(E)-3-Furan-2-yl-N-p-tolyl-acrylamide and its Derivative DM489 Decrease Neuropathic Pain in Mice Predominantly by α7 Nicotinic Acetylcholine Receptor Potentiation

The main objective of this study was to determine whether (E)-3-furan-2-yl-N-p-tolyl-acrylamide (PAM-2) and its structural derivative DM489 produce anti-neuropathic pain activity using the streptozotocin (STZ)- and oxaliplatin-induced neuropathic pain animal models. To assess possible mechanisms of action, the pharmacological activity of these compounds was determined at alpha 7 and a9a10 nicotinic acetylcholine receptors (nAChRs) and Ca-v,2.2 channels expressed alone or coexpressed with G protein-coupled GABA(B) receptors. The animal results indicated that a single dose of 3 mg/kg PAM-2 or DM489 decreases STZ-induced neuropathic pain in mice, and chemo- therapy-induced neuropathic pain is decreased by PAM-2 (3 mg/DIV14a(-) kg) and DM489 (10 mg/kg). The observed anti-neuropathic pain activity was inhibited by the alpha 7-selective antagonist methyllycaco- nitine. The coadministration of oxaliplatin with an inactive dose (1 mg/kg) of PAM-2 decreased the development of neuropathic pain after 14, but not 7, days of cotreatment. The electrophysiological results indicated that PAM-2 potentiates human (h) and rat (r) alpha 7 nAChRs with 2-7 times higher potency than that for hCa v 2.2 channel inhibition and an even greater difference compared to that for ra9a10 nAChR inhibition. These results support the notion that alpha 7 nAChR potentiation is likely the predominant molecular mechanism underlying the observed anti-nociceptive pain activity of these compounds.