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Characterization of Δ9-Tetrahydrocannabinol and Anandamide Antinociception in Nonarthritic and Arthritic Rats

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Abstract

Little is known about the effectiveness of Δ9-tetrahydrocannabinol (THC) and anandamide in blocking mechanical nociception. Even less is known about their antinociceptive efficacy in chronic inflammatory arthritis induced by Freund’s complete adjuvant. The hypothesis was tested that THC and anandamide elicit antinociception in the paw pressure test, and that arthritic rats would exhibit a different response. In nonarthritic rats, THC- and anandamide-induced antinociception lasted 90 min and 15 min, respectively, while antinociception lasted 90 min and 30 min, respectively, in arthritic rats. Area under the curve calculations revealed no effect of arthritis on THC- and anandamide-induced antinociception. Another hypothesis was that paw pressure thresholds in arthritic rats reflect chronic cannabinoid receptor stimulation due to elevations in free anandamide levels. Yet, the CB1 receptor antagonist SR141716A failed to alter paw pressure thresholds in either nonarthritic or arthritic rats. Further investigation revealed that SR141716A significantly blocked THC antinociception, with no effect on anandamide. Thus, anandamide’s effects did not result from CB1 receptor stimulation, and any potential contribution of endogenous anandamide in arthritis was not revealed. Finally, THC and anandamide appear to release an as yet unknown endogenous opioid, because naloxone significantly blocked their effects. This study indicates that anandamide and THC may act at different receptor sites to modulate endogenous opioid levels in mechanical nociception.

Section snippets

Animals

Male Sprague–Dawley rats (Harlan Laboratories, Indianapolis, IN), which weighed 250–300 g, were housed in the animal care quarters maintained at 22 ± 2°C on a 12 L:12 D cycle. Food and water were available ad lib. The rats were brought to a test room (at 22 ± 2°C) on the day of testing. All experiments were conducted according to guidelines established by the Institutional Animal Care and Use Committee of the Medical College of Virginia.

Freund’s Adjuvant Treatment

A volume of 0.5 ml of vehicle (85:15 paraffin oil:Arlacel

Results

Experiments were conducted to test the hypothesis that THC elicits antinociception in the paw-pressure test in nonarthritic and arthritic rats. Before conducting the THC experiments, it was necessary to demonstrate that the treatment with Freund’s complete adjuvant caused a significant reduction in paw pressure threshold (Table 1). These results indicate that the arthritic rats were significantly more sensitive to mechanical nociception than nonarthritic rats. In nonarthritic rats (Fig. 1A),

Discussion

The results of this study indicate that THC and anandamide elicited significant antinociception in the paw-pressure test in nonarthritic rats. THC had a rapid onset and long duration of action. Early studies by Sofia et al. [40]also established that THC (PO) is effective in the rat paw pressure test, as well as the Haffner tail-pinch test in mice. In another study, the synthetic cannabinoid WIN 55,212-2 in anesthetized rats effectively blocked the response of wide dynamic range dorsal spinal

Acknowledgements

This work was supported by the National Institute on Drug Abuse Grants: DA05274, DA09789, DA03672, and K02-00186. We wish to thank Dr. Billy R. Martin, Department of Pharmacology and Toxicology, Medical College of Virginia, for his assistance and collaboration on this project.

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