N-Acetyl-Cysteine, a Drug that Enhances the Endogenous Activation of Group-II Metabotropic Glutamate Receptors, Inhibits Nociceptive Transmission in Humans

N-Acetyl-Cysteine, a Drug that Enhances the Endogenous Activation of Group-II Metabotropic Glutamate Receptors, Inhibits Nociceptive Transmission in Humans

Molecular Pain, March 2015

25889381

Andrea Truini, Serena Piroso, Erica Pasquale, Serena Notartomaso, Giulia Di Stefano, Roberta Lattanzi, Giuseppe Battaglia, Ferdinando Nicoletti, Giorgio Cruccu

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.