Antinociceptive action of amlodipine blocking N-type Ca2+ channels at the primary afferent neurons in mice.
We investigated the antinociceptive action of amlodipine, a dihydropyridine derivative, which acts on both L- and N-type voltage-dependent Ca2+ channels (VDCCs), in mice. Intrathecal injection of amlodipine (300 nmol/kg) significantly shortened the licking time in the late phase of a formalin test, while no effect was found with another dihydropyridine derivative, nicardipine (300 nmol/kg). Cilnidipine and omega-conotoxin GVIA also showed marked analgesic effects under the same experimental conditions. Transcripts of alpha1A, alpha1B, alpha1E, alpha1F, alpha1H, beta3, and beta4 subunits were detected by polymerase-chain reaction (PCR) in the dorsal root ganglion, suggesting the existence of a variety of voltage-dependent Ca2+ channels. Electrophysiological experiments showed that amlodipine and cilnidipine inhibit N-type currents in the dorsal root ganglion cells. These results suggest that amlodipine, cilnidipine, and omega-conotoxin GVIA exert their antinociceptive actions by blocking N-type Ca2+ channels in the primary nociceptive afferent fibers. Blocking of the Ca2+ channels results in attenuation of synaptic transmission of nociceptive neurons. Furthermore, it is suggested that some N-type Ca2+ channel blockers might have therapeutic potential as analgesics when applied directly into the subarachnoidal space.
Murakami
M
M
Department of Molecular Pharmacology, Tohoku University School of Medicine, Sendai, Japan. mmura@mail.cc.tohoku.ac.jp
Nakagawasai
O
O
Fujii
S
S
Kameyama
K
K
Murakami
S
S
Hozumi
S
S
Esashi
A
A
Taniguchi
R
R
Yanagisawa
T
T
Tan-no
K
K
Tadano
T
T
Kitamura
K
K
Kisara
K
K
D017311:Amlodipine / Q000494:pharmacology*; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D005557:Formaldehyde / Q000037:antagonists & inhibitors / Q000633:toxicity; D005727:Ganglia, Spinal / Q000187:drug effects*; D007278:Injections, Spinal; D051379:Mice; D009475:Neurons, Afferent / Q000187:drug effects* / Q000502:physiology; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy*; D016133:Polymerase Chain Reaction; D012313:RNA / Q000302:isolation & purification; D051381:Rats; D017208:Rats, Wistar
D000700:Analgesics; D002121:Calcium Channel Blockers; D005557:Formaldehyde; D017311:Amlodipine; D012313:RNA