken together, these observations may suggest a role of the red nucleus in pain control in CH patients.…”

Functional magnetic resonance imaging of regional impaired cerebrovascular reactivity for migraineurs in the interictal state

“…Excessive glutamate presence had been reported at the red nucleus of rats under the condition of neuropathic pain. 29 MR spectroscopy (MRS) that can correlate elevated glutamate level with abnormal CVR at the red nucleus of migraineurs could be an interesting research target in future.…”