Antinociceptive action of amlodipine blocking N-type Ca2+ channels at the primary afferent neurons in mice

Murakami, Manabu; Nakagawasai, Osamu; Fujii, Shigeo; Kameyama, Kimiko; Murakami, Shohei; Hozumi, Soichi; Esashi, Akihisa; Taniguchi, Ryoo; Yanagisawa, Teruyuki; Tan-No, Koichi; Tadano, Takeshi; Kitamura, Kenji; Kisara, Kensuke

doi:10.1016/s0014-2999(01)00985-2

Cited by 26 publications

(18 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…1), it is likely that the deletion of the ␤3 subunit might have an impact on neuronal functioning in various regions of the nervous system and, thus, at different levels of pain processing pathways. It is known that blockers of Ntype calcium channels exert spinal antinociceptive actions (37)(38)(39). Additionally, P/Q-type calcium channels may be also involved in nociceptive processes at the spinal level (38,40).…”

Section: Resultsmentioning

confidence: 99%

“…Accordingly, intrathecal injection of specific blockers of L-type calcium channels has no effect on the nociceptive behavior of rodents either during the early phase or during the late phase of the formalin test (29,39). Unfortunately, a comparison between the phenotypes of ␤3-, ␣1C-, and ␣1A-deficient mice is not possible because ␣1C (Ca v 1.2) and ␣1A (Ca v 2.1) deletion were embryonic lethal and generate strong neurological deficits, respectively (59,60).…”

Section: Discussionmentioning

confidence: 99%

“…Nevertheless, application of the P-type blocker -agatoxin IVA to the surface of the spinal cord selectively blocks the excitability of dorsal horn neurones in phase 2 (38), and accordingly, intrathecal injection of the P-type blocker reduces the nociceptive behavior during the late phase but not during the acute phase of the formalin test in the rat (40). On the other hand, intrathecal injection of the N-type blocker -conotoxin GVIA reduces the nociceptive behavior in phase 1 and 2 of the formalin test in mice (39) and rats (29). In the formalin tests that were repeated independently in three laboratories of the authors, no clear differences were observed in the behavior of wild type and ␤3Ϫ/Ϫ mice during the early phase (Fig.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Pain Perception in Mice Lacking the β3 Subunit of Voltage-activated Calcium Channels

Murakami

Fleischmann

Felipe

et al. 2002

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

The importance of voltage-activated calcium channels in pain processing has been suggested by the spinal antinociceptive action of blockers of N-and P/Q-type calcium channels as well as by gene targeting of the ␣1B subunit (N-type). The accessory ␤3 subunits of calcium channels are preferentially associated with the ␣1B subunit in neurones. Here we show that deletion of the ␤3 subunit by gene targeting affects strongly the pain processing of mutant mice. We pinpoint this defect in the pain-related behavior and ascending pain pathways of the spinal cord in vivo and at the level of calcium channel currents and proteins in single dorsal root ganglion neurones in vitro. The pain induced by chemical inflammation is preferentially damped by deletion of ␤3 subunits, whereas responses to acute thermal and mechanical harmful stimuli are reduced moderately or not at all, respectively. The defect results in a weak wind-up of spinal cord activity during intense afferent nerve stimulation. The molecular mechanism responsible for the phenotype was traced to low expression of N-type calcium channels (␣1B) and functional alterations of calcium channel currents in neurones projecting to the spinal cord.Voltage-activated calcium channels represent a family of ionic channels that play a crucial role in the nervous system by controlling membrane excitability and neurotransmitter release. Neurones express L-, N-, P/Q-, and R-type calcium channels, which are composed of the pore-forming subunit ␣1 and the accessory subunits ␤, ␣2␦, (1, 2) and probably ␥ (3). The importance of ␣1D (L-type), ␣1B (N-type), ␣1A (P/Q-type), and ␣1E (probably R-type) for the function of the nervous system in vivo is underlined by recent studies with genetically engineered mice (4). By contrast, the in vivo function of the four known ␤ subunits (␤1, ␤2, ␤3, ␤4) of calcium channels is less understood. In heterologous expression systems, ␤ subunits are required for the functional expression of ␣1 subunits (5-7), enhance the current density, and shift the voltage dependence of the activation and inactivation of recombinant calcium channels (8 -11). Additionally, ␤ subunits have been implicated in the modulation of calcium channels by G proteins (12-14). In vivo, the expression of ␤ subunits is modified in pathological states such as cardiac dysfunction (15) and diabetes (16). A natural occurring mutation of ␤4 is associated with ataxia and absence seizures in lethargic (lh/lh) mice, and this mutation modifies N-and P/Q-type calcium channels in the brain (17). The targeted disruption of ␤1 is lethal (18). In sympathetic neurones of ␤3-deficient mice, N-and L-type calcium channel currents are reduced, the activation of P/Q type calcium channels is altered, and no difference appears concerning inhibitory effects of norepinephrine on calcium channel currents (19). Such alterations of calcium channel currents in sympathetic neurones might be related to the cardiovascular phenotype of mice lacking the ␤3 subunit (20). Yet, the in vivo functions of the ␤3 subunit of ...

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Pain Perception in Mice Lacking the β3 Subunit of Voltage-activated Calcium Channels

Murakami

Fleischmann

Felipe

et al. 2002

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…Ca V 1.4 is found at synaptic terminals of retinal bipolar cells, and RNA encoding Ca V 1.4 has also been PCR amplified from dorsal root ganglia (Berntson et al 2003;Murakami et al 2001). Interestingly, the Ca V 1.4 gene sequence is more homologous to Ca V 1.3, based on comparisons among available Ca V clones (Fig.…”

Section: Four Mammalian Ca V 1 Genes Encode L-type Calcium Channelsmentioning

confidence: 99%

L-Type Calcium Channels: The Low Down

Lipscombe

Helton

2004

Journal of Neurophysiology

377

301

View full text Add to dashboard Cite

type calcium channels couple membrane depolarization in neurons to numerous processes including gene expression, synaptic efficacy, and cell survival. To establish the contribution of L-type calcium channels to various signaling cascades, investigators have relied on their unique pharmacological sensitivity to dihydropyridines. The traditional view of dihydropyridine-sensitive L-type calcium channels is that they are high-voltage-activating and have slow activation kinetics. These properties limit the involvement of L-type calcium channels to neuronal functions triggered by strong and sustained depolarizations. This review highlights literature, both long-standing and recent, that points to significant functional diversity among L-type calcium channels expressed in neurons and other excitable cells. Past literature contains several reports of low-voltageactivated neuronal L-type calcium channels that parallel the unique properties of recently cloned Ca V 1.3 L-type channels. The fast kinetics and low activation thresholds of Ca V 1.3 channels stand in stark contrast to criteria currently used to describe L-type calcium channels. A more accurate view of neuronal L-type calcium channels encompasses a broad range of activation thresholds and recognizes their potential contribution to signaling cascades triggered by subthreshold depolarizations. L-type calcium channels regulate numerous neuronal functionsL-type calcium channels are perhaps the best characterized of the voltage-gated calcium channels. They were first recognized as essential for coupling excitation to contraction in skeletal, cardiac, and smooth muscle cells (Beam et al. 1989; Franzini-Armstrong and Protasi 1997; Reuter 1985;Schneider and Chandler 1973; Tanabe et al. 1990). L-type calcium channels are also expressed in neurons and endocrine cells where they regulate a multitude of processes including secretion of neurohormones and transmitters, gene expression, mRNA stability, neuronal survival, ischemic-induced axonal injury, synaptic efficacy, and the activity of other ion channels (Ashcroft et al. 1994; Bading et al. 1993; Bean 1989; Charles et al. 1999; Christie et al. 1997; De Koninck and Cooper 1995; Deisseroth et al. 1998; Dunlap et al. 1995; Finkbeiner and Greenberg 1998; Fuchs 1996; Galli et al. 1995; Heidelberger and Matthews 1992; Kamsler and Segal 2003; Lei et al. 2003; Marrion and Tavalin 1998;Marshall et al. 2003;Murphy et al. 1991;Norris et al. 1998;Ouardouz et al. 2003; Sand et al. 2001;Schorge et al. 1999;Shinnick-Gallagher et al. 2003; Smith et al. 1993; Tachibana et al. 1993; Thaler et al. 2001; Thibault et al. 2001; Weisskopf et al. 1999; Wiser et al. 1999;Zhang and Townes-Anderson 2002). The unique pharmacological sensitivity of L-type calcium channels to dihydropyridine agonists and antagonists has proved critical for their identification in physiological assays and also for their biochemical isolation (Kanngiesser et al. 1988). Biochemical purification of the dihydropyridine receptor from skeletal muscle was the essenti...

show abstract

“…In addition, the antinociceptive activities of some calcium channel blockers such as, nifedipine, nimodipine, verapamil, and diltiazem had been reported previously. These finding suggest a pharmacological role of Ca 2+ channel blockers in the modulation of antinociception under acute condition [8][9][10].Changes in substitution pattern at the C-3, C-4, and C-5 positions of nifedipine alter activity and tissue selectivity [11][12][13]. It was our interest to determine the effects of different C-3 alkyl substituents, in conjugation with C-4 nitroimidazolyl substituents, on the calcium channel antagonist activity.We now report the synthesis, calcium channel antagonist and antinociceptive activities of dialkyl 1,4-dihydro-2,6-dimethyl-4-(1-methyl-5-nitro-2-imidazolyl)-3,5-pyridinedicacboxylate.…”

mentioning

confidence: 99%

Synthesis and Evaluation of Pharmacological Activities of 3, 5‐Dialkyl 1, 4‐Dihydro‐2, 6‐Dimethyl‐4‐Nitroimidazole‐3, 5‐Pyridine Dicarboxylates

Miri

Javidnia

Kebriaie-Zadeh

et al. 2003

Archiv der Pharmazie

View full text Add to dashboard Cite

New analogues of nifedipine, in which the 2-nitrophenyl group at position 4 is replaced by a 1-methyl-5-nitro-2-imidazolyl substituent, were synthesized. The symmetrical dialkyl 1, 4-dihydro-2, 6-dimethyl-4-(1-methyl-5-nitro-2-imidazolyl)-3, 5-pyridinedicarboxylates were prepared by a classical Hantzsch condensation. The asymmetrical analogues were synthesized using a procedure reported by Iwanami that involved the condensation of alkylacetoacetate with methyl-, ethyl- or isopropyl3-aminocrotonate and 1-methyl-5-nitroimidazole-2-carboxaldehyde. Calcium channel antagonist activities were determined in vitro using a guinea pig ileum longitudinal smooth muscle (GPILSM)assay. Many compounds exhibited superior, or equipotent, calcium antagonist activity (IC(50) = 10(-10) to 10(-13) M range) relative to the reference drug nifedipine (IC(50) = 1.09 +/- 0.12 x 10(-11) M). Antinociceptive effects of some compounds were evaluated by the mouse tail-flick assay in vivo. Results demonstrate that some of the compounds were active as an antinociceptive.

show abstract

Antinociceptive action of amlodipine blocking N-type Ca2+ channels at the primary afferent neurons in mice

Cited by 26 publications

References 24 publications

Pain Perception in Mice Lacking the β3 Subunit of Voltage-activated Calcium Channels

Pain Perception in Mice Lacking the β3 Subunit of Voltage-activated Calcium Channels

L-Type Calcium Channels: The Low Down

Synthesis and Evaluation of Pharmacological Activities of 3, 5‐Dialkyl 1, 4‐Dihydro‐2, 6‐Dimethyl‐4‐Nitroimidazole‐3, 5‐Pyridine Dicarboxylates

Contact Info

Product

Resources

About