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 Ca(2+) 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 Ca(2+) 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.
Palazzo
Enza
E
Department of Experimental Medicine, Section of Pharmacology, The Second University of Naples, via Costantinopoli 16, 80138 Naples, Italy. enza.palazzo@unina2.it
Rimoli
Maria Grazia
MG
De Chiaro
Maria
M
Guida
Francesca
F
Melisi
Daniela
D
Curcio
Annalisa
A
de Novellis
Vito
V
Marabese
Ida
I
Rossi
Francesco
F
Abignente
Enrico
E
Maione
Sabatino
S
D000200:Action Potentials / Q000187:drug effects; D000700:Analgesics / Q000494:pharmacology* / Q000627:therapeutic use*; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005013:Ethosuximide / Q000494:pharmacology; D005557:Formaldehyde / Q000009:adverse effects; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D008526:Medulla Oblongata / Q000166:cytology*; D008845:Microinjections / Q000379:methods; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy*; D010147:Pain Measurement / Q000379:methods; D010487:Periaqueductal Gray / Q000187:drug effects / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011930:Reaction Time / Q000187:drug effects; D013997:Time Factors
D000700:Analgesics; D000927:Anticonvulsants; D011725:Pyridines; D005557:Formaldehyde; D005013:Ethosuximide; C001439:imidazo(1,2-a)pyridine