Suppression of formalin-induced nociception by cilnidipine, a voltage-dependent calcium channel blocker.
Cilnidipine is a 1,4-dihydropyridine-derived voltage-dependent calcium channel (VDCC) blocker and suppresses N-type VDCC currents in addition to L-type VDCC currents. An earlier investigation has suggested that intrathecally injected cilnidipine produces antinociception by blocking N-type VDCCs in mice. The present study using the rat formalin model examined antinociceptive effects of intrathecally and orally administered cilnidipine to elucidate a putative site of antinociception of cilnidipine, assess the efficacy of oral cilnidipine for pain relief, and clarify the mechanism(s) responsible for the antinociceptive effect of oral cilnidipine. Cilnidipine (whether intrathecal or oral) suppressed nociception in phases 1 and 2 of the formalin model. In addition, the potency of oral cilnidipine to suppress formalin-induced nociception in phase 2 was greater than that of oral gabapentin, a clinically available drug for treatment of neuropathic pain. Cilnidipine elicited antinociceptive effects without neurological side-effects including serpentine-like tail movement, whole body shaking, and allodynia. Such side-effects can be induced by higher doses of intrathecal ziconotide, a clinically available N-type VDCC blocker. In contrast, orally administered nifedipine, an L-type VDCC blocker, had no effect on either phase of formalin-induced nociception. These results suggest that cilnidipine acts on the spinal cord to produce antinociception and is efficacious for pain relief after oral administration with better safety profile than that of ziconotide. Furthermore, the failure of orally administered nifedipine to affect formalin-induced nociception raises the possibility that oral cilnidipine produces antinociception through, at least in part, spinal N-type VDCC blockade.
Pharmaceutical Research Laboratories, Ajinomoto Co., Inc., Kawasaki-ku, Kawasaki 210-8681, Japan. hajime_koganei@ajinomoto.com
Hajime
H
Koganei
Masataka
M
Shoji
Seinosuke
S
Iwata
D000284:Administration, Oral; D000588:Amines / Q000494:pharmacology / Q000627:therapeutic use; D000700:Analgesics / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D002121:Calcium Channel Blockers / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D020864:Calcium Channels, N-Type / Q000187:drug effects*; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology / Q000627:therapeutic use; D004095:Dihydropyridines / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D005557:Formaldehyde; D000077206:Gabapentin; D008297:Male; D023421:Models, Animal; D009543:Nifedipine / Q000494:pharmacology / Q000627:therapeutic use; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000187:drug effects*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology / Q000627:therapeutic use; D020960:omega-Conotoxins / Q000009:adverse effects / Q000627:therapeutic use
D000588:Amines; D000700:Analgesics; D002121:Calcium Channel Blockers; D020864:Calcium Channels, N-Type; D003509:Cyclohexanecarboxylic Acids; D004095:Dihydropyridines; D020960:omega-Conotoxins; D005557:Formaldehyde; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; C078452:ziconotide; C038806:1,4-dihydropyridine; C065927:cilnidipine; D009543:Nifedipine