Elsevier

Neuroscience

Volume 117, Issue 3, 31 March 2003, Pages 659-670
Neuroscience

Research paper
A peripheral cannabinoid mechanism suppresses spinal fos protein expression and pain behavior in a rat model of inflammation

https://doi.org/10.1016/S0306-4522(02)00870-9Get rights and content

Abstract

The present studies were conducted to test the hypothesis that systemically inactive doses of cannabinoids suppress inflammation-evoked neuronal activity in vivo via a peripheral mechanism. We examined peripheral cannabinoid modulation of spinal Fos protein expression, a marker of neuronal activity, in a rat model of inflammation. Rats received unilateral intraplantar injections of carrageenan (3%). In behavioral studies, carrageenan induced allodynia and mechanical hyperalgesia in response to stimulation with von Frey monofilaments. The cannabinoid agonist WIN55,212-2 (30 μg intraplantarly), administered concurrently with carrageenan, attenuated carrageenan-evoked allodynia and hyperalgesia relative to control conditions. In immunocytochemical studies, WIN55,212-2 suppressed the development of carrageenan-evoked Fos protein expression in the lumbar dorsal horn of the spinal cord relative to vehicle treatment. The same dose administered systemically or to the noninflamed contralateral paw failed to alter either carrageenan-evoked allodynia and hyperalgesia or carrageenan-evoked Fos protein expression, consistent with a peripheral site of action. The suppressive effects of WIN55,212-2 (30 μg intraplantarly) on carrageenan-evoked Fos protein expression and pain behavior were blocked by local administration of either the CB2 antagonist SR144528 (30 μg intraplantarly) or the CB1 antagonist SR141716A (100 μg intraplantarly). WIN55,212-3, the enantiomer of the active compound, also failed to suppress carrageenan-evoked Fos protein expression. These data provide direct evidence that a peripheral cannabinoid mechanism suppresses the development of inflammation-evoked neuronal activity at the level of the spinal dorsal horn and implicate a role for CB2 and CB1 in peripheral cannabinoid modulation of inflammatory nociception.

Section snippets

Subjects

One hundred and forty six adult male Sprague–Dawley rats (Harlan, Indianapolis, IN, USA), weighing 275–350 g, were used in these experiments. All procedures were approved by the University of Georgia Animal Care and Use Committee and followed the guidelines for the treatment of animals of the International Association for the Study of Pain (Zimmermann, 1983). All efforts were made to minimize the number of animals and their suffering.

Drugs and chemicals

Lambda carrageenan and WIN55,212-2 were obtained from Sigma

Behavioral studies

In all studies, the threshold and frequency of paw withdrawal elicited in response to the von Frey monofilaments did not differ between groups prior to i.p.l. administration of carrageenan. Carrageenan lowered the threshold (P<0.0002 for each experiment) and increased the frequency (P<0.002 for each experiment) of paw withdrawal in response to stimulation with von Frey monofilaments.

Experiment 1: Effects of local and systemic administration of WIN55,212-2 on the development of carrageenan-evoked allodynia and mechanical hyperalgesia

In experiment 1, the threshold for paw withdrawal was higher in groups receiving the cannabinoid agonist

Discussion

The present studies demonstrate that systemically inactive doses of cannabinoids suppress the development of inflammation-evoked neuronal activity in rat lumbar spinal cord in vivo through a peripheral mechanism. Administration (i.p.l.) of the selective cannabinoid agonist WIN55,212-2 suppressed carrageenan-evoked allodynia and hyperalgesia as well as carrageenan-evoked Fos protein expression in the rat lumbar dorsal horn. These effects were mediated by a peripheral mechanism because the

Conclusions

In conclusion, the present studies provide direct evidence that systemically inactive doses of cannabinoids suppress the development of inflammation-evoked neuronal activity in rat lumbar spinal cord in vivo through a peripheral mechanism. These data are consistent with the ability of local but not systemic injections of a cannabinoid agonist to attenuate the development of behavioral sensitization evoked by punctate mechanical stimuli in the carrageenan model of inflammation. Fos protein

Acknowledgements

Supported by UGARF and DA014265 (AGH). The authors are grateful to Mark H. Neely for assistance with data analysis.

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