Selective activation of cannabinoid CB2 receptors suppresses spinal fos protein expression and pain behavior in a rat model of inflammation

doi:10.1016/S0306-4522(03)00126-X

Neuroscience

Volume 119, Issue 3, 4 July 2003, Pages 747-757

https://doi.org/10.1016/S0306-4522(03)00126-X Get rights and content

Abstract

Activation of cannabinoid CB₂ receptors attenuates thermal nociception in untreated animals while failing to produce centrally mediated effects such as hypothermia and catalepsy [Pain 93 (2001) 239]. The present study was conducted to test the hypothesis that activation of CB₂ in the periphery suppresses the development of inflammatory pain as well as inflammation-evoked neuronal activity at the level of the CNS. The CB₂-selective cannabinoid agonist AM1241 (100, 330 μg/kg i.p.) suppressed the development of carrageenan-evoked thermal and mechanical hyperalgesia and allodynia. The AM1241-induced suppression of carrageenan-evoked behavioral sensitization was blocked by the CB₂ antagonist SR144528 but not by the CB₁ antagonist SR141716A. Intraplantar (ipl) administration of AM1241 (33 μg/kg ipl) suppressed hyperalgesia and allodynia following administration to the carrageenan-injected paw but was inactive following administration in the contralateral (noninflamed) paw, consistent with a local site of action. In immunocytochemical studies, AM1241 suppressed spinal Fos protein expression, a marker of neuronal activity, in the carrageenan model of inflammation. AM1241 suppressed carrageenan-evoked Fos protein expression in the superficial and neck region of the dorsal horn but not in the nucleus proprius or the ventral horn. The suppression of carrageenan-evoked Fos protein expression induced by AM1241 was blocked by coadministration of SR144528 in all spinal laminae. These data provide evidence that actions at cannabinoid CB₂ receptors are sufficient to suppress inflammation-evoked neuronal activity at rostral levels of processing in the spinal dorsal horn, consistent with the ability of AM1241 to normalize nociceptive thresholds and produce antinociception in inflammatory pain states.

Section snippets

Subjects

One hundred fifteen adult male Sprague–Dawley rats (285–385 g; Harlan, Indianapolis, IN, USA and Charles River Laboratories, Wilmington, MA, USA) 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

λ-Carrageenan was

Experiment 1: assessment of thermal hyperalgesia

Paw-withdrawal latencies in response to radiant heat did not differ between groups prior to administration of carrageenan (mean±S.E.M.: 8.35±0.13 s versus 8.00±0.11 s in left and right paws, respectively; see Table 1). In all studies, intraplantar carrageenan reduced paw-withdrawal latencies to thermal stimulation (P<0.0002).

Thermal hyperalgesia differed between groups receiving AM1241 (33, 100 and 330 μg/kg ip) and vehicle (F_1,22=5.22, P<0.04). Carrageenan-evoked thermal hyperalgesia was

Discussion

In the present study, selective activation of CB₂ attenuated the development of thermal and mechanical hyperalgesia and tactile allodynia in the carrageenan model of inflammation. The CB₂-selective agonist AM1241 suppressed carrageenan-evoked mechanical hyperalgesia and allodynia in a dose-dependent manner. This effect was mediated by a peripheral mechanism because administration of AM1241 directly to the site of inflammation suppressed the development of thermal and mechanical hyperalgesia in

Acknowledgements

Supported by DA14265, DA14022 and the University of Georgia Research Foundation.

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Citation Excerpt :
Indeed, NTG may induce a direct hyperalgesic effect via formation of NO and liberation of CGRP in the NTC [49], or indirectly via activation of NOS at the meningeal level as a consequence of sensitization of the trigeminovascular system. Collectively, NTG-potentiated formalin test can be considered a relevant model for investigating migraine circuitry, which it has been shown that formalin injection in the paw elevates the expression level of Fos in NTC, and other brainstem areas such as locus coeruleus involving in the modulation of migraine pain [49,50]. Hopefully, it was observed that WIN 55,212-2 attenuates the first phase of formalin at all doses, while the high dose had a significant effect in the second inflammatory phase of formalin test in the acute model.
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Our data supported the argument that activation of CB₁ and CB₂ receptors by WIN 55,212-2 may be considered a new medication for migraine, however in lack of each receptor leads to different responses from deletion to the reduction of analgesic effects.
Small molecule inhibitors of PSD95–nNOS protein–protein interactions suppress formalin-evoked Fos protein expression and nociceptive behavior in rats
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Selective activation of cannabinoid CB2 receptors suppresses spinal fos protein expression and pain behavior in a rat model of inflammation

Abstract

Section snippets

Subjects

Drugs and chemicals

Experiment 1: assessment of thermal hyperalgesia

Discussion

Acknowledgements

Neuroscience

Neuroscience

FEBS Lett

Eur J Pharmacol

Neuroscience

Eur J Pharmacol

Eur J Pharmacol

J Neurosci Methods

Neuropharmacology

Pain

Pain

Pain

Neuroscience

Neuroscience

Life Sci

Neurosci Lett

Pain

Brain Res

Pain

Pain

Biochim Biophys Acta

Neurosci Lett

Pain

Eur J Pharmacol

Neuroscience

Brain Res Mol Brain Res

Neuropharmacology

Pain

Prostaglandins Leukot Essent Fatty Acids

Selective activation of cannabinoid CB₂ receptors suppresses spinal fos protein expression and pain behavior in a rat model of inflammation