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Involvement of the L‐arginine/nitric oxide/cyclic guanosine monophosphate pathway in peripheral antinociception induced by N‐palmitoyl‐ethanolamine in rats
Author(s) -
Romero Thiago R.L.,
Galdino Giovane S.,
Silva Grazielle C.,
Resende Lívia C.,
Perez Andréa C.,
Cortes Steyner F.,
Duarte Igor D.G.
Publication year - 2012
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.22797
Subject(s) - cyclic guanosine monophosphate , pharmacology , chemistry , nitric oxide , hyperalgesia , zaprinast , nitric oxide synthase , soluble guanylyl cyclase , nociception , receptor , medicine , biochemistry , guanylate cyclase , organic chemistry
N‐palmitoyl‐ethanolamine (PEA) is an endogenous substance that was first identified in lipid tissue extracts. It has been classified as a CB 2 receptor agonist. Exogenous PEA has the potential to become a valid treatment for neuropathic and inflammatory pain. In spite of the well‐demonstrated antiinflammatory properties of PEA, its involvement in controlling pain pathways remains poorly characterized. The participation of the L‐arginine/nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) pathway in peripheral antinociception has been established by our group to the μ‐, κ‐ or δ‐opioid receptor agonists, nonsteroidal analgesics, α 2C ‐adrenoceptor agonists, and even nonpharmacological electroacupuncture. The aim of this study was to verify whether the peripheral antinociception effects of PEA involve the activation of this pathway. All drugs were locally administered to the right hind paw of male Wistar rats. The paw pressure test was used, with hyperalgesia induced by intraplantar injection of prostaglandin E 2 . PEA elicited a local peripheral antinociceptive effect that was antagonized by the nonselective NO synthase (NOS) inhibitor L‐NOARG and the selective neuronal NOS (nNOS) inhibitor L‐NPA. Selective inhibition of endothelial (eNOS) and inducible (iNOS) NOS via L‐NIO and L‐NIL, respectively, was ineffective at blocking the effects of a local PEA injection. In addition, the dosage of nitrite in the homogenized paw, as determined by colorimetric assay, indicated that exogenous PEA is able to induce NO release. The soluble guanylyl cyclase inhibitor ODQ antagonized the PEA effect, whereas the cGMP‐phosphodiesterase inhibitor zaprinast potentiated the antinociceptive effect of low‐dose PEA. This study provides evidence that PEA activates nNOS, thus initiating the NO/cGMP pathway and inducing peripheral antinociceptive effects. © 2012 Wiley Periodicals, Inc.