The Antinociceptive and Anti-Inflammatory Properties of the α7 nAChR Weak Partial Agonist p-CF3 N,N-diethyl-N′-phenylpiperazine

Chronic pain and inflammatory diseases can be regulated by complex mechanisms involving alpha 7 nicotinic acetylcholine receptors (nAChRs), making this subtype a promising drug target for anti-inflammatory therapies. Recent evidence suggests that suchtreatment of inflammatory pain may rely on metabotropic-like rather than ionotropic activation of the alpha 7 receptor subtype in non-neuronal cells. We previously identified para-trifluoromethyl (p-CF3) N,N-diethyl-N'-phenyl-piperazinium (diEPP) iodide to be among the compounds classified as silent agonists, which are very weak alpha 7 partial agonists that are able to induce positive allosteric modulator (PAM)-sensitive desensitization. Such drugs have been shown to selectively promote alpha 7 ionotropic-independent functions. Therefore, we here further investigated the electrophysiological profile of p-CF3 diEPP and its in vivo antinociceptive activity using Xenopus oocytes expressing alpha 7, alpha 4 beta 2, or alpha 3 beta 4 nAChRs. The evoked currents confirmed p-CF3 diEPP to be alpha 7-selective with a maximal agonism 5% that of acetylcholine (ACh). Coapplication of p-CF3 diEPP with the type II PAM 4-naphthalene-1-yl-3a,4,5,9b-tetrahydro-3-H-cyclopenta[c]quinoline-8-sulfonic acid amide (TQS) produced desensitization that could be converted to PAM-potentiated currents, which at a negative holding potential were up to 13-fold greater than ACh controls. Voltage-dependence experiments indicated that channel block may limit both control ACh and TQS-potentiated responses. Although no p-CF3 diEPP agonist activity was detected for the heteromeric nAChRs, it was a noncompetitive antagonist of these receptors. The compound displayed remarkable antihyperalgesic and antiedema effects in in vivo assays. The antinociceptive activity was dose and time dependent. The anti-inflammatory components were sensitive to the alpha 7-selective antagonist methyllycaconitine, which supports the idea that these effects are mediated by the alpha 7 nAChR.