arachidonyl-2-chloroethylamide and Inflammation

Previous studies have demonstrated that locally administered cannabinoids attenuate allodynia and hyperalgesia through activation of peripheral cannabinoid receptors (CB(1) and CB(2)). However, it is currently unknown if cannabinoids alter the response properties of nociceptors. In the present study, correlative behavioral and in vivo electrophysiological studies were conducted to determine if peripheral administration of the cannabinoid receptor agonists arachidonyl-2'-chloroethylamide (ACEA) or (R)-(+)-methanandamide (methAEA) could attenuate mechanical allodynia and hyperalgesia, and decrease mechanically evoked responses of Adelta nociceptors. Twenty-four hours after intraplantar injection of complete Freund's adjuvant (CFA), rats exhibited allodynia (decrease in paw withdrawal threshold) and hyperalgesia (increase in paw withdrawal frequency), which were attenuated by both ACEA and methAEA. The antinociceptive effects of these cannabinoids were blocked by co-administration with the CB(1) receptor antagonist N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophen yl)-4-methyl-1H-pyrazole-3-carboxamide (AM251) but not with the CB(2) receptor antagonist 6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-y l](4-methoxyphenyl)methanone (AM630). ACEA and methAEA did not produce antinociception under control, non-inflamed conditions 24 h after intraplantar injection of saline. In parallel studies, recordings were made from cutaneous Adelta nociceptors from inflamed or control, non-inflamed skin. Both ACEA and methAEA decreased responses evoked by mechanical stimulation of Adelta nociceptors from inflamed skin but not from non-inflamed skin, and this decrease was blocked by administration of the CB(1) receptor antagonist AM251. These results suggest that attenuation of mechanically evoked responses of Adelta nociceptors contributes to the behavioral antinociception produced by activation of peripheral CB(1) receptors during inflammation.

Topics: Action Potentials; Analysis of Variance; Animals; Arachidonic Acids; Cannabinoids; Dose-Response Relationship, Drug; Drug Interactions; Freund's Adjuvant; Inflammation; Male; Nerve Fibers, Myelinated; Neural Conduction; Nociceptors; Pain Measurement; Pain Threshold; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Reaction Time; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Skin

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

Spinally administered cannabinoid receptor agonists are anti-nociceptive in a variety of models of acute and persistent pain. The present study investigated the effects of activation of spinal cannabinoid CB(1) receptors on mechanically evoked responses of spinal neurones in acute and inflammatory pain states. In vivo electrophysiology studies were carried out in anaesthetised rats. Effects of spinal administration of a selective cannabinoid CB(1) receptor agonist, arachidonyl-2-chloroethylamide (ACEA), on mechanically evoked responses of dorsal horn neurones in control rats and rats with peripheral hindpaw carrageenan-induced inflammation were compared. ACEA (0.27 nM-27 microM) significantly inhibited innocuous and noxious mechanically evoked responses of dorsal horn neurones in control rats. Pre-administration of the CB(1) receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1(2,4-dichlorophenyl)-4-methyl-1-H-pyrazole-3-carboxyamide, SR141716A, (0.43 microM) attenuated the inhibitory effects of ACEA (27 microM). ACEA did not alter mechanically evoked responses of dorsal horn neurones in rats with hindpaw carrageenan-induced inflammation. Following peripheral inflammation, there is a loss of spinal CB(1) receptor-mediated inhibition of mechanically evoked responses, which is suggestive of a functional down-regulation of CB(1) receptors under these conditions.

Topics: Animals; Arachidonic Acids; Dose-Response Relationship, Drug; Evoked Potentials; Hindlimb; Inflammation; Male; Nerve Fibers, Unmyelinated; Neural Inhibition; Pain Measurement; Physical Stimulation; Posterior Horn Cells; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1

The presence of cannabinoid1 (CB1) receptors on primary afferent fibres may provide a novel target for cannabinoid analgesics. The present study investigated the ability of peripheral CB1 receptors to modulate innocuous and noxious transmission in noninflamed rats and rats with peripheral carrageenan inflammation. Effects of peripheral injection of arachidonyl-2-choroethylamide (ACEA; 10 and 30 micro g in 50 micro L), a selective CB1 receptor agonist, on mechanically evoked responses of dorsal horn neurons were studied in noninflamed rats and rats with peripheral carrageenan inflammation. Peripheral injection of ACEA (30 micro g in 50 micro L) significantly inhibited innocuous (12 g) mechanically evoked responses of spinal neurons in noninflamed (27 +/- 4% of control; P < 0.01) and inflamed (12 +/- 8% of control; P < 0.05) rats. Similarly, noxious (80 g) mechanically evoked responses of spinal neurons were inhibited by peripheral injection of ACEA (30 micro g in 50 micro L) in noninflamed rats (51 +/- 9% of control; P < 0.01) and rats with peripheral carrageenan inflammation (21 +/- 8% of control; P < 0.01). Inhibitory effects of ACEA were significantly greater in rats with peripheral carrageenan inflammation than in noninflamed rats (P < 0.05). Inhibitory effects of ACEA were significantly blocked by coadministration of the CB1 receptor antagonist SR141716A in both groups of rats. Peripheral injection of SR141716A alone did not alter mechanically evoked responses of spinal neurons in either group of rats. These data demonstrate that activation of peripheral CB1 receptors can inhibit innocuous and noxious somatosensory processing. Furthermore, following peripheral inflammation there is an enhanced inhibitory effect of a peripherally administered CB1 receptor agonist on both innocuous and noxious mechanically evoked responses of spinal neurons.

Topics: Animals; Arachidonic Acids; Carrageenan; Diterpenes; Dose-Response Relationship, Drug; Drug Interactions; Evoked Potentials; Hindlimb; Inflammation; Male; Neural Inhibition; Physical Stimulation; Piperidines; Posterior Horn Cells; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Receptors, Drug; Rimonabant; Spinal Cord; Time Factors