T-type Ca 2+ channels (T-channels) serve as targets for treatment of pain. We have reported that 6-prenylnaringenin (6-PNG), a hop component, and its derivative, KTt45, inhibit T-channels. Interestingly, many of cannabinoids block T-channels, while some of T-channel blockers stimulate cannabinoid CB 1 or CB 2 receptors. Thus, we compared the effects of 6-PNG and KTt45 as well as cannabinoids on Ca v 3.2 T-channels and CB 1 /CB 2 receptors. In Ca v 3.2expressing HEK293 cells, 6-PNG, KTt45, ACEA, a CB 1 agonist, and cannabidiol, a possible CB 1 antagonist/CB 2 inverse agonist, blocked T-currents, as assessed by whole-cell recordings; IC 50 values (μM) were 0.69, 0.41, 0.57 and 0.64, respectively. Neither 6-PNG nor KTt45, exhibited agonistic activity in CB 1 -expressing HEK293 cells, whereas 6-PNG at 0.3-1 μM, but not KTt45, agonistic activity in CB 2 -expressing CHO cells. In distinct mouse models for neuropathic and bladder pain, i.p. administration of 6-PNG at 20-30 mg/kg and KTt45 at 10-30 mg/kg exhibited analgesic/anti-allodynic activity. Thus, 6-PNG and KTt45, T-channel blockers, are useful for treatment of intractable pain, and 6-PNG is considered a mixed T-channel blocker/CB 2 agonist.
