Activation of peripheral cannabinoid CB₁ and CB₂ receptors suppresses the maintenance of inflammatory nociception: a comparative analysis

Abstract

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 Àarachidonyl-2-chloroethylamide (ACEA) and (R,S)-(2-iodo-5-nitrophenyl)-[l-(l-methyl-piperidin-2-ylmethyl)-lH-ubdik-3-yl]-methanone ((R,S)-AM1241), respectivelyÀ on mechanical and thermal hypersensitivity were compared on day 2. Pharmacological specificity was evaluated using locally administered CB 1 and CB 2 -selective antagonistsKey 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.

Peripheral cannabinoids attenuate carcinoma-induced nociception in mice

“…[10] Intraplantar administration of AM1241 is antinociceptive in inflammatory hyperalgesia in the rat. [14] In these three studies contralateral intraplantar administration had no antinociceptive effect on the paw being tested confirming a local antinociceptive effect with the cannabinoid agonists. CBr2 activation inhibits cytokine release and might contribute to antinociception.…”

Retraction: The Dietary Polyphenols trans-Resveratrol and Curcumin Selectively Bind Human CB1 Cannabinoid Receptors with Nanomolar Affinities and Function as Antagonists/Inverse Agonists

“…Activation of peripheral CB1 receptors is effective at suppressing inflammation that leads to chronic pain states (Gutierrez et al, 2007). However, the potential use of current CB1 agonists for this application is severely limited by concurrent stimulation of central CB1 receptors, resulting in unacceptable psychotropic side effects.…”

The cannabinoid receptor agonist, WIN 55, 212-2, attenuates tumor-evoked hyperalgesia through peripheral mechanisms

“…This observation is also consistent with earlier studies in which activation of CB 2 receptors produced both antinociception and antihyperalgesia in a variety of pain models. Peripheral or systemic administration of selective CB 2 receptor agonists produced antinociception to heat (Malan Jr. et al, 2001;Ibrahim et al, 2005;Ibrahim et al, 2006) and attenuated hyperalgesia produced by carrageenan (Nackley et al, 2003;Quartiho et al, 2003;Elmes et al, 2005;Gutierrez et al, 2007), capsaicin (Hohmann et al, 2004), and neuropathic injury . Peripheral injection of CB 2 receptor agonists also decreased mechanically-evoked responses of nociceptive spinal cord neurons following carrageenan-evoked inflammation and spinal nerve ligation (Elmes et al, 2004).…”

“…Peripheral administration of cannabinoids produced antihyperalgesic effects in animal models of inflammatory pain (Richardson et al, 1998;Amaya et al, 2006;Gutierrez et al, 2007), neuropathic pain (Fox et al, 2001;Guidon and Beaulieu, 2006), heat injury (Johanek and Simone, 2004), and capsaicin-evoked hyperalgesia (Johanek at al., 2001) through activation of CB 1 receptors. Interestingly, we also found that the antihyperalgesic effects of WIN 55,212-2 on tumor-evoked mechanical hyperalgesia were due to activation of CB 2 receptors.…”