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ABSTRACT: 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.
Journal of Neuroscience Research 03/2012; 90(7):1474-9. · 2.74 Impact Factor
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ABSTRACT: 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.
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.
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).
Our results suggest that ketamine stimulates the L-arginine/NO/cyclic GMP pathway via neuronal NO synthase to induce peripheral antinociceptive effects.
Anesthesia and analgesia 07/2011; 113(5):1254-9. · 3.08 Impact Factor
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ABSTRACT: Hypertensive subjects present an increased nociceptive threshold, and the lack or delay of pain perception may impede detection of angina and myocardial infarction. Nutritional interventions, like potassium chloride (KCl) diet supplementation, and exercises are common nonpharmacological indications for treating hypertension. Spontaneous hypertensive rats (SHR) and normotensive male Wistar rats were submitted to a combination of exercise and KCl diet supplementation. Exercise reduced the nociceptive threshold in SHR; however, this effect was inhibited by KCl supplementation. Exercise and KCl supplementation did not alter systolic blood pressure. Reduction of the nociceptive threshold by exercise may be important for the detection of angina and myocardial infarction in hypertensive individuals.
Applied Physiology Nutrition and Metabolism 04/2010; 35(2):184-7. · 2.13 Impact Factor
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ABSTRACT: Physical exercise is responsible for increasing the nociceptive threshold. The present study aimed to investigate the involvement of the nitric oxide/(C)GMP/K(ATP) pathway in antinociception induced by acute aerobic exercise (AAc) in rats.
Wistar rats performed exercise in a rodent treadmill, according to an AAc protocol. The nociceptive threshold was measured by mechanical and thermal nociceptive tests (paw-withdrawal, tail-flick and face-flick). To investigate the involvement of the NO/(C)GMP/K(ATP) pathway the following nitric oxide synthase (NOS) unspecific and specific inhibitors were used: N-nitro-l-arginine (NOArg), Aminoguanidine, N(5)-(1-Iminoethyl)-l-ornithine dihydrocloride (L-NIO), N(omega)-Propyl-l-arginine (L-NPA); guanylyl cyclase inhibitor, 1H-[1,2,4]oxidiazolo[4,3-a]quinoxalin-1-one (ODQ); and K(ATP) channel blocker, Glybenclamide; all administered subcutaneously at a dose of 2mg/kg 10min before exercise started. Plasma and cerebrospinal fluid (CSF) nitrite levels were determined by spectrophotometry.
In the paw-withdrawal, tail-flick and face-flick tests, the AAc protocol produced antinociception, which lasted for more than 15min. This effect was significantly reversed (P<0.05) by NOS specific and unspecific inhibitors, guanylyl cyclase inhibitor (ODQ) and K(ATP) channel blocker (Glybenclamide). Acute exercise was also responsible for increasing nitrite levels in both plasma and cerebrospinal fluid.
Taken together, these results suggest that the NO/(C)GMP/K(ATP) pathway participates in antinociception induced by exercise.
Life sciences 02/2010; 86(13-14):505-9. · 2.56 Impact Factor
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ABSTRACT: Aims: Phys. exercise is responsible for increasing the nociceptive threshold. The present study aimed to investigate the involvement of the nitric oxide/CGMP/KATP pathway in antinociception induced by acute aerobic exercise (AAc) in rats. Main methods: Wistar rats performed exercise in a rodent treadmill, according to an AAc protocol. The nociceptive threshold was measured by mech. and thermal nociceptive tests (paw-withdrawal, tail-flick and face-flick). To investigate the involvement of the NO/CGMP/KATP pathway the following nitric oxide synthase (NOS) unspecific and specific inhibitors were used: N-nitro-L-arginine (NOArg), Aminoguanidine, N5-(1-Iminoethyl)-L-ornithine dihydrocloride (L-NIO), NÏ-Propyl-L-arginine (L-NPA); guanylyl cyclase inhibitor, 1H-[1,2,4]oxidiazolo[4,3-a]quinoxalin-1-one (ODQ); and KATP channel blocker, Glybenclamide; all administered s.c. at a dose of 2 mg/kg 10 min before exercise started. Plasma and cerebrospinal fluid (CSF) nitrite levels were detd. by spectrophotomet
Life Sciences. 86(13-14):505-509.
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ABSTRACT: AIMS: Physical exercise is responsible for increasing the nociceptive threshold. The present study aimed to investigate the involvement of the nitric oxide/(C)GMP/K(ATP) pathway in antinociception induced by acute aerobic exercise (AAc) in rats. MAIN METHODS: Wistar rats performed exercise in a rodent treadmill, according to an AAc protocol. The nociceptive threshold was measured by mechanical and thermal nociceptive tests (paw-withdrawal, tail-flick and face-flick). To investigate the involvement of the NO/(C)GMP/K(ATP) pathway the following nitric oxide synthase (NOS) unspecific and specific inhibitors were used: N-nitro-l-arginine (NOArg), Aminoguanidine, N(5)-(1-Iminoethyl)-l-ornithine dihydrocloride (L-NIO), N(omega)-Propyl-l-arginine (L-NPA); guanylyl cyclase inhibitor, 1H-[1,2,4]oxidiazolo[4,3-a]quinoxalin-1-one (ODQ); and K(ATP) channel blocker, Glybenclamide; all administered subcutaneously at a dose of 2mg/kg 10min before exercise started. Plasma and cerebrospinal fluid (CSF) nitrite l
Life sciences. 86(13-14):505-9.
