Elsevier

Life Sciences

Volume 70, Issue 24, 3 May 2002, Pages 2857-2869
Life Sciences

Modulation of NSAID-induced antinociceptive and anti-inflammatory effects by α2-adrenoceptor agonists with gastroprotective effects

https://doi.org/10.1016/S0024-3205(02)01549-7Get rights and content

Abstract

Tizanidine, an α2-adrenergic receptor agonist with myospasmolytic action, is indicated for the treatment of back pain either as monotherapy or in combination with nonsteridal anti-inflammatory drugs (NSAIDs).

Tizanidine (0.25–1.0 mg/kg) significantly produced analgesic and anti-inflammatory effect in acetic acid induced writhing in mice and carrageenan-induced paw edema in rats, respectively. The effects were comparable with clonidine (0.25 and 0.50 mg/kg), another α2-agonist. Yohimbine (1 mg/kg), α2-adrenergic antagonist reversed the effect of tizanidine. Tizanidine (0.25 mg/kg) and clonidine (0.25 mg/kg) significantly potentiated the antinociceptive and anti-inflammatory effect of NSAIDs (nimesulide, meloxicam and naproxen). Tizanidine (1 mg/kg) did not alter basal pH, acidity (free and total) of gastric content and did not produce any mucosal injury in fasted rats. Tizanidine (1 mg/kg) significantly reduced meloxicam (UD503.21 mg/kg), nimesulide (UD5024.52 mg/kg) and naproxen (UD5014.10 mg/kg) - induced ulcerogenic effect (ulcer index, pH and free/total acidity). It is expected that tizanidine exerted gastrotprotection through stimulation of gastric and central α2-adrenergic receptors. Present investigation suggested that tizanidine not only enhance the analgesic and anti-inflammatory effect of NSAIDs but also improved gatstrointestinal tolerability of NSAIDs through modulation of central alpha-2-receptors.

From this study, it can be speculated that tizanidine and NSAID combination therapy would prove to be a novel approach to treat nociceptive /inflammatory conditions with improved gastric tolerability of NSAIDs

Introduction

Acute back pain is one of the common health problems with substantial socioeconomic impact because of its high incidence. It is estimated that 80 - 100% of the adult population experience back pain at least once in their life time [1]. The standard treatment of back pain involves administration of nonsteroidal anti-inflammatory drugs (NSAIDs) and bed rest. Unfortunately, NSAIDs are associated with some adverse effects. The most common adverse effect of NSAIDs, related to the gastrointestinal system, include abdominal pain or discomfort, heart burn, dyspepsia, nausea and vomiting, gastric ulcers, over bleeding and perforations [2]. Back pain, also involves reflux muscle spasm-pain cycle. Beside NSAIDs, muscle relaxants are also commonly used to treat patients with back pain [3].

Tizanidine, an imidazoline derivative is a centrally acting myospasmolytic drug. Its mechanism of action is thought to be through stimulation of central α2-adrenergic receptors. It preferentially inhibits polysynaptic mechanisms responsible for excessive muscle tone, mainly by reducing the release of excitatory amino acids from inter neurons [4]. In various clinical trials, it is reported that tizanidine to be effective in the treatment of local pain syndromes as monotherapy or in combination with NSAIDs [5], [6], [7], [8]. In addition, it is suggested that when combined with NSAIDs, tizanidine may reduce NSAIDs-induced gastrointestinal adverse effects [8], [9]. In present study the antinociceptive and anti-inflammatory effects of tizanidine alone and in combination with NSAIDs was investigated against acetic acid–induced chemonociception and carrageenan–induced paw edema in experimental animals, respectively. The gastroprotection offered by tizanidine was also noted.

Section snippets

Animals

Albino Wistar rats (150–200 g) and Swiss mice of either sex (Central Animal House, Panjab University, Chandigarh, India) were used. Animals were housed under standard laboratory conditions. They were maintained on rat chow and had free access to water.

Analgesic study: Writhing test (acetic acid writhing assay)

1% acetic acid solution (10 ml/kg, i.p.) was used to produce writhing in mice. Number of wriths per animal (constriction of abdomen, turning of trunk (twist) and extension of hind legs) counted during a 20 min session, beginning 3 min. after the

Effect of α2-adrenergic receptor agonists on acetic acid-induced writhing in mice

Tizanidine dose dependently (0.25–1.0 mg/kg, p.o.) and significantly (p < 0.05) increased the pain threshold in mice. The analgesic effect of tizanidine (0.5 mg/kg, p.o.) was significantly reversed by yohimbine (1.0 mg/kg, p.o.), an α2-adrenergic receptor antagonist. Clonidine (0.25 and 0.50 mg/kg, p.o.), another α2-agonist also significantly increased the pain threshold (Fig. 1).

Effect of α2-adrenergic receptor agonist on NSAID-induced antinociception against acetic acid-induced writhing in mice

Meloxicam (0.5 mg/kg, p.o.), nimesulide (1.0 mg/kg, p.o.) and naproxen (5.0 mg/kg, p.o.) produced significant

Discussion

Tizanidine (5-chloro-4(2-imidazolin-2-yl-amino)-2,1,3-benzothiadiazole), an α2-adrenergic receptor agonist with myospasmolytic and direct central analgesic effect [13]. It is clinically used in management of painful muscle spasm associated with static and functional disorders of the spinal cord (cervical and lumber syndromes). α2-adrenergic receptor agonists (clonidine and related 2-imadazoline derivatives) are reported to possess antinociceptive, antisecretory and anti-ulcer properties [14],

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