Modulation of NSAID-induced antinociceptive and anti-inflammatory effects by α2-adrenoceptor agonists with gastroprotective effects
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.
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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],
References (30)
Nonsteroidal anti-inflammatory drugs and gastroenteropathy: the second hundred years
Gastroenterology
(1997)- et al.
Antinociceptive and anti-inflammatory effects of Tanacetum parthenium L. extract in mice and rats
Journal of Ethnopharmacology
(1999) - et al.
Antinociceptice activity induced by tizanidine and alpha-2-adrenoceptors
Neuropharmacology
(1987) - et al.
A new method for quantification of ion fluxes across in vivo human gastric mucosa: effect of aspirin, acetaminophen, ethanol and hyperosmolar solutions
Gastroenterology
(1984) Gastroprotective effects of tizanidine: an overview
Current Therapeutic Research
(1998)- et al.
Some pharmacological effects of tizanidine on smooth muscle organs and alpha-2 adrenoceptor
General Pharmacology
(1985) General aspects of back pain: an overview
The role of muscle relaxants in the treatment of muscle spasms
The use of Sirdalud in painful muscle tonic syndromes
Terapevticheskii Arkhiv
(1997)A comparative trial of DS 103–282 and placebo in the treatment of acute skeletal muscle spasms due to disorders of the back
Current Therapeutic Research
(1979)
Acute musculoskeletal conditions of the neck
Clinical Trials Journal
Tizanidine and ibuprofen in acute low-back pain: results of a double-blind multicentre study in general practice
J Internal Medicine Research
Clinical efficacy and gastrointestinal side effects of Ternelin tablet plus an NSAID compared with the NSAID administered alone
Shinryo to Shinyaku
Analgesic, anti-inflammatory and ulcerogenic activity of a zinc-naproxen complex in mice and rats
Pharmacy Pharmacologyl Communications
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