N-Acetyl-cysteine causes analgesia by reinforcing the endogenous activation of type-2 metabotropic glutamate receptors

Molecular Pain

Volumn 8, Issue , 2012, Pages

  Bernabucci, Matteo ^a   Notartomaso, Serena ^a   Zappulla, Cristina ^a   Fazio, Francesco ^a   Cannella, Milena ^a   Motolese, Marta ^a   Battaglia, Giuseppe ^a   Bruno, Valeria ^a,b   Gradini, Roberto ^a,c   Nicoletti, Ferdinando ^a,b  

^a IRCCS NEUROMED   (Italy)

^b SAPIENZA UNIVERSITY OF ROME   (Italy)

^c SAPIENZA UNIVERSITY OF ROME   (Italy)

Author keywords

AGS3; Analgesia; Cystine glutamate antiporter; mGlu2 receptors; N acetyl cysteine

Indexed keywords

2 AMINO 2 (2 CARBOXYCYCLOPROPYL) 3 (XANTHEN 9 YL)PROPIONIC ACID; ACETYLCYSTEINE; ANTIPORTER; CYSTEINE GLUTAMATE MEMBRANE EXCHANGER CATALYTIC SUBUNIT; FORMALDEHYDE; FREUND ADJUVANT; G PROTEIN SIGNALING TYPE 3; GUANINE NUCLEOTIDE BINDING PROTEIN; METABOTROPIC RECEPTOR 2; SALAZOSULFAPYRIDINE; UNCLASSIFIED DRUG;

ANALGESIA; ANALGESIC ACTIVITY; ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; CHRONIC CONSTRICTION INJURY; CHRONIC PAIN; CONTROLLED STUDY; DRUG EFFICACY; DRUG TOLERABILITY; ENZYME ACTIVATION; INFLAMMATION; LUMBAR SPINAL CORD; MALE; MOUSE; NEUROPATHIC PAIN; NOCICEPTION; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; SCIATIC NERVE; SPINAL CORD; TISSUE LEVEL;

ACETYLCYSTEINE; AMINO ACID TRANSPORT SYSTEM Y+; ANALGESICS; ANIMALS; MALE; MICE; MICE, INBRED C57BL; MICE, KNOCKOUT; PAIN; RECEPTORS, METABOTROPIC GLUTAMATE;

EID: 84867667405     PISSN: None     EISSN: 17448069     Source Type: Journal    
DOI: 10.1186/1744-8069-8-77     Document Type: Article

References (56)

1. Chiechio S, Copani A, Zammataro M, Battaglia G, Gereau RW, Nicoletti F. Transcriptional regulation of type-2 metabotropic glutamate receptors: an epigenetic path to novel treatments for chronic pain. Trends Pharmacol Sci 2010, 31(4):153-160. 10.1016/j.tips.2009.12.003, 20064669.
2. Varney MA, Gereau RW. Metabotropic glutamate receptor involvement in models of acute and persistent pain: prospects for the development of novel analgesics. Curr Drug Targets CNS Neurol Disord 2002, 1(3):283-296. 10.2174/1568007023339300, 12769620.
3. Goudet C, Magnaghi V, Landry M, Nagy F, Gereau RW, Pin JP. Metabotropic receptors for glutamate and GABA in pain. Brain Res Rev 2009, 60(1):43-56. 10.1016/j.brainresrev.2008.12.007, 19146876.
4. Yang D, Gereau RW. Peripheral group II metabotropic glutamate receptors (mGluR2/3) regulate prostaglandin E2-mediated sensitization of capsaicin responses and thermal nociception. J Neurosci 2002, 22(15):6388-6393.
5. Yang D, Gereau RW. Group II metabotropic glutamate receptors inhibit cAMP-dependent protein kinase-mediated enhancemednt of tetrodotoxin-resistant sodium currents in mouse dorsal root ganglion neurons. Neurosci Lett 2004, 357(3):159-162. 10.1016/j.neulet.2003.11.074, 15003274.
6. Carlton SM, Du J, Zhou S. Group II metabotropic glutamate receptor activation on peripheral nociceptors modulates TRPV1 function. Brain Res 2009, 1248:86-95. 2850281, 19026992.
7. Gerber G, Zhong J, Youn D, Randic M. Group II and group III metabotropic glutamate receptor agonists depress synaptic transmission in the rat spinal cord dorsal horn. Neuroscience 2000, 100(2):393-406. 10.1016/S0306-4522(00)00269-4, 11008177.
8. Carlton SM, Hargett GL, Coggeshall RE. Localization of metabotropic glutamate receptors 2/3 on primary afferent axons in the rat. Neuroscience 2001, 105(4):957-969. 10.1016/S0306-4522(01)00238-X, 11530234.
9. Maione S, Oliva P, Marabese I, Palazzo E, Rossi F, Berrino L, Filippelli A. Periaqueductal gray matter metabotropic glutamate receptors modulate formalin-induced nociception. Pain 2000, 85(1-2):183-189.
10. Li W, Neugebauer V. Differential changes of group II and group III mGluR function in central amygdala neurons in a model of arthritic pain. J Neurophysiol 2006, 96(4):1803-1815. 10.1152/jn.00495.2006, 16760343.
11. Zammataro M, Chiechio S, Montana MC, Traficante A, Copani A, Nicoletti F, Gereau RW. mGlu2 metabotropic glutamate receptors restrain inflammatory pain and mediate the analgesic activity of dual mGlu2/mGlu3 receptor agonists. Mol Pain 2011, 7:6. 10.1186/1744-8069-7-6, 3030510, 21235748.
12. Dolan S, Kelly JG, Monteiro AM, Nolan AM. Up-regulation of metabotropic glutamate receptor subtypes 3 and 5 in spinal cord in a clinical model of persistent inflammation and hyperalgesia. Pain 2003, 106(3):501-512. 10.1016/j.pain.2003.09.017, 14659534.
13. Neto FL, Schadrack J, Platzer S, Zieglgänsberger W, Tölle TR, Castro-Lopes JM. Up-regulation of metabotropic glutamate receptor 3 mRNA expression in the cerebral cortex of monoarthritic rats. J Neurosci Res 2001, 63(4):356-367. 10.1002/1097-4547(20010215)63:4<356::AID-JNR1030>3.0.CO;2-3, 11170186.
14. Boxall SJ, Berthele A, Laurie DJ, Sommer B, Zieglgänsberger W, Urban L, Tölle TR. Enhanced expression of metabotropic glutamate receptor 3 messenger RNA in the rat spinal cord during ultraviolet irradiation induced peripheral inflammation. Neuroscience 1998, 82(2):591-602.
15. Yamamoto T, Nozaki-Taguchi N, Sakashita Y, Inagaki T. Inhibition of spinal N-acetylated-alpha-linked acidic dipeptidase produces an antinociceptive effect in the rat formalin test. Neuroscience 2001, 102(2):473-479. 10.1016/S0306-4522(00)00502-9, 11166133.
16. Yamamoto T, Nozaki-Taguchi N, Sakashita Y. Spinal N-acetyl-alpha-linked acidic dipeptidase (NAALADase) inhibition attenuates mechanical allodynia induced by paw carrageenan injection in the rat. Brain Res 2001, 909(1-2):138-144.
17. Carpenter KJ, Sen S, Matthews EA, Flatters SL, Wozniak KM, Slusher BS, Dickenson AH. Effects of GCP-II inhibition on responses of dorsal horn neurones after inflammation and neuropathy: an electrophysiological study in the rat. Neuropeptides 2003, 37(5):298-306. 10.1016/j.npep.2003.08.001, 14607107.
18. Yamamoto T, Saito O, Aoe T, Bartolozzi A, Sarva J, Zhou J, Kozikowski A, Wroblewska B, Bzdega T, Neale JH. Local administration of N-acetylaspartylglutamate (NAAG) peptidase inhibitors is analgesic in peripheral pain in rats. Eur J Neurosci 2007, 25(1):147-158. 10.1111/j.1460-9568.2006.05272.x, 17241276.
19. Adedoyin MO, Vicini S, Neale JH. Endogenous N-acetylaspartylglutamate (NAAG) inhibits synaptic plasticity/transmission in the amygdala in a mouse inflammatory pain model. Mol Pain 2010, 22:6-60.
20. Yamada T, Zuo D, Yamamoto T, Olszewski RT, Bzdega T, Moffett JR, Neale JH. NAAG peptidase inhibition in the periaqueductal gray and rostral ventromedial medulla reduces flinching in the formalin model of inflammation. Mol Pain 2012, 8(1):67. 10.1186/1744-8069-8-67, 22971334.
21. Nagel J, Belozertseva I, Greco S, Kashkin V, Malyshkin A, Jirgensons A, Shekunova E, Eilbacher B, Bespalov A, Danysz W. Effects of NAAG peptidase inhibitor 2-PMPA in model chronic pain - relation to brain concentration. Neuropharmacology 2006, 51(7-8):1163-1171.
22. Jones CK, Eberle EL, Peters SC, Monn JA, Shannon HE. Analgesic effects of the selective group II (mGlu2/3) metabotropic glutamate receptor agonists LY379268 and LY389795 in persistent and inflammatory pain models after acute and repeated dosing. Neuropharmacology 2005, 49(Suppl 1):206-218.
23. Chiechio S, Zammataro M, Morales ME, Busceti CL, Drago F, Gereau RW, Copani A, Nicoletti F. Epigenetic modulation of mGlu2 receptors by histone deacetylase inhibitors in the treatment of inflammatory pain. Mol Pharmacol 2009, 75(5):1014-1020. 10.1124/mol.108.054346, 19255242.
24. Chiechio S, Caricasole A, Barletta E, Storto M, Catania MV, Copani A, Vertechy M, Nicolai R, Calvani M, Melchiorri D, Nicoletti F. L-Acetylcarnitine induces analgesia by selectively up-regulating mGlu2 metabotropic glutamate receptors. Mol Pharmacol 2002, 61(5):989-996. 10.1124/mol.61.5.989, 11961116.
25. Chiechio S, Copani A, De Petris L, Morales ME, Nicoletti F, Gereau RW. Transcriptional regulation of metabotropic glutamate receptor 2/3 expression by the NF-kappaB pathway in primary dorsal root ganglia neurons: a possible mechanism for the analgesic effect of L-acetylcarnitine. Mol Pain 2006, 2:20. 10.1186/1744-8069-2-20, 1550235, 16764720.
26. De Grandis D, Minardi C. Acetyl-L-carnitine (levacecarnine) in the treatment of diabetic neuropathy. A long-term, randomised, double-blind, placebo-controlled study. Drugs R D 2002, 3(4):223-231. 10.2165/00126839-200203040-00001, 12455197.
27. Sima AA, Calvani M, Mehra M, Amato A. Acetyl-L-carnitine improves pain, nerve regeneration, and vibratory perception in patients with chronic diabetic neuropathy: an analysis of two randomized placebo-controlled trials. Diabetes Care 2005, 28(1):89-94. 10.2337/diacare.28.1.89, 15616239.
28. Youle M. Acetyl-L-carnitine in HIV-associated antiretroviral toxic neuropathy. CNS Drugs 2007, 21(Suppl 1):25-30. discussion 45-6..
29. Evans JD, Jacobs TF, Evans EW. Role of acetyl-L-carnitine in the treatment of diabetic peripheral neuropathy. Ann Pharmacother 2008, 42(11):1686-1691. 10.1345/aph.1L201, 18940920.
30. Nicoletti F, Bockaert J, Collingridge GL, Conn PJ, Ferraguti F, Schoepp DD, Wroblewski JT, Pin JP. Metabotropic glutamate receptors: from the workbench to the bedside. Neuropharmacology 2011, 60(7-8):1017-1041.
31. Kalivas PW. The glutamate homeostasis hypothesis of addiction. Nat Rev Neurosci 2009, 10(8):561-572. 10.1038/nrn2515, 19571793.
32. Bridges RJ, Natale NR, Patel SA. System xc(-) cystine/glutamate antiporter: an update on molecular pharmacology and roles within the CNS. Br J Pharmacol 2012, 165(1):20-34. 10.1111/j.1476-5381.2011.01480.x, 21564084.
33. Coderre TJ, Melzack R. The contribution of excitatory amino acids to central sesitization and persistent nociception after formalin-induced tissue injury. J Neurosci , 12:3665-3670.
34. Tjolsen A, Berge OG, Hunskaar S, Rosland JH, Hole K. The formalin test:an evaluation of the method. Pain 1992, 51:5-17. 10.1016/0304-3959(92)90003-T, 1454405.
35. Gout PW, Buckley AR, Simms CR, Bruchovsky N. Sulphasalazine, a potent suppressor of lymphoma growth by inhibition of the x(c)- cystine transporter: a new action for an old drug. Leukemia 2001, 15(10):1633-1640. 10.1038/sj.leu.2402238, 11587223.
36. Lyons SA, Chung WJ, Weaver AK, Ogunrinu T, Sontheimer H. Autocrine glutamate signaling promotes glioma cell invasion. Cancer Res 2007, 67(19):9463-9471. 10.1158/0008-5472.CAN-07-2034, 2045073, 17909056.
37. de Groot J, Sontheimer H. Glutamate and the biology of gliomas. Glia 2011, 59(8):1181-1189. 10.1002/glia.21113, 3107875, 21192095.
38. Moussawi K, Pacchioni A, Moran M, Olive MF, Gass JT, Lavin A, Kalivas PW. N-acetyl-cysteine reverses cocaine-induced metaplasticity. Nat Neurosci 2009, 12(2):182-189. 10.1038/nn.2250, 2661026, 19136971.
39. Moussawi K, Zhou W, Shen H, Reichel CM, See RE, Carr DB, Kalivas PW. Reversing cocaine-induced synaptic potentiation provides enduring protection from relapse. Proc Natl Acad Sci U S A 2011, 108(1):385-390. 10.1073/pnas.1011265108, 3017187, 21173236.
40. Moussawi K, Riegel A, Nair S, Kalivas PW. Extracellular glutamate: functional compartments operate in different concentration ranges. Front Syst Neurosci 2011, 5:94. 3254064, 22275885.
41. Knackstedt LA, Moussawi K, Lalumiere R, Schwendt M, Klugmann M, Kalivas PW. Extinction training after cocaine self-administration induces glutamatergic plasticity to inhibit cocaine seeking. J Neurosci 2010, 30(23):7984-7992. 10.1523/JNEUROSCI.1244-10.2010, 2893028, 20534846.
42. Amen SL, Piacentine LB, Ahmad ME, Li SJ, Mantsch JR, Risinger RC, Baker DA. Repeated N-acetyl cysteine reduces cocaine seeking in rodents and craving in cocaine-dependent humans. Neuropsychopharmacology 2011, 36(4):871-878. 10.1038/npp.2010.226, 3052624,3052624, 21160464.
43. Yang D, Gereau RW. Peripheral group II metabotropic glutamate receptors mediate endogenous anti-allodynia in inflammation. Pain 2003, 106(3):411-417. 10.1016/j.pain.2003.08.011, 14659524.
44. Karim F, Bhave G, Gereau RW. Metabotropic glutamate receptors on peripheral sensory neuron terminals as targets for the development of novel analgesics. Mol Psychiatry 2001, 6(6):615-617. 10.1038/sj.mp.4000961, 11673787.
45. Neugebauer V. Peripheral metabotropic glutamate receptors: fight the pain where it hurts. Trends Neurosci 2001, 24(10):550-552. 10.1016/S0166-2236(00)02007-5, 11576647.
46. Ye ZC, Sontheimer H. Glioma cells release excitotoxic concentrations of glutamate. Cancer Res 1999, 59(17):4383-4391.
47. Patel SA, Warren BA, Rhoderick JF, Bridges RJ. Differentiation of substrate and non-substrate inhibitors of transport system xc(-): an obligate exchanger of L-glutamate and L-cystine. Neuropharmacology 2004, 46(2):273-284. 10.1016/j.neuropharm.2003.08.006, 14680765.
48. Schoepp DD, Tizzano JP, Wright RA, Fix AS. Reversible and irreversible neuronal injury induced by intrahippocampal infusion of the mGluR agonist 1S,3R-ACPD in the rat. Neurodegeneration 1995, 4(1):71-80. 10.1006/neur.1995.0008, 7600186.
49. Baumgart DC, Sandborn WJ. Inflammatory bowel disease: clinical aspects and established and evolving therapies. Lancet 2007, 369(9573):1641-1657. 10.1016/S0140-6736(07)60751-X, 17499606.
50. Lanier SM. AGS proteins, GPR motifs and the signals processed by heterotrimeric G proteins. Biol Cell 2004, 96(5):369-372.
51. Anderson SM, Park ZH, Patel RV. Intravenous N-acetylcysteine in the prevention of contrast media-induced nephropathy. Ann Pharmacother 2011, 45(1):101-107. 10.1345/aph.1P275, 21205947.
52. Millea PJ. N-acetylcysteine: multiple clinical applications. Am Fam Physician 2009, 80(3):265-269.
53. Heard KJ. Acetylcysteine for acetaminophen poisoning. N Engl J Med 2008, 359(3):285-292. 10.1056/NEJMct0708278, 2637612, 18635433.
54. Rogers DF. Mucoactive agents for airway mucus hypersecretory diseases. Respir Care 2007, 52(9):1176-1179.
55. Bennett GJ, Xie YK. A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 1988, 33(1):87-107. 10.1016/0304-3959(88)90209-6, 2837713.
56. Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL. Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods 1994, 53(1):55-63. 10.1016/0165-0270(94)90144-9, 7990513.