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Ketamine activates the L-arginine/Nitric oxide/cyclic guanosine monophosphate pathway to induce peripheral antinociception in rats.
Anesth Analg. 2011 Nov; 113(5):1254-9.A&A

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+Show Affiliations

Departamento de Farmacologia, Instituto de Ciências Biológicas, ICB-UFMG, Av. Antônio Carlos, 6627, Pampulha, CEP 31.270-100, Belo Horizonte, MG, Brazil.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21788321

Citation

Romero, Thiago R L., et al. "Ketamine Activates the L-arginine/Nitric Oxide/cyclic Guanosine Monophosphate Pathway to Induce Peripheral Antinociception in Rats." Anesthesia and Analgesia, vol. 113, no. 5, 2011, pp. 1254-9.
Romero TR, Galdino GS, Silva GC, et al. Ketamine activates the L-arginine/Nitric oxide/cyclic guanosine monophosphate pathway to induce peripheral antinociception in rats. Anesth Analg. 2011;113(5):1254-9.
Romero, T. R., Galdino, G. S., Silva, G. C., Resende, L. C., Perez, A. C., Côrtes, S. F., & Duarte, I. D. (2011). Ketamine activates the L-arginine/Nitric oxide/cyclic guanosine monophosphate pathway to induce peripheral antinociception in rats. Anesthesia and Analgesia, 113(5), 1254-9. https://doi.org/10.1213/ANE.0b013e3182285dda
Romero TR, et al. Ketamine Activates the L-arginine/Nitric Oxide/cyclic Guanosine Monophosphate Pathway to Induce Peripheral Antinociception in Rats. Anesth Analg. 2011;113(5):1254-9. PubMed PMID: 21788321.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Ketamine activates the L-arginine/Nitric oxide/cyclic guanosine monophosphate pathway to induce peripheral antinociception in rats. AU - Romero,Thiago R L, AU - Galdino,Giovane S, AU - Silva,Grazielle C, AU - Resende,Lívia C, AU - Perez,Andréa C, AU - Côrtes,Steyner F, AU - Duarte,Igor D G, Y1 - 2011/07/25/ PY - 2011/7/27/entrez PY - 2011/7/27/pubmed PY - 2011/12/13/medline SP - 1254 EP - 9 JF - Anesthesia and analgesia JO - Anesth Analg VL - 113 IS - 5 N2 - 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. SN - 1526-7598 UR - https://www.unboundmedicine.com/medline/citation/21788321/Ketamine_activates_the_L_arginine/Nitric_oxide/cyclic_guanosine_monophosphate_pathway_to_induce_peripheral_antinociception_in_rats_ L2 - https://doi.org/10.1213/ANE.0b013e3182285dda DB - PRIME DP - Unbound Medicine ER -