Activation of peripheral cannabinoid CB<sub>1</sub> and CB<sub>2</sub> receptors suppresses the maintenance of inflammatory nociception: a comparative analysis

T Gutierrez

J Farthing

A Zvonok

A Makriyannis

A Hohmann

^{Neuroscience and Behavior Program, Department of Psychology, University of Georgia, Athens, GA, USA}

^{Center for Drug Discovery, Northeastern University, Boston, MA, USA}

^{Author for correspondence:}

Received 2006 Jul 21; Revised 2006 Sep 13; Accepted 2006 Oct 26.

Abstract

Background and Purpose:

Effects of locally administered agonists and antagonists for cannabinoid CB₁ and CB₂ receptors on mechanical and thermal hypersensitivity were compared after the establishment of chronic inflammation.

Experimental approach:

Carrageenan was administered unilaterally to the rat hindpaw on day 1. Prophylactic efficacy of locally administered CB₁- and CB₂-selective agonists −arachidonyl-2-chloroethylamide (ACEA) and (R,S)-(2-iodo-5-nitro-phenyl)-[l-(l-methyl-piperidin-2-ylmethyl)-lH-ubdik-3-yl]-methanone ((R,S)-AM1241), respectively− on mechanical and thermal hypersensitivity were compared on day 2. Pharmacological specificity was evaluated using locally administered CB₁ and CB₂-selective antagonists −N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamidehydrochloride (SR141716A) and N-[(1S)-endo-1,3,3-trimethyl bicycle [2.2.1] heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide (SR144528), respectively.

Key Results:

Administration of either ACEA or AM1241 to the inflamed but not noninflamed paw suppressed the maintenance of carrageenan-evoked mechanical hyperalgesia and tactile allodynia and attenuated thermal hyperalgesia. The ACEA-induced suppression of mechanical and thermal hypersensitivity was blocked by local injection of SR141716A but not SR144528. AM1241 suppressed mechanical hypersensitivity with the reverse pharmacological specificity. The AM1241-induced suppression of thermal hyperalgesia was blocked by SR144528 and to a lesser extent by SR14176A. Co-administration of ACEA with AM1241 in the inflamed paw increased the magnitude but not the duration of thermal antihyperalgesia compared to intraplantar administration of either agonist alone.

Conclusions and Implications:

Cannabinoids act locally through distinct CB₁ and CB₂ mechanisms to suppress mechanical hypersensitivity after the establishment of chronic inflammation, at doses that produced modest changes in thermal hyperalgesia. Additive antihyperalgesic effects were observed following prophylactic co-administration of the CB₁- and CB₂-selective agonists. Our results suggest that peripheral cannabinoid antihyperalgesic actions may be exploited for treatment of inflammatory pain states.

Keywords: carrageenan, endocannabinoid, peripheral inflammation, allodynia, hyperalgesia

Abstract

Acknowledgments

Supported by DA14265, DA14022 (AGH) and DA9158, DA3801 (AM).

Acknowledgments

Abbreviations

ANCOVA	analysis of covariance
ANOVA	analysis of variance
CNS	central nervous system
Fr	Friedman statistic
i.pl.	intraplantar
KW	Kruskal–Wallis statistic

Abbreviations

Notes

Conflict of interest

One of the authors declares a conflict of interest. AM serves as a consultant for MAK Scientific.

Notes