Activation of Peripheral Cannabinoid CB1 and CB2 Receptors Suppresses the Maintenance of Inflammatory Nociception: a Comparative Analysis

Background And Purpose: Effects of locally administered agonists and antagonists for cannabinoid CB(1) and CB(2) 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 CB(1)- and CB(2)-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 CB(1) and CB(2)-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 CB(1) and CB(2) 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 CB(1)- and CB(2)-selective agonists. Our results suggest that peripheral cannabinoid antihyperalgesic actions may be exploited for treatment of inflammatory pain states.