title: N-acetyl-cysteine, a drug that enhances the endogenous activation of group-II metabotropic glutamate receptors, inhibits nociceptive transmission in humans.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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.).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Neurology and Psychiatry, University Sapienza, Rome, Italy. andrea.truini@uniroma1.it.
authors.forename: Andrea
authors.initials: A
authors.lastname: Truini
authors.affiliation: Department of Neurology and Psychiatry, University Sapienza, Rome, Italy. piroso.s@libero.it.
authors.forename: Serena
authors.initials: S
authors.lastname: Piroso
authors.affiliation: Department of Neurology and Psychiatry, University Sapienza, Rome, Italy. erica_psq@hotmail.it.
authors.forename: Erica
authors.initials: E
authors.lastname: Pasquale
authors.affiliation: Department of Neurology and Psychiatry, University Sapienza, I.R.C.C.S. Neuromed, Pozzilli, Italy. serena.notartomaso@uniroma1.it.
authors.forename: Serena
authors.initials: S
authors.lastname: Notartomaso
authors.affiliation: Department of Neurology and Psychiatry, University Sapienza, Rome, Italy. distefano.giulia83@gmail.com.
authors.forename: Giulia
authors.initials: G
authors.lastname: Di Stefano
authors.affiliation: Department of Physiology and Pharmacology, University Sapienza, Piazzale Aldo Moro, Rome, 500185, Italy. roberta.lattanzi@uniroma1.it.
authors.forename: Roberta
authors.initials: R
authors.lastname: Lattanzi
authors.affiliation: Department of Molecular Pathology, I.R.C.C.S. Neuromed, Pozzilli, Italy. giuseppe.battaglia@neuromed.it.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Battaglia
authors.affiliation: Department of Physiology and Pharmacology, University Sapienza, Piazzale Aldo Moro, Rome, 500185, Italy. ferdinandonicoletti@hotmail.com.|I.N.M. Neuromed, Pozzilli, Italy. ferdinandonicoletti@hotmail.com.|Department of Molecular Pathology, I.R.C.C.S. Neuromed, Pozzilli, Italy. ferdinandonicoletti@hotmail.com.
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Nicoletti
authors.affiliation: Department of Neurology and Psychiatry, University Sapienza, Rome, Italy. giorgio.cruccu@uniroma1.it.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Cruccu
mesh_terms: D000111:Acetylcysteine / Q000627:therapeutic use*; D000328:Adult; D000596:Amino Acids / Q000627:therapeutic use; D000700:Analgesics / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010146:Pain / Q000188:drug therapy*; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome; D014966:Xanthenes / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D000596:Amino Acids; D000700:Analgesics; C114624:LY 341495; D018094:Receptors, Metabotropic Glutamate; D014966:Xanthenes; D000111:Acetylcysteine