title: Ketamine activates the L-arginine/Nitric oxide/cyclic guanosine monophosphate pathway to induce peripheral antinociception in rats.
abstract: BACKGROUND
  The involvement of the L-arginine/nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) pathway in antinociception has been implicated as a molecular mechanism of antinociception produced by several antinociceptive agents, including μ-, κ-, or δ-opioid receptor agonists, nonsteroidal analgesics, cholinergic agonist, and α2C adrenoceptor agonist. In this study, we investigated whether ketamine, a dissociative anesthetic N-methyl-D-aspartate receptor antagonist, was also capable of activating the L-arginine/NO/cGMP pathway and eliciting peripheral antinociception.
  
  
  METHODS
  The rat paw pressure test was used, with hyperalgesia induced by intraplantar injection of prostaglandin E2. All drugs were locally administered into the right hindpaw of male Wistar rats.
  
  
  RESULTS
  Ketamine (10, 20, 40, 80 μg/paw) elicited a local antinociceptive effect that was antagonized by the nonselective NOS inhibitor L-NOARG (12, 18, and 24 μg/paw) and by the selective neuronal NOS inhibitor L-NPA (12, 18, and 24 μg/paw). In another experiment, we used the inhibitors L-NIO and L-NIL (24 μg/paw) to selectively inhibit endothelial and inducible NOS, respectively. These 2 drugs were ineffective at blocking the effects of the peripheral ketamine injection. In addition, the level of nitrite in the homogenized paw indicated that exogenous ketamine is able to induce NO release. The soluble guanylyl cyclase inhibitor ODQ (25, 50, and 100 μg/paw) blocked the action of ketamine, and the cGMP-phosphodiesterase inhibitor zaprinast (50 μg/paw) enhanced the antinociceptive effects of low-dose ketamine (10 μg/paw).
  
  
  CONCLUSIONS
  Our results suggest that ketamine stimulates the L-arginine/NO/cyclic GMP pathway via neuronal NO synthase to induce peripheral antinociceptive effects.
authors.affiliation: Departamento de Farmacologia, Instituto de Ciências Biológicas, ICB-UFMG, Av. Antônio Carlos, 6627, Pampulha, CEP 31.270-100, Belo Horizonte, MG, Brazil.
authors.forename: Thiago R L
authors.initials: TR
authors.lastname: Romero
authors.forename: Giovane S
authors.initials: GS
authors.lastname: Galdino
authors.forename: Grazielle C
authors.initials: GC
authors.lastname: Silva
authors.forename: Lívia C
authors.initials: LC
authors.lastname: Resende
authors.forename: Andréa C
authors.initials: AC
authors.lastname: Perez
authors.forename: Steyner F
authors.initials: SF
authors.lastname: Côrtes
authors.forename: Igor D G
authors.initials: ID
authors.lastname: Duarte
mesh_terms: D000698:Analgesia; D000778:Anesthetics, Dissociative / Q000494:pharmacology*; D000818:Animals; D001120:Arginine / Q000378:metabolism / Q000502:physiology*; D000242:Cyclic AMP / Q000502:physiology*; D015232:Dinoprostone / Q000494:pharmacology; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D006930:Hyperalgesia / Q000188:drug therapy / Q000523:psychology; D007649:Ketamine / Q000494:pharmacology*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D019335:Nitroarginine / Q000494:pharmacology; D010069:Oxadiazoles / Q000494:pharmacology; D010146:Pain / Q000188:drug therapy*; D010523:Peripheral Nervous System Diseases / Q000188:drug therapy*; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D000778:Anesthetics, Dissociative; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D010069:Oxadiazoles; D011810:Quinoxalines; D016194:Receptors, N-Methyl-D-Aspartate; D019335:Nitroarginine; D009569:Nitric Oxide; D007649:Ketamine; D001120:Arginine; D000242:Cyclic AMP; D019001:Nitric Oxide Synthase; D006162:Guanylate Cyclase; D015232:Dinoprostone