Effect of the inhibition of serotonin biosynthesis on the antinociception induced by nonsteroidal anti-inflammatory drugs

doi:10.1016/S0361-9230(03)00144-8

Brain Research Bulletin

Volume 61, Issue 4, 30 August 2003, Pages 417-425

https://doi.org/10.1016/S0361-9230(03)00144-8 Get rights and content

Abstract

The antinociceptive activity of nonsteroidal anti-inflammatory drugs (NSAIDs) has been explained mainly on the basis of their inhibition of the enzyme cyclooxygenase (COX); however, this inhibition is not enough to completely explain the analgesic efficacy of these drugs. The modulation exerted by serotonergic systems on antinociception is well known. The purpose of the present work was to further explore the role of serotonin in the antinociceptive activity of NSAIDs using the writhing test and the tail-flick test of the mice after the inhibition of serotonin biosynthesis with intraperitoneal p-chlorophenylalanine (p-CPA). Pretreatment with p-CPA produced a significant decrease in the antinociceptive activity of NSAIDs administered either by the intraperitoneal or intrathecal routes, in both algesiometric tests. These results suggest a complementary mechanism of antinociception for NSAIDs, independent of their ability to inhibit the activity of COX, involving the activation of descending serotonergic pathways. By the pharmacological nature of the study, one limitation was the absence of biochemical measurement of the synthesis of 5-HT, since the reduction of the brain 5-HT synthesis by pretreatment with p-CPA will be expressed as a disminished antinociceptive activity of NSAIDs, which would be a new argument to consider NSAIDs acting as central analgesic agents.

Introduction

The antinociceptive activity of nonsteroidal anti-inflammatory drugs (NSAIDs) has been adscribed to the inhibition of cyclooxygenase enzymes 8., 12., 32., 33.. However, their antinociceptive effect seems not to be exerted only through the inhibition of prostaglandin biosynthesis, but a variety of other mechanisms are implicated. Thus, NSAIDs have nonprostaglandin inhibitory actions, as the ability to inhibit a variety of membrane associated processes, like neutrophil cell–cell aggregation [5], generation of hydrogen peroxide [6] and phosphodiesterase activity [1]. Furthermore, previous studies have demonstrated that in the antinociceptive activity of NSAIDs adrenergic and cholinergic mechanisms are involved 19., 21., 24.. In addition, there are evidences indicating that 5-HT receptors have a role in the modulation of pain 4., 13., 23., 26., 31., 35.. The purpose of the present study was to systematically explore the role of serotonin in the modulation of the antinociceptive activity of NSAIDs, using p-chlorophenylalanine (p-CPA), a serotonin biosynthesis competitive inhibitor, which has been used as effective inhibitor of brain regional 5-HT synthesis [30]. The antinociceptive activity was evaluated in two different algesiometric assays: the acetic acid writhing test and the tail-flick test. The writhing test was chosen as a visceral acute pain model and the tail-flick test as a somatic acute pain model. These models were selected because they closely resemble clinical relevant acute postoperatory pain in humans 17., 27., 34..

Section snippets

Animals

CF-1 mice of either sex, weighing 30±1 g, were used throughout the experimental work. The animals were acclimatized to the laboratory environment for at least 2 h before being used and ethical standard guidelines were followed as previously described [20] and the protocol was approved by the ethical commission of the Faculty of Medicine of the University of Chile. In particular, the duration of the experiments was as short as possible, the number of animals involved was kept to a minimum and the

Antinociceptive effects of NSAIDs and p-CPA

The i.p. or i.t. administration of NSAIDs produced a dose-dependent antinociceptive effect in both algesiometric tests, with different potencies. The values for the antinociceptive activity of NSAIDs in the writhing test and in the tail-flick test, are shown in Table 1.

Mice were pretreated with p-CPA 48 h before the test (320 mg/kg, i.p.), according to a previous reported schedule [29]. The i.p. administration of 320 mg/kg of p-CPA did not induce any antinociceptive activity in the algesiometric

Discussion

In the present work, it was found that several NSAIDs, administered either via i.p. or i.t., were capable of inducing dose-dependent antinociception in two acute pain assays: a viscero somatic model (tonic pain) reflected in a significant reduction of the acetic acid-induced abdominal writhes, and a thermal test involving thermal stimuli (phasic pain), as evidenced by increase in tail-flick latency. These results are important, because there is a consensus that the tail-flick test is truly

Acknowledgements

Work supported by Project No. 1990842, FONDECYT, Chile. The authors acknowledge the expert technical assistance of J. Lopez and A. Correa.

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Effect of the inhibition of serotonin biosynthesis on the antinociception induced by nonsteroidal anti-inflammatory drugs

Abstract

Introduction

Section snippets

Animals

Antinociceptive effects of NSAIDs and p-CPA

Discussion

Acknowledgements

Eur. J. Pharmacol.

Eur. J. Med. Chem.

Pharmacol. Biochem. Behav.

Eur. J. Pharmacol.

Brain Res.

Behav. Brain Res.

Neurochem. Int.

Brain Res.

Life Sci.

Mol. Med. Today

The mechanisms of action of nonsteroidal antiinflammatory drugs

Arthritis Rheum.

Ondansetron inhibits the analgesic effects of tramadol: a possible 5-HT3 spinal receptor involvement in acute pain in humans

Anesth. Analg.

Central antinociceptive effects of non-steroidal anti-inflammatory drugs and paracetamol

Acta Anaesthesiol. Scand. Suppl.

Nonsteroidal antiinflammatory drugs—differences and similarities

N. Engl. J. Med.

The mechanisms of action of NSAIDs in analgesia

Drugs

A method for determining loss of pain sensation

J. Pharmacol. Exp. Ther.

The analgesic efficacy of tramadol is impaired by concurrent administration of ondansetron

Anesth. Analg.

Ondansetron inhibits the analgesic effects of tramadol: a possible 5-HT₃ spinal receptor involvement in acute pain in humans