Cannabinoid Modulation of Cutaneous Aδ Nociceptors During Inflammation

Abstract

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.

Pain-related behaviors and neurochemical alterations in mice expressing sickle hemoglobin: modulation by cannabinoids

“…In other conditions, activation of cannabinoid receptors in the periphery reduces hyperalgesia after inflammation. 37,38 Importantly, we also observed strong expression of CB1 and CB2 receptors in the brain and spinal cord, and to a similar extent in younger and older hBERK1 and BERK mice (data not shown). This could contribute to the effectiveness of a relatively low dose of CP 55940, whereas a relatively higher dose of morphine is required because of the lower expression of MOR.…”

CB1 cannabinoid receptor agonist prevents NGF-induced sensitization of TRPV1 in sensory neurons

“…The idea that CB1 receptors reside on afferent nerve endings and that their activation there has analgesic actions is supported by several studies of both somatic and visceral pain. Subcutaneous intraplantar injection of cannabinoid agonists at the site of experimental inflammation suppressed pain responses [1, 14, 15, 20] and decreased the activation of cutaneous nerve fibers innervating inflamed skin [20]. In a model of interstitial cystitis pain, intravesical administration of a cannabinoid agonist also reduced the sensitization of bladder afferent nerves in a CB1-dependent manner [27].…”

Characterisation of cannabinoid 1 receptor expression in the perikarya, and peripheral and spinal processes of primary sensory neurons

“…However, while Stander et al (2005) found CB1 receptor-expressing myelinated fibres, our samples apparently lacked such fibres in the skin. Interestingly, the CB1 receptor expressed by myelinated afferent fibres in the skin might not be in a responding configuration in naive conditions, as Potenzieri and colleagues (Potenzieri et al 2008) reported recently that CB1 receptor agonists reduce Aδ nociceptor activity only in inflammatory conditions.…”