am-1241 and Chronic-Disease

The stimulation of spinal cannabinoid type 2 (CB(2)) receptors is a suitable strategy for the alleviation of experimental pain symptoms. Several reports have described the up-regulation of spinal cannabinoid CB(2) receptors in neuropathic settings together with the analgesic effects derived from their activation. Besides, we have recently reported in two murine bone cancer models that the intrathecal administration of cannabinoid CB(2) receptor agonists completely abolishes hyperalgesia and allodynia, whereas spinal cannabinoid CB(2) receptor expression remains unaltered. The present experiments were designed to measure the expression of spinal cannabinoid CB(2) receptors as well as the analgesic efficacy derived from their stimulation in mice chronically inflamed by the intraplantar injection of complete Freund's adjuvant 1 week before. Both spinal cannabinoid CB(2) receptors mRNA measured by real-time PCR and cannabinoid CB(2) receptor protein levels measured by western blot remained unaltered in inflamed mice. Besides, the intrathecal (i.t.) administration of the cannabinoid CB(2) receptor agonists AM1241, (R,S)-3-(2-Iodo-5-nitrobenzoyl)-1-(1-methyl-2-piperidinylmethyl)-1H-indole, (0.03-1 μg) and JWH 133, (6aR,10aR)-3-(1,1-Dimethylbutyl)-6a,7,10,10a-tetrahydro-6,6,9-trimethyl-6H-dibenzo[b,d]pyran, (3-30 μg) dose-dependently blocked inflammatory thermal hyperalgesia and mechanical allodynia. The analgesic effects induced by both agonists were counteracted by the coadministration of the selective cannabinoid CB(2) receptor antagonist SR144528, 5-(4-chloro-3-methylphenyl)-1-[(4-methylphenyl)methyl]-N-[(1S,2S,4R)-1,3,3-trimethylbicyclo[2.2.1]hept-2-yl]-1H-pyrazole-3-carboxamide, (5 μg) but not by the cannabinoid CB(1) receptor antagonist AM251, N-(Piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide, (10 μg). The effects induced by AM1241 were also inhibited by the coadministration of the opioid receptor antagonist, naloxone (1 μg). These results demonstrate that effective analgesia can be achieved in chronic inflammatory settings through the stimulation of spinal cannabinoid CB(2) receptors even if this receptor population is not up-regulated.

Topics: Analgesics; Animals; Cannabinoids; Chronic Disease; Freund's Adjuvant; Gene Expression Regulation; Hyperalgesia; Inflammation; Male; Mice; Receptor, Cannabinoid, CB2; RNA, Messenger; Spinal Cord; Temperature

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.. 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.. 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.. 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.

Topics: Animals; Arachidonic Acids; Cannabinoids; Carrageenan; Chronic Disease; Drug Synergism; Hot Temperature; Hyperalgesia; Inflammation; Male; Pain; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Touch