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Chronic pain and inflammatory diseases can be regulated by complex mechanisms involving α 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 α 7 receptor subtype in non-neuronal cells. We previously identified para-trifluoromethyl ( p -CF 3 ) N , N -diethyl- N '-phenylpiperazinium (diEPP) iodide to be among the compounds classified as silent agonists, which are very weak α 7 partial agonists that are able to induce positive allosteric modulator (PAM)-sensitive desensitization. Such drugs have been shown to selectively promote α 7 ionotropic-independent functions. Therefore, we here further investigated the electrophysiological profile of p -CF 3 diEPP and its in vivo antinociceptive activity using Xenopus oocytes expressing α 7, α 4 β 2, or α 3 β 4 nAChRs. The evoked currents confirmed p -CF 3 diEPP to be α 7-selective with a maximal agonism 5% that of acetylcholine (ACh). Coapplication of p -CF 3 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 -CF 3 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 α 7-selective antagonist methyllycaconitine, which supports the idea that these effects are mediated by the α 7 nAChR.

the journal of pharmacology and experimental therapeutics/the journal of pharmacology and experimental therapeutics

The Antinociceptive and Anti-Inflammatory Properties of the α7 nAChR Weak Partial Agonist p-CF3N,N-diethyl-N′-phenylpiperazine