Cannabinoid Modulation of Cutaneous A Nociceptors During InﬂammationCarl Potenzieri, 1,3 Thaddeus S. Brink, 1 Cholawat Pacharinsak, 1,2
and Donald A. Simone1,31 Departments of Diagnostic and Biological Sciences, 2 Veterinary and Biomedical Sciences, and 3 Graduate Program in Neuroscience, University of Minnesota, Minneapolis, Minnesota Submitted 25 July 2008; accepted in ﬁnal form 4 September 2008
Potenzieri C, Brink TS, Pacharinsak C, Simone DA. Cannabinoid modulation of cutaneous A nociceptors during inﬂammation. J Neurophysiol 100: 2794 —2806, 2008. First published September 10, 2008; doi:10.1152/jn.90809.2008. Previous studies have demonstrated that locally administered cannabinoids attenuate allodynia and hyperalgesia through activation of peripheral cannabinoid receptors (CB1 and CB2). 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 A 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 attenuate by both ACEA and methAEA. The antinociceptive effects of these cannabinoids were blocked by co-administration with the CB1 receptor antagonist N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophen yl)-4 methyl-1Hpyrazole-3-carboxamide (AM251) but not with the CB2 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 A nociceptors from inﬂamed or control, non-inﬂamed skin. Both ACEA and methAEA decreased responses evoked by mechanical stimulation of A nociceptors from inﬂamed skin but not from non-inﬂamed skin, and this decrease was blocked by administration of the CB1 receptor antagonist AM251. These results suggest that attenuation of mechanically evoked responses of A nociceptors contributes to the behavioral antinociception produced by activation of peripheral CB1 receptors during inﬂammation.
Soruce: Cannabinoid Modulation of Cutaneous A