Intra-periaqueductal grey microinjections of an imidazo[1,2-b]pyridazine derivative, DM2, affects rostral ventromedial medulla cell activity and shows antinociceptive effect

The 6-methoxy-2-phenylimidazo[1,2-b]pyridazine-3-carboxylic acid, DM2, exerts anti-absence activity and blocks Cav3.1 channel, a T-type voltage-dependent Ca2+ channel subtype, in vitro. The current study investigated the effect of intra-ventrolateral periaqueductal grey (VLPAG) administration of DM2 on formalin-induced nocifensive responses in rats. In addition, the effect of intra-VLPAG microinjection of DM2 on the ongoing and tail flick-related activities of rostral ventromedial medulla (RVM) cell population was also investigated. Formalin was injected subcutaneously into the dorsal surface of the hind paws of awake rats. We found that DM2 reduced nocifensive responses in the late phase of the formalin test. Moreover, in the RVM, the intra-VLPAG microinjection of DM2 reduced the ongoing and tail flick-related activity of the nociceptive ON cells, whereas it increased the ongoing activity and reduced the tail flick-induced pause of the antinociceptive OFF cells, consistent with antinociception. Behavioural and electrophysiological effects were reproduced by intra-VLPAG microinjection of ethosuximide, a conventional T-type Ca2+ channel blocker. Finally, DM2 administration did not produce any adverse cardiovascular effects as blood pressure and heart rate remained unchanged. In conclusion, DM2 plays an analgesic role in vivo and changes RVM cell activity, consistent with antinociception. These effects were even more potent than those elicited by ethosuximide treatments.