N-acetyl-cysteine, a drug that enhances the endogenous activation of group-II metabotropic glutamate receptors, inhibits nociceptive transmission in humans.

Emerging research seeking novel analgesic drugs focuses on agents targeting group-II metabotropic glutamate receptors (mGlu2 and mGlu3 receptors). N-Acetylcysteine (NAC) enhances the endogenous activation of mGlu2/3 receptors by activating the glial glutamate:cystine membrane exchanger. Here, we examined whether NAC inhibits nociceptive responses in humans and animals. We tested the effect of oral NAC (1.2 g) on thermal-pain thresholds and laser-evoked potentials in 10 healthy volunteers, according to a crossover, double-blind, placebo-controlled design, and the effect of NAC (100 mg/kg, i.p.) on the tail-flick response evoked by radiant heat stimulation in mice.In healthy subjects, NAC treatment left thermal-pain thresholds unchanged, but significantly reduced pain ratings to laser stimuli and amplitudes of laser-evoked potentials. NAC induced significantly greater changes in these measures than placebo. In the tail-flick test, NAC strongly reduced the nocifensive reflex response to radiant heat. The action of NAC was abolished by the preferential mGlu2/3 receptor antagonist, LY341495 (1 mg/kg, i.p.).Our findings show for the first time that NAC inhibits nociceptive transmission in humans, and does the same in mice by activating mGlu2/3 receptors. These data lay the groundwork for investigating the therapeutic potential of NAC in patients with chronic pain

Switch in the expression of mGlu1 and mGlu5 metabotropic glutamate receptors in the cerebellum of mice developing experimental autoimmune encephalomyelitis and in autoptic cerebellar samples from patients with multiple sclerosis

Recent evidence suggests that changes in the expression of membrane receptors/ion channels in cerebellar Purkinje cells contribute to the onset of cerebellar motor symptoms in patients with multiple sclerosis (MS). We examined the expression of group-I metabotropic glutamate receptors (mGlu1 and mGlu5 receptors) in the cerebellum of mice developing experimental autoimmune encephalomyelitis (EAE) and in autoptic cerebellar samples of MS patients. EAE was induced in mice by immunization with the 35-55 fragment of MOG (myelin oligodendrocyte glycoprotein). EAE mice showed a progressive loss of mGlu1a receptors in the cerebellum, associated with an increased expression of mGlu5 receptors. These changes were restricted to Purkinje cells and their dendritic arborization, as shown by immunohistochemistry. A reduced expression of mGlu1a receptors in cerebellar Purkinje cells was also found in 7 of 9 MS patients. In addition, a light/moderate to very strong mGlu5 receptor immunoreactivity was detected in Purkinje cells of 8 MS patients, but was always absent in non-MS control patients. In EAE mice, an acute treatment with the mGlu1 receptor enhancer, 9H-xanthene-9-carboxylic acid (4-trifluoromethyl-oxazol-2-yl)-amide (RO0711401), significantly improved motor coordination, whereas treatment with the mGlu5 receptor antagonists, 2-methyl-6-(phenylethynyl)-pyridine (MPEP) and 6-methyl-2-(phenylazo)-3-pyridinol (SIB-1757), had no effect. We conclude that mGlu1 receptor enhancers improve motor symptoms associated with EAE and might be helpful as symptomatic drugs in patients with M

Perineuronal nets are under the control of type-5 metabotropic glutamate receptors in the developing somatosensory cortex

mGlu5 metabotropic glutamate receptors are highly functional in the early postnatal life, and regulate developmental plasticity of parvalbumin-positive (PV+) interneurons in the cerebral cortex. PV+ cells are enwrapped by perineuronal nets (PNNs) at the closure of critical windows of cortical plasticity. Changes in PNNs have been associated with neurodevelopmental disorders. We found that the number of Wisteria Fluoribunda Agglutinin (WFA)+ PNNs and the density of WFA+/PV+ cells were largely increased in the somatosensory cortex of mGlu5−/− mice at PND16. An increased WFA+ PNN density was also observed after pharmacological blockade of mGlu5 receptors in the first two postnatal weeks. The number of WFA+ PNNs in mGlu5−/− mice was close to a plateau at PND16, whereas continued to increase in wild-type mice, and there was no difference between the two genotypes at PND21 and PND60. mGlu5−/− mice at PND16 showed increases in the transcripts of genes involved in PNN formation and a reduced expression and activity of type-9 matrix metalloproteinase in the somatosensory cortex suggesting that mGlu5 receptors control both PNN formation and degradation. Finally, unilateral whisker stimulation from PND9 to PND16 enhanced WFA+ PNN density in the contralateral somatosensory cortex only in mGlu5+/+ mice, whereas whisker trimming from PND9 to PND16 reduced WFA+ PNN density exclusively in mGlu5−/− mice, suggesting that mGlu5 receptors shape the PNN response to sensory experience. These findings disclose a novel undescribed mechanism of PNN regulation, and lay the groundwork for the study of mGlu5 receptors and PNNs in neurodevelopmental disorders