Dose Dependent Effects of Celecoxib on CB-1 Agonist Induced Antinociception in Mice

Article excerpt

Objective: Endocannabinoid produces analgesia which is comparable to opioids. The antinociceptive effects of (Δ) - 9 tetrahydrocannabinol (THC) is suggested to be caused by cyclooxygenase (COX) pathway. In the present study, the effects of two extreme dose ranges of celecoxib (mg/kg and ng/kg), and a cyclooxygenase-2 (COX-2) antagonist on arachidonylcyclopropylamide (ACPA, a selective CB1 agonist) induced antinociception in mice was examined.

Methods: We have investigated the interaction between celecoxib at the doses of mg/kg (50, 100, 200 and 400 intrapritoneal(IP)). and ultra low dose (ULD) (25 and 50 ng/kg, IP) on the antinociceptive effect of intracerebroventricular (ICV) administration of ACPA (0.004, 0.0625 and 1 µg/mice) using formalin test in mice.

Results: ICV administration of ACPA induced antinociception. Intraperitoneal administration of celecoxib (mg/kg) and its ULD (ng/kg) attenuated and potentiated ACPA antinociceptive effects respectively .

Conclusion: It is concluded that the mg/kg doses of COX-2 antagonist showed opposite effects compared to the ultra-low dose of the drug.

Keywords: Arachidonylcyclopropylamide, Celecoxib, Mice, Pain measurement

Iran J Psychiatry 2009; 4:56-61

It is now well established that the endocannabinoid system is involved in a number of physiological processes including pain perception, modulation of neurotransmitter release, learning and memory (1). A few preparations of cannabis have been used to relieve pain. Endocannabinoids produce analgesia which is comparable with those of opiates in potency and efficacy. Attempts have been made to ascribe this analgesic effect of the complex mixture present in the plant preparation to the psychoactive principle of (Δ) - 9 tetrahydrocannabinol (THC) when it was tested with a variety of animal models for analgesia (2-4).

The mechanism of endocannabinoid-induced analgesia has been the subject of speculations. Based on certain experimental observations, it was concluded that the mechanism differed when involved in opiate-induced analgesia (5). THC, the principal active ingredient of the cannabis, produces its effect by binding to G protein coupled receptors which are identified as the cannabinoid CB1 receptors mainly found in the brain (6) and CB2 receptors mainly found in the periphery (7) and may CB3 receptors which are waiting to be cloned (8, 9). Specific agonists have been synthesized for both CB1 and CB2 receptors, e.g. arachidonylcyclopropylamide (ACPA, CB1 receptor

agonist) (10). Previous studies have linked the CB1 receptor to the antinociceptive effect of THC (11, 12).

Since the antinociceptive effects of THC is suggested to be caused by cyclooxygenase (COX) pathway (13- 15), and mg/kg doses of celecoxib (a selective COX-2 antagonist) showed opposite effects compared to its ultra-low doses in morphine state-dependent learning (16), the aim of the present study was twofold: first, to study the effect of combination of celecoxib and ACPA on nociception. Second, to compare the effects of two extreme dose ranges of celecoxib (mg/kg and ng/kg) combined with ACPA on formalin test in mice.

Materials and Method

Animals

We used male albino NMRI mice weighing 20.7-29.9 g. The animals were housed in groups of 7 in Plexiglas cages with a 12-h light/12-h dark cycle and controlled temperature (22±2°C). They were given food and water ad libitum. Each animal was used only once per experiment. All procedures were carried out in accordance with institutional guidelines for animal care and use.

Drugs

Arachidonylcyclopropylamide (ACPA) and Celecoxib were purchased from Sigma-Aldrich Co. Ltd, Gillingham, England. ACPA was emulsified by 5 percent Soya oil and Dimethylsulfoxide (DMSO). Celecoxib suspension was prepared in saline. Other drugs were dissolved in saline. ACPA was administrated intracerebroventricularly (ICV) in a volume of 5 µl/mice at most; celecoxib was administrated intraperitonealy (IP). …