M-channels generate sub-threshold, non-inactivating voltage-gated K+ currents that play an important role in controlling neuronal excitability. In our quest to target neuronal M-type K+ channels, encoded by Kv7.2/Kv7.3 subunit assembly, we previously designed novel diphenylamine carboxylates that are powerful Kv7.2 channel openers or blockers. Recently, we designed a Kv7.2 channel opener, NH29, which was found to stabilize the Kv7.2 channel open state by interacting with its voltage sensing domain (VSD). Using the same structural framework, we designed a novel gating-modifier molecule, NH34, to test its activity on neuronal excitability and probe its potency in vivo on inflammatory and neuropathic pain. In transfected CHO cells, NH34 significantly increased Kv7.2 currents, by producing a hyperpolarizing voltage shift of the activation curve and slowing deactivation kinetics (EC50 = 17.5 µM). Interestingly, two S4 mutants, R198A and R207W significantly decreased the opener potency of the drug, suggesting that NH34, like NH29, may interact with the VSD of Kv7.2 channels. Results indicated that NH34 preferentially acts as an opener of Kv7.2 and Kv7.3 homomeric and heteromeric channels. NH34 was ineffective on Kv7.4 and Kv7.5 channels but produced a significant inhibition of TRPV1 cation channels. Patch-clamp intracellular recording of CA1 pyramidal neurons from 2 weeks-old rat hippocampal slices showed that NH34 reduced the spike discharge frequency evoked by injection of depolarizing current. Data from hippocampal slices also revealed that NH34 significantly depressed the slope of field EPSPs and the fiber volley amplitude recorded extracellularly in the CA1 pyramidal region following stimulation of the Schaeffer collaterals. NH34 reduced the frequency of evoked spike discharge in dorsal root ganglion neurons. In vivo, NH34 (3-30 mg/kg p.o) significantly relieved the hyperalgesia evoked by mechanical pressure of the paw in a rat model of inflammatory pain (Complete freund adjuvant). Similarly, NH34 (3-30 mg/kg p.o) was very efficient in alleviating the hyperalgesia evoked by mechanical pressure or cold allodynia in a Seltzer rat model of neuropathic pain. In all, the data suggest that NH34 is a very promising drug template for treating inflammatory and neuropathic pain.