Antinociceptive effect of cilnidipine, a novel N-type calcium channel antagonist

Murakami, Manabu; Nakagawasai, Osamu; Fujii, Shigeo; Hosono, Masahiro; Hozumi, Soichi; Esashi, Akihisa; Taniguchi, Ryoo; Okamura, Tadashi; Suzuki, Takashi; Sasano, Hironobu; Yanagisawa, Teruyuki; Tan-No, Koichi; Tadano, Takeshi; Kitamura, Kenji; Kisara, Kensuke

doi:10.1016/s0006-8993(00)02295-2

Cited by 21 publications

(11 citation statements)

References 17 publications

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“…The present study showed that intrathecally injected cilnidipine suppressed formalin-induced nociception in agreement with the earlier finding in the mouse formalin model, 30) suggesting that the spinal cord is a putative site of antinociception of cilnidipine. Cilnidipine blocks N-type VDCCs and L-type VDCCs.…”

Section: Discussionsupporting

confidence: 93%

“…Given the previous 30) and present results showing antinociceptive effects of oral and intrathecal cilnidipine in addition to the fact that an L-type VDCC blocker nicardipine had no effect on formalininduced nociception, 30) the failure of oral nifedipine to affect formalin-induced nociception suggests that oral cilnidipine produces antinociception, at least in part, through spinal Ntype VDCC blockade. It should be noted that oral cilnidipine may also act on other sites to produce antinociception, since this drug is widely distributed throughout the body.…”

Section: 237-41)supporting

confidence: 49%

“…35) Several lines of evidence, however, have suggested that L-type VDCCs play only a minimal role in spinal nociceptive transmission of formalin-induced pain. 4,30,36) The previous study has suggested that, in comparison with an L-type VDCC blocker nicardipine, intrathecal cilnidipine produces antinociception by blocking N-type VDCCs. 30) In addition, Malmberg and Yaksh have reported that an L-type VDCC blocker nifedipine has no effect in the rat formalin model, when intrathecally injected even at 29 nmol 4) that is equal to 10 mg because molecular weight of nifedipine is 346.3.…”

Section: Discussionmentioning

confidence: 99%

“…4,30,36) The previous study has suggested that, in comparison with an L-type VDCC blocker nicardipine, intrathecal cilnidipine produces antinociception by blocking N-type VDCCs. 30) In addition, Malmberg and Yaksh have reported that an L-type VDCC blocker nifedipine has no effect in the rat formalin model, when intrathecally injected even at 29 nmol 4) that is equal to 10 mg because molecular weight of nifedipine is 346.3. In the present study, intrathecal cilnidipine at 100 ng, the highest intrathecal dose examined in the formalin model, suppressed formalin-induced nociception.…”

Section: Discussionmentioning

confidence: 99%

“…[27][28][29] An earlier investigation has suggested that intrathecal cilnidipine produces antinociception by blocking N-type VDCCs in the mouse formalin model. 30) Accumulating evidence has led us to believe that cilnidipine is the first member of a novel class of N-type VDCC blockers. However, it remains to be determined whether oral cilnidipine produces antinociception.…”

mentioning

confidence: 99%

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Suppression of Formalin-Induced Nociception by Cilnidipine, a Voltage-Dependent Calcium Channel Blocker

Koganei

Shoji

Iwata

2009

Biological & Pharmaceutical Bulletin

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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.

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Section: Discussionsupporting

confidence: 93%

Section: 237-41)supporting

confidence: 49%