T-type calcium channels: an emerging therapeutic target for the treatment of pain

DRUG DEVELOPMENT RESEARCH 67:404–415 (2006) Research Overview DDR T-Type Calcium Channels: An Emerging Therapeutic Target for the Treatment of Pain Terrance P. Snutch and Laurence S. David Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada Strategy, Management and Health Policy Preclinical Development Clinical Development Toxicology, Formulation Phases I-III Regulatory, Quality, It has become generally accepted that presynaptic high voltage–activated N-type calcium channels located in the spinal dorsal horn are a validated clinical target for therapeutic interventionsassociated with severe intractable pain. Low voltage–activated (T-type) calcium channels play a numberof critical roles in nervous system function, including controlling thalamocortical bursting behaviours andthe generation of spike wave discharges associated with slow wave sleep patterns. There is a growing bodyof evidence that T-type calcium channels also contribute in several ways to both acute and neuropathicnociceptive behaviours. In the one instance, the Cav3.1 T-type channel isoform likely contributes an anti-nociceptive function in thalamocortical central signalling, possibly through the activation of inhibitorynRT neurons. In another instance, the Cav3.2 T-type calcium channel subtype acts at the level of primaryafferents in a strongly pro-nociceptive manner in both acute and neuropathic models. While a numberof classes of existing clinical agents non-selectively block T-type calcium channels, there are no subtype-specific drugs yet available. The development of agents selectively targeting peripheral Cav3.2 T-typecalcium channels may represent an attractive new avenue for therapeutic intervention. Drug Dev. Res.
67:404–415, 2006.
c 2006 Wiley-Liss, Inc.
Key words: calcium channel; T-type; Cav3.2; nociception; mibefradil; ethosuximide pathophysiological states (e.g., spike-wave discharges associated with absence epilepsy [reviewed in Hugue- [1981a,b] first described low-threshold calcium-depen- nard, 1996, 2002]. Underlying low-threshold calcium- dent spikes in the mammalian inferior olive, a dependent spiking activity is a physiologically and phenomenon that has since been demonstrated in pharmacologically unique class of voltage-gated cal- many brain nuclei including those found in the cium channel called low-voltage-activated (LVA) or hippocampus, hypothalamus, thalamus, habenula, cor- T-type calcium channels [Carbone and Lux, 1984; tex, and globus pallidus [reviewed in Perez-Reyes, Nowycky et al., 1985].
2003]. Low-threshold calcium spikes generally act aspacemakers, helping to trigger bursts of sodium-dependent action potentials after neuronal membrane Grant sponsor: Canadian Institutes for Health Research.
hyperpolarization [Huguenard and Prince, 1992; Correspondence to: Dr. T.P. Snutch, Rm 219– 2185 East McCormick and Huguenard, 1992]. They also con- Mall, Michael Smith Laboratories, University of British Columbia, tribute to oscillatory and rebound burst firing behaviors Vancouver, B.C., Canada V6T 1Z4. E-mail: [email protected] relevant to both normal physiological functions (e.g., Published online in Wiley InterScience (www.interscience.wiley.
thalamocortical processes such as deep sleep) and to com). DOI: 10.1002/ddr.20103 2006 Wiley-Liss, Inc.

T-TYPE CALCIUM CHANNELS IN PAIN TREATMENT T-type calcium channels are generally distinct channels also contribute to secretatory processes such from high voltage–activated (HVA) calcium channels as hormone release, the regulation of muscle contrac- (the L-, N-, P/Q, and R-types) in their both negative tion, olfaction, and cellular differentiation and prolif- and overlapping activation (initial activation  70 to eration. The complete description of the physiological 60 mV) and inactivation (V50inact  55 to contributions of native T-type calcium channels has ranges, fast kinetics of inactivation (tinact 10 to 20 ms), been complicated by several factors including (1) the rapid recovery from inactivation, slow deactivation co-expression in many cells of multiple types of HVA (closing), and small single-channel conductance (5 to and LVA calcium currents with overlapping voltage- 10 pS). The low-threshold calcium spikes first observed dependent and kinetic properties, and (2) a lack of by Llinas can largely be attributed to the unique specific, high-affinity T-type channel pharmacological properties of T-type calcium channels, which become tools. Additionally, even amongst native T-type currents deinactivated after inhibitory synaptic inputs and there exits considerable heterogeneity in their activa- subsequently trigger calcium-dependent bursting as a tion, inactivation, permeation, and pharmacological result of their negative activation properties.
properties. While historically referred to as a single T-type calcium channels are expressed in many class of ion channel, native T-type calcium channels central and peripheral neurons, as well as in other are now known to be encoded by at least three distinct tissues including the heart, smooth muscle, kidney, a1 subunit genes (a1G/Cav3.1, a1H/Cav3.2, and a1I/ embryonic skeletal muscle, pituitary, pancreas, adrenal, Cav3.3) and that considerable alternative splicing exists retina, and testes [reviewed in Perez-Reyes, 2003].
to generate further diversity (Fig. 1) [Cribbs et al., In addition to their pacemaker roles in neurons, these 1998; Lee et al., 1999; McRory et al., 2001; Mittman High Voltage-Activated Calcium Channels
Class α subunit
L - type: Cav1.1, Cav1.2, Cav1.3, Cav 1.4
P/Q - type: Cav2.1
N - type: Cav2.2
R - type: Cav2.3
β subunits: β , β , β , β
α subunits:
-1, -2, δ
subunits: γ - γ
Low Voltage-Activated Calcium Channels (T- type)
α subunits: Cav3.1, Cav3.2, Cav3.3
Fig. 1. Composition of neuronal voltage-gated calcium channels. High voltage-activated (HVA) calcium channels are a heteromeric complexconsisting of a large (200–260 kDa) pore-forming a1 subunit that contains the voltage-sensor and pore region and is the target of knownpharmacological agents. There are ten identified a1 subunit genes in the mammalian genome. Neuronal HVA channels also contain an ancillaryb subunit (four genes) and a2d subunit (four genes) that contribute to modulating a number of channel functions including activation, inactivationand kinetic properties, second-messenger regulation, and channel complex intracellular processing. Biochemical purification of the skeletalmuscle HVA L-type calcium channel (Cav1.1) shows that it contains a fourth subunit, g, although reconstitution of neuronal HVA channelproperties does not require a g subunit and it remains to be determined whether native neuronal HVA calcium channel complexes contain thisprotein. Low voltage-activated (LVA or T-type) calcium channels have not yet been biochemically purified although known biophysical,pharmacological, and regulatory characteristics can be fully reconstituted with a Cav3 a1 subunit alone.
Drug Dev. Res. DOI 10.1002/ddr et al., 1999; Monteil et al., 2000a,b; Perez-Reyes Snutch, 1998]. Knock-out of the N-type channel et al., 1998].
genetically in mice results in animals largely resistant Pathophysiologically, both Cav3.1 and Cav3.2 to the induction of neuropathic and inflammatory pain T-type calcium channels may contribute to the genesis although otherwise exhibiting normal sensory and of absence seizures: (1) the genetic absence epilepsy motor functions [Ino et al., 2001; C. Kim et al., 2001; inbred strain of rat (GAERS) exhibits spontaneous Saegusa et al., 2001]. Clinically, intrathecal ziconitide spike-wave discharges and absence seizures that are (PrialtTM) is highly efficacious in the treatment of associated with an increased basal level of thalamic morphine-refractory neuropathic and malignant pain reticular T-type currents [Tsakiridou et al., 1995]; (2) conditions, although it exhibits a narrow therapeutic gene knock-out of the Cav3.1 T-type channel gene index (ratio of relative toxicity to relative efficacy) and in mice results in animals insensitive to GABAB must be titrated carefully in each patient. Interestingly, receptor agonist-induced spike wave discharges [D.
while the N-type channel is downstream in the opioid Kim et al., 2001]; and (3) a number of point mutations receptor pathway, the direct N-type channel blockade have been recently identified in the Cav3.2 T-type by ziconitide does not result in opioid-type side effects channel gene in patients with childhood absence such as tolerance and addiction [Brose et al., 1997; epilepsy and generalized idiopathic epilepsy [Chen McGuire et al., 1997; Ridgeway et al., 2000; Staats et al., 2003b; Heron et al., 2004]. Introduction of some et al., 2004].
of the epilepsy mutations into the wildtype Cav3.2 In the second instance of approved pain ther- channel results in biophysical changes consistent with apeutics targeting HVA calcium channels, the orally gain-of-function alterations to channel activity and administered small organic molecules gabapentin and are consistent with the notion that some clinical pregabalin bind to the a2d subunit associated with HVA antiepileptics act mechanistically to inhibit T-type calcium channel complexes. Gabapentin and pregaba- calcium channel activity [Coulter et al., 1989; 1990; lin are clinically effective anticonvulsants that while Khosravani et al., 2004, 2005; Peloquin et al., 2006; synthetic analogs of the neurotransmitter g-aminobu- Vitko et al., 2005].
tyric acid (GABA), do not exert their effects viainteracting with GABA receptors or transporters but CALCIUM CHANNELS AND PAIN rather bind with high affinity to the HVA calcium Nociceptive processes are known to be highly channel ancillary a2d-1 and a2d-2 subunits [Gee et al., sensitive to intracellular calcium levels and to date 1996; Marais et al., 2001]. Peripheral nerve injury there have been two distinct classes of pain therapeu- upregulates a2d expression in both the DRG and spinal tics developed to target components of HVA calcium dorsal horn, leading to the proposal that the a2d channels. In one instance, the N-type calcium channel subunit contributes to central sensitization [Li et al., blocking peptide, ziconitide, is a 25 amino acid 2004; Luo et al., 2002]. Numerous open label and synthetic peptide (o-conotoxin MVIIA) derived from double-blinded clinical trials show that gabapentin is the marine hunting cone snail Conus magus, which has efficacious in the treatment of neuropathic pain recently been approved (PrialtTM) both in the United conditions including diabetic neuropathy, postherpetic States and in Europe for the treatment of intractable neuralgia, trigeminal neuralgia, migraine, and pain pain [Snutch, 2005]. N-type calcium channels are associated with cancer and multiple sclerosis [Backonja highly concentrated in the cell bodies and synaptic et al., 1998; Caraceni et al., 1999; Di Trapani et al., terminals of a subset of primary afferents that 2000; Houtchens et al., 1997; Laird and Gidal, 2000; terminate in the dorsal horn of the spinal cord (mainly Rowbotham et al., 1998]. Interestingly, while the a2d C-fibers and A-d fibers). In animals, block of N-type subunit is associated with all known HVA calcium channels by the intrathecal administration of ziconitide channel a1 subunits, including the L-type channels inhibits the release of the nociceptive transmitters, found in skeletal, smooth, and cardiac muscles, substance P and CGRP, consistent mechanistically with gabapentin and pregabalin exhibit relatively few motor the role of N-type channels in triggering neurotransmis- or cardiovascular adverse effects even at high ther- sion at dorsal horn primary afferent terminals [Evans apeutic doses. Along these lines, determination of the et al., 1996]. The activation m-opioid receptors attenuates exact mechanism of action of gabapentin has proven N-type channel activity through the direct binding of a elusive with reports both supporting and refuting direct inhibitory actions on HVA calcium channels bg dimer to the N-type channel a1 subunit consistent with the notion that opioids in part mediate [Bayer et al., 2004; Brown and Randall, 2005; Sutton their analgesic affects through inhibiting presynaptic and Snutch, 2002].
calcium channel activity [Bourinet et al., 1996; Soldo and Is there a role for T-type calcium channels in pain Moises, 1998; Zamponi et al., 1997; Zamponi and processing? A significant component of neuropathic Drug Dev. Res. DOI 10.1002/ddr T-TYPE CALCIUM CHANNELS IN PAIN TREATMENT pain related to peripheral nerve injury is thought to concomitant increase in both the vocalization threshold result from hypersensitivity and/or abnormal sponta- and tail withdrawal latency in response to noxious acute neous firing along the primary afferent pathway. Wind- mechanical and thermal stimuli. Similarly, a complete up is a frequency-dependent facilitation of spinal cord reversal of mechanical allodynia in the Bennett excitability mediated via afferent C-fibers and has been neuropathic model was noted in Cav3.2 knock-down suggested to be linked to the central sensitization animals. In agreement with the low levels of detectable observed after peripheral nerve damage [for review Cav3.1 and Cav3.3 in the DRG, the intrathecal see Herrero et al., 2000]. As T-type calcium channels injection of antisense oligonucleotides against Cav3.1 activate at sub-threshold membrane potentials, one and Cav3.3 did not significantly affect nociceptive physiological route to altering the ectopic discharge behavior in rats. Taken together, these data are strongly of primary afferents may involve either the altered suggestive for the Cav3.2 T-type calcium channel expression and/or modulation of T-type calcium selectively contributing both to normal acute nocicep- channels. Of particular relevance, reducing agents tion and to chronic pain hyperexcitable states.
such as L-cysteine modulate both thermal and While the low expression of the Cav3.1 T-type in mechanical nociception when injected into peripheral DRG neurons suggests a minimal role for this calcium receptive fields [Todorovic et al., 2001]. Redox channel related to peripheral pain mechanisms, the modulation appears to occur through a mechanism Cav3.1 channel is highly expressed in the thalamus involving the selective up-regulation of T-type whole and appears to play a significant role in central pain cell currents in a subset of DRGs [Nelson et al., 2005; processing at least as it relates to visceral pain. Kim and Todorovic et al., 2001, 2004]. Interestingly, both in the co-workers found that either knock-out of the higher CNS and spinal cord there also exists a number Cav3.1 gene in mice or infusion of mibefradil directly of similarities between the proposed physiological into the ventroposterolateral (VPL) thalamus (to block functions of T-type calcium channels in processes such Cav3.1 channels) act to enhance the pain response as long-term potentiation and kindling, and those elicited by intraperitoneal administration of acetic acid for the central sensitization associated with neuropathic or magnesium sulphate [Kim et al., 2003]. In response pain wherein postsynaptic responses progressively to visceral pain stimuli, wild type VPL neurons increase [Ikeda et al., 2003].
generate both increased single spikes and clustered Which of the three functionally distinct T-type bursts of action potentials. In Cav3.1 knockout mice, calcium channel isoforms might be involved in VPL neurons exhibit normal single spike activity but nociceptive behaviors? In the periphery, a subset of an almost total absence of burst spikes suggesting that small- and medium-size DRG neurons are known Cav3.1-dependent bursting activity mediates a down- to express large whole cell T-type calcium currents stream inhibitory process likely involving nRT neurons.
[Schroeder et al., 1990; Scroggs and Fox, 1992]. In situ In contrast to that for the Cav3.2 channel, it therefore hybridization and reverse-transcription PCR studies appears that central native Cav3.1 T-type channels act show that of the three known T-type channel subtypes, in an anti-nociceptive capacity. It remains to be Cav3.2 (a1 H) is most highly expressed in DRGs while determined whether the selective pharmacological these same cells express relatively low levels of Cav3.3 blockade of this low-threshold calcium channel might (a1I) and little to none of Cav3.1 (a1G). In D-hair cell have the unwanted effect of enhancing the central mechanoreceptors (a subset of medium sized DRGs), perception of noxious stimuli.
the Cav3.2 T-type channel has also been shown tocontribute to a slow after depolarizing potential that CLINICAL AGENTS WITH T-TYPE CALCIUM lowers the voltage-threshold for action potential CHANNEL BLOCKING ACTIVITY generation. Pharmacological block of Cav3.2 in D-hair There appears a strong connection both mechan- cells suggests that this T-type channel subtype is istically and pharmacologically between epilepsy, neu- required for the normal transduction of slow-moving ropathic pain, and migraine headache; thus targeting mechanical stimuli [Dubreuil et al., 2004; Shin the T-type calcium channels that contribute to these et al., 2003].
Utilizing intrathecal injection of antisense oligo- Although selectively targeting T-type calcium channels nucleotides, Bourinet et al. [2005] found that selective for therapeutic purposes has been of significant Cav3.2 T-type channel knock-down affects both acute interest, to date there are no ‘‘pure'' T-type channel and neuropathic pain behaviors in rat. An approximate blockers presently in clinical usage. In spite of this 50% reduction in Cav3.2 mRNA expression resulted critical pharmacological limitation, there are a number in a 75 to 90% decrease in whole cell T-type current of structurally distinct classes of drugs that more density in small- and medium-size DRGs, and a broadly interact with multiple ionic conductances Drug Dev. Res. DOI 10.1002/ddr including T-type calcium channels. These agents may cultured neurons of rat cerebral cortex, the mean provide important clues concerning the validation of percentage reduction in T-type current is approxi- the T-type channel targets, and perhaps also suggest mately 60% at 500 mM with no observed block of chemical backbones relevant towards future com- L-type currents [Suzuki et al., 1992]. In addition, pound-based structure-activity development.
50 mM zonisamide also reduces T-type currents (by40%) in cultured neuroblastoma cells [Kito et al., 1996]. In the Bennett chronic constriction rat model, Zonisamide (Fig. 2) is a widely utilized broad- zonisamide relieves thermal hyperalgesia in a dose- spectrum antiepileptic. Mechanistically, zonisamide is dependent manner although it has little effect on known to variously inhibit nitric oxide formation, to mechanical allodynia [Hord et al., 2003]. Clinically, in increase serotonergic transmission and basal acetylcho- a number of open-label case studies, zonisamide has line and gamma-aminobutyric acid (GABA) release, been shown to be effective in a variety of treatment- and to block both voltage-gated sodium channels (Kd refractory neuropathic pain conditions [Guay, 2003; 1 mM) and T-type calcium channels [Mimaki et al., Takahashi et al., 2004]. Additionally, in several open- 1990; Schauf, 1987; Zhu et al., 2002]. Zonisamide label analyses of treatment-refractory migraine pa- blocks T-type calcium currents in a concentration- tients, zonisamide is also highly effective as a dependent manner without altering either the voltage- prophylactic agent [Drake et al., 2004]. Zonisamide is dependence of activation or inactivation kinetics. In contraindicated in patients with sulfonamide allergies Fig. 2. Structures of compounds mentioned in the text.
Drug Dev. Res. DOI 10.1002/ddr T-TYPE CALCIUM CHANNELS IN PAIN TREATMENT and any future structure-activity relation (SAR) studies pain [McCleane, 1999]. The antinociceptive properties targeted at improving T-type affinity and/or selectivity of phenytoin have been attributed to its ability to block might also address this limitation.
both voltage-dependent sodium and calcium channels.
Phenytoin blocks sodium channels from rat cortical synaptosomes (IC50 4800 mM) and cloned sodium channels expressed in Xenopus oocytes [Anderson (MPS) and ethosuximide (Fig. 2) are widely utilized et al., 2003; Lingamaneni and Hemmings, 1999; antiepileptics thought to in part act therapeutically Twombly et al., 1988]. In N1E-115 neuroblastoma via the inhibition of cortical-thalamic T-type calcium cells, phenytoin at concentrations of between 3 and channels involved in mediating 3 Hz spike-wave dis- 100 mM inhibits T-type calcium currents without ethosuximide inhibit altering channel activation or kinetic properties. How- T-type calcium channels in a state-dependent manner ever, the steady-state inactivation profile is shifted and at concentrations considered to be clinically relevant more hyperpolarized. Phenytoin blocks cloned a1G (IC50s; 0.3 to 1 mM for Cav3.1, Cav3.2, and Cav3.3 (Cav3.1) and a1H (Cav3.2) T-type channels expressed subtypes vs. therapeutic plasma levels 0.1 mM for in HEK 293 cells at IC50s of 140 and 8.3 mM, MPS and 0.3 to 0.7 mM for ethosuximide [Gomora respectively [Todorovic et al., 2000]. In addition, in et al., 2001]). In both nerve-injured and sham-operated cultured dorsal root ganglia neurons (DRGs) phenytoin animals, in vivo recordings show that ethosuximide blocks whole cell T-type calcium currents in a applied directly to the spinal cord inhibits both concentration-dependent manner (IC50 8.3 mM). In mechanical and thermal-evoked responses in a dose- a bradykinin-induced pain model in rats, phenytoin dependent manner [Matthews and Dickenson, 2001].
produces dose-dependent analgesic affects at an ED50 Direct spinal application of ethosuximide produces the of 3 mg/kg applied subcutaneously [Foong et al., 1982].
greatest maximal inhibition on C-fibers and Ad-fibers In a mouse acute pain model using plantar and tail compared to Ab-fibers, consistent with the notion both pressure to evaluate acute thermal and mechanical that T-type channels are differentially expressed nociception, phenytoin preferentially relieves thermal amongst DRG neurons and are preferentially localized pain at dose between 2.5 to 25 mg/kg applied to C-fibers and Ad-fibers that convey thermal and intraperitoneally [Sakaue et al., 2004]. Clinically, in nociceptive information and not to Ab-fibers that a randomized, double-blinded, placebo-controlled, subserve proprioception and responses to tactile stimuli.
crossover study, phenytoin relieves flare-ups of chronic Examining L5/L6 nerve-injured animals, Dogrul neuropathic pain and has also been shown to and colleagues found that i.p. administration of significantly enhance buprenorphine analgesia in ethosuximide produces a dose-dependent inhibition cancer patients [McCleane, 1999; Yajnik et al., 1992].
of both thermal hyperalgesia (A50 5 126 mg/kg) andmechanical allodynia (A 50 5 174 mg/kg) [Dogrul et al., 2003]. Direct intrathecal (i.t.) administration of etho- The neuroleptics comprise a chemically diverse suximide is without effect, perhaps suggesting a set of molecules that largely act clinically to inhibit peripheral target site of action, although the direct dopamine D2 receptors although, interestingly, a injection of ethosuximide into the injured paw subset of these agents also exhibit potent calcium (intraplantar) is also without effect. Ethosuximide channel blocking activity. In particular, the diphenyl- administered i.p. also completely reverses capsaicin- butylpiperidines, pimozide and penfluridol (Fig. 2), induced mechanical allodynia (ED50 5 108 mg/kg) block T-type channels in a variety of cell types and is antinociceptive in both the early and late phases including from adrenal, heart, neural crest, and of the formalin response as well as the acute tail flick spermatogenic tissues [Enyeart et al., 1990a,b, 1992].
assay [Barton et al., 2005]. Finally, i.p.-administered Examination of pimozide and penfluridol on cloned T- ethosuximide is highly efficacious in reversing paclitaxil- type channels showed that they block all three and vincristine-induced peripheral neuropathy [Flatters mammalian T-type channel isoforms (Cav3.1, Cav3.2, and Bennett, 2004]. In spite of these promising animal and Cav3.3) with a higher affinity than either data, in the over 40 years that ethosuximide has been ethosuximide or mibefradil (Kds ranging from 40 to utilized clinically there are few if any reports of it being 100 nM) [Santi et al., 2002]. Block is state dependent, efficacious towards human neuropathies.
profiles to more negative potentials, but does not affect T-type channel activation or kinetic parameters.
Phenytoin (Fig. 2) is clinically utilized as both an Interestingly, from a structure-activity perspective, anticonvulsant as well as an analgesic for neuropathic the highly structurally related diphenyldiperazine, Drug Dev. Res. DOI 10.1002/ddr flunarizine, and the butyrophenone antipsychotic, channels, mibefradil has been shown to be a somewhat haloperidol, show both significantly less potent T-type non-selective blocker of both HVA calcium channels channel-blocking activities (Kds ranging from 500 (IC50 values in barium recording saline; P/Q-type to 3,500 nM for Cav3.1, Cav3.2, and Cav3.3) and also 0.3 mM, R-type 0.4 mM, L-type 10 to 20 mM) and exhibit distinct clinical pharmacologies in patients T-type channels (IC50 values; 1 mM for Cav3.1, [Opler and Feinberg, 1991].
Cav3.2, and Cav3.3) [Jimenez et al., 2000]. There are In one study examining a mouse formalin model conflicting reports concerning the mechanism of of inflammatory pain, relatively low doses of pimozide mibefradil mediated T-type channel blockade with (0.05–0.25 mg/kg i.p.) were not shown to be highly resting-, inactivated-, and open-state block all being efficacious [Saddi and Abbott, 2000]. Interestingly, suggested, and with some evidence that reducing however, although pimozide has been widely used channel availability can increase affinity by up to clinically as a neuroleptic to treat conditions such tenfold [Martin et al., 2000].
as schizophrenia, Tourette's, and obsessive compulsive In L5/L6 nerve-injured rats, i.p.-administered disorder, it has also proven efficacious in several mibefradil effectively inhibits both tactile allodynia neuropathic pain conditions. In particular, and while (A50 5 7.4 mg/kg) and thermal hyperalgesia (A50 5 the pathophysiological mechanism underlying its ther- 12 mg/kg) [Dogrul et al., 2003]. Interestingly, while the apeutic effects are unknown, pimozide appears to direct injection of mibefradil into the injured limb also provide significant relief in the management of trigem- produces a dose-dependent reversal of tactile allodynia inal neuralgia, a relatively uncommon but severe facial (A50 5 92 mg) suggestive of a peripheral mechanism of pain syndrome associated with repetitive action poten- action, a similar direct administration of ethosuximide tials [Green and Selman, 1991; Lechin et al., 1989].
(up to 500 mg) is without effect. Barton and colleaguesreport that while i.p.-administered mibefradil has no Antiarrhythmics and Antihypertensives effect on capsaicin-induced allodynia, i.t.-administered A number of cardiovascular agents are thought mibefradil both potently reverses mechanical allodynia to act in part mechanistically via inhibiting T-type in a dose range similar to that for intrathecal morphine calcium channels, either solely or as mixed T-type and (ED50 5 9.2 and 4.1 mg for mibefradil and morphine, L-type calcium channel blockers. None of these agents respectively) and is also antinociceptive in both the early has yet to be shown efficacious in the clinical setting for and late phases of the formalin response [Barton et al., pain management although given their pharmacologi- 2005]. In contrast to that for ethosuximide, mibefradil cal characteristics, there is compelling reason to (up to 30 mg/rat i.t.) is without affect in the acute tail flick examine some of these drugs in various neuropathies.
reflex. Dogrul and coworkers also observed no effect of Bepridil (Fig. 2) is a widely utilized clinical i.t.-administered mibefradil in the rat acute tail-flick antiarrhythmic agent with antianginal properties assay but found that mibefradil significantly potentiates known to non-specifically inhibit a variety of ionic the ability of low-dose i.t. morphine to prolong response conductances including various sodium (IC50 30 mM) latency (a 5-fold increase in ED50 for morphine) and and potassium channels (IC50 from 1 to 30 mM) as well that the response is specific for the m-opioid receptor as the L-type calcium channel (IC50 from 0.5 to 30 mM) subtype (a 30-fold increase in the ED50 for DAMGO) [Hollingshead et al., 1992; Li et al., 1999; Wang et al., [Dogrul et al., 2001]. While mibefradil was removed 1999; Yatani et al., 1986]. More recently, bepridil has from the market for issues related to drug–drug been shown to inhibit the Cav3.2 (a1 H) T-type calcium interactions, it may yet represent an attractive chemical channel with an IC50 400 nM. Block is not affected by backbone for the further development of selective pulse frequency but is strongly dependent upon T-type calcium channel antagonists.
holding potential and also shifts steady-state inactiva-tion and activation profiles to more hyperpolarized potentials [Uchino et al., 2005].
Efonidipine (Fig. 2) is an orally active anti- hypertensive with inhibitory effects on both L- and T-type calcium channels [Masumiya et al., 2000]. In Next to ethosuximide, mibefradil (Fig. 2) is baby hamster kidney (BHK) cells and Xenopus oocytes, probably the most widely recognized agent generally efonidipine (mixture of R( ) and S(1)-isomers) described as a selective T-type calcium channel inhibits exogenously expressed HVA a1C (L-type) blocker. In fact, while this tetralol derivative was calcium currents with IC50 values ranging from 0.5 originally developed by Roche and briefly brought to 2 mM (BHK cells) to 8 to 20 mM (oocytes). It also onto the market as an effective antihypertensive and blocks the cloned Cav3.1 T-type calcium channel with chronic stable angina pectoris agent targeting T-type similar affinities in both cell types [Furukawa et al., Drug Dev. Res. DOI 10.1002/ddr T-TYPE CALCIUM CHANNELS IN PAIN TREATMENT 2004]. Interestingly, the R( )-efonidipine isomer selec- in part, against excitotoxicity by modulating neuronal tively blocks Cav3.1 T-type channels. Inhibition is frequency-dependent, with an increasing potency at Fig. 2) is an endogenous CB1 cannabinoid receptor higher stimulation frequencies. In fact, in myocardial ligand that mimics many of the psychoactive effects cells, efonidipine was shown to inhibit native T-type of delta9-tetrahydrocannabinol, the most widely recog- calcium currents in a frequency-dependent manner nized active component of marijuana [Lambert and with IC50 values of 13 nM, 2 mM, and 6.3 mM with Fowler, 2005]. Anandamide has also been shown to stimulation frequencies of 1, 0.2, and 0.05 Hz, respec- activate TRPV1 vanilloid and a7-nicotinic acetylcholine tively [Masumiya et al., 2000]. Clinically, efonidipine receptors, to inhibit Kv1.2 and TASK-1 potassium decreases heart rate and has favourable effects on the channels, and to bind to the 1,4-dihydropyridine site nervous system supporting its significance in improving of L-type calcium channels, although the exact the prognosis in patients with hypertension and its physiological consequences of these interactions re- protective influence on the heart and other organs main unknown.
[Harada et al., 2003].
Independent of CB1 receptors, at sub-micromo- lar concentrations anandamide has also been shown to x-3 fatty acids block the Cav3.2 T-type calcium channel (IC50 The cis-polyunsaturated o-3 fatty acids are 300 nM for Cav3.2) and at micromolar concentrations essential dietary agents that exhibit a range of to inhibit Cav3.1 and Cav3.3 T-type channels (IC50 physiological effects including possessing both cardio- 4 mM for Cav3.1 and 1 mM for Cav3.3) [Chemin et al., protective and neuroprotective activities. At least in 2001]. Anandamide does not affect T-type activation part, their protective effects may result from their properties but blockade is strongly dependent upon the blockade of voltage-gated sodium channels and HVA channel inactivation state and would therefore result in L-type calcium channels resulting in reduced electrical a significant decrease in the available window current.
excitability in cardiac muscle and neurons [for review, In the case of Cav3.3 channels, the potency see van der Stelt and Di Marzo, 2005]. More recently, of a block by anandamide could be increased  tenfold Enyeart and colleagues found that the o-3 fatty acids (IC50 100 nM) under depolarizing waveforms that docosahexaenoic acid (DHA; Fig 2), eicosapentaenoic mimic thalamocortical firing activity. Of particular acid, and a-linolenic acid also inhibit native T-type relevance, unlike that for the effects of cannabinoids calcium channels at potencies significantly higher than on the high threshold N-type and P/Q-type calcium that for the clinically utilized succinimides [Danthi channels [Mackie and Hille, 1992], anandamide block- et al., 2005]. Block of whole cell T-type currents ade of the T-type channels appears to be a result by the o-3 fatty acids in bovine adrenal zona fasiculata of direct binding to the channel and is independent cells occurs with IC50s ranging from 2.5 to 14 mM and is of G-proteins, phospholipases, and protein kinases.
accompanied by changes in T-type channel voltage- Similar to that for DHA, it will be interesting to examine dependent and kinetic parameters. DHA in particular the effects of both peripherally and centrally adminis- shows significant use-dependent inhibition, suggestive tered anandamide on acute and neuropathic pain states.
of a preferential interaction with T-type channel open While the psychoactive effects of anandamide likely or inactivated states, and a characteristic of most precluded the use of this agent for the treatment of pain clinical ion channel blocking agents that exhibit good (at least centrally), there exists considerable room for therapeutic ratios. The major T-type channel isoform the development of structurally related derivatives.
expressed in zona glomerulosa cells is reported to beCav3.2 [Schrier et al., 2001], the same subtype POTENTIAL ADVERSE AFFECTS OF CAV3.2 T-TYPE implicated in primary afferent nociceptive behaviour CHANNEL BLOCKADE? and it will, therefore, be interesting to examine the Implication of the Cav3.2 T-type calcium channel affects of DHA on both acute and neuropathic pain in pain mechanisms raises a whole new series of states. A significant number of o-3 fatty acid derivatives clinically relevant issues that may require addressing.
have already been synthesized around this backbone For example, gene knockout of the Cav3.2 T-type and, given the abundance of DHA in the human diet, channel gene in mice has been shown to result in both DHA and its metabolites should prove relatively abnormal cardiovascular function including constitu- safe [Itoh et al., 2006] tively constricted coronary arterioles and focal myo-cardial fibrosis [Chen et al., 2003a]. T-type calcium channels are known to be critically involved in early Endocannabinoids are highly lipophilic molecules development and neuritogenesis; thus, there also may thought to act as retrograde messengers and to protect, be developmentally related issues of concern [Chemin Drug Dev. Res. DOI 10.1002/ddr et al., 2002; McCobb et al., 1989]. T-type calcium Bourinet E, Alloui A, Monteil A, Barrere C, Couette B, Poirot O, channels are also implicated in the calcium-dependent Pages A, McRory J, Snutch TP, Eschalier A, et al. 2005. Silencing secretion of a variety of hormones from endocrine of the Cav3.2 T-type calcium channel gene in sensory neurons tissues and the Cav3.2 channel appears selectively demonstrates its major role in nociception. Embo J 24:315–324.
expressed in the adrenal cortex and implicated in Brose WG, Gutlove DP, Luther RR, Bowersox SS, McGuire D.
aldosterone secretion [Schrier et al., 2001]. What might 1997. Use of intrathecal SNX-111, a novel, N-type, voltage-sensitive, calcium channel blocker, in the management of be the physiological consequences of long-term block- intractable brachial plexus avulsion pain. Clin J Pain 13:256–259.
ade of this channel aimed at treating chronic/neuro- Brown JT, Randall A. 2005. Gabapentin fails to alter P/Q-type Ca21 pathic pain conditions? In isolation, these issues may channel-mediated synaptic transmission in the hippocampus in seem to raise a significant barrier to targeting the vitro. Synapse 55:262–269.
Cav3.2 T-type calcium channel. In fact, as described Caraceni A, Zecca E, Martini C, De Conno F. 1999. Gabapentin above a number of clinical agents that non-selectively as an adjuvant to opioid analgesia for neuropathic cancer pain.
target T-type calcium channels have been long used J Pain Symptom Manage 17:441–445.
clinically, many with few apparent serious adverse Carbone E, Lux HD. 1984. A low voltage-activated, fully inactivat- affects. Additionally, as per the reality of many other ing Ca channel in vertebrate sensory neurones. Nature 310: clinical agents targeting voltage-gated ion channels (e.g., L-type calcium, sodium, and potassium channels), Chemin J, Monteil A, Perez-Reyes E, Nargeot J, Lory P. 2001.
while many of the apparent physiological barriers in Direct inhibition of T-type calcium channels by the endogenouscannabinoid anandamide. Embo J 20:7033–7040.
isolation might suggest the potential for serious clinical Chemin J, Nargeot J, Lory P. 2002. Neuronal T-type alpha 1H obstacles, these can often be overcome by the calcium channels induce neuritogenesis and expression of high- development of selective, state-dependent drugs that voltage-activated calcium channels in the NG108-15 cell line.
block a subset of pathophysiologically relevant target J Neurosci 22:6856–6862.
Chen CC, Lamping KG, Nuno DW, Barresi R, Prouty SJ, Lavoie JL, Cribbs LL, England SK, Sigmund CD, Weiss RM, et al. 2003a.
Abnormal coronary function in mice deficient in alpha1 H T-type We thank Ms. Cynthia Chow and Dr. Hassan Ca21 channels. Science 302:1416–1418.
Pajouhesh for help with the figures and Dr. Emmanuel Chen Y, Lu J, Pan H, Zhang Y, Wu H, Xu K, Liu X, Jiang Y, Bao X, Yao Z, et al. 2003b. Association between genetic variation of Bourinet for comments on the manuscript. The CACNA1 H and childhood absence epilepsy. Ann Neurol 54: authors' work at the Michael Smith Laboratories is supported by an operating grant from the Canadian Coulter DA, Huguenard JR, Prince DA. 1989. Characterization of Institutes for Health Research and by a Canadian ethosuximide reduction of low-threshold calcium current in Research Tier 1 Chair in Neurobiology-Genomics.
thalamic neurons. Ann Neurol 25:582–593.
L.S.D. is supported by a fellowship from the Heart and Coulter DA, Huguenard JR, Prince DA. 1990. Differential effects of Stroke Foundation of Canada.
petit mal anticonvulsants and convulsants on thalamic neurones:calcium current reduction. Br J Pharmacol 100:800–806.
Cribbs LL, Lee JH, Yang J, Satin J, Zhang Y, Daud A, Barclay J, Anderson JD, Hansen TP, Lenkowski PW, Walls AM, Choudhury Williamson MP, Fox M, Rees M, and others. 1998. Cloning and IM, Schenck HA, Friehling M, Holl GM, Patel MK, Sikes RA, characterization of alpha1H from human heart, a member of the et al. 2003. Voltage-gated sodium channel blockers as cytostatic T-type Ca21 channel gene family. Circ Res 83:103–109.
inhibitors of the androgen-independent prostate cancer cell line Danthi SJ, Enyeart JA, Enyeart JJ. 2005. Modulation of native T- PC-3. Mol Cancer Ther 2:1149–1154.
type calcium channels by omega-3 fatty acids. Biochem Biophys Backonja M, Beydoun A, Edwards KR, Schwartz SL, Fonseca V, Res Commun 327:485–493.
Hes M, LaMoreaux L, Garofalo E. 1998. Gabapentin for the Di Trapani G, Mei D, Marra C, Mazza S, Capuano A. 2000.
symptomatic treatment of painful neuropathy in patients with Gabapentin in the prophylaxis of migraine: a double-blind diabetes mellitus: a randomized controlled trial. JAMA 280: randomized placebo-controlled study. Clin Ter 151:145–148.
Dogrul A, Yesilyurt O, Isimer A, Guzeldemir ME. 2001. L-type and Barton ME, Eberle EL, Shannon HE. 2005. The antihyperalgesic T-type calcium channel blockade potentiate the analgesic effects effects of the T-type calcium channel blockers ethosuximide, of morphine and selective mu opioid agonist, but not to selective trimethadione, and mibefradil. Eur J Pharmacol 521:79–85.
delta and kappa agonist at the level of the spinal cord in mice.
Bayer K, Ahmadi S, Zeilhofer HU. 2004. Gabapentin may inhibit Pain 93:61–68.
synaptic transmission in the mouse spinal cord dorsal horn Dogrul A, Gardell LR, Ossipov MH, Tulunay FC, Lai J, Porreca F.
through a preferential block of P/Q-type Ca21 channels.
2003. Reversal of experimental neuropathic pain by T-type calcium channel blockers. Pain 105:159–168.
Bourinet E, Soong TW, Stea A, Snutch TP. 1996. Determinants of Drake ME Jr, Greathouse NI, Renner JB, Armentbright AD. 2004.
the G protein-dependent opioid modulation of neuronal calcium Open-label zonisamide for refractory migraine. Clin Neurophar- channels. Proc Natl Acad Sci USA 93:1486–1491.
macol 27:278–280.
Drug Dev. Res. DOI 10.1002/ddr T-TYPE CALCIUM CHANNELS IN PAIN TREATMENT Dubreuil AS, Boukhaddaoui H, Desmadryl G, Martinez-Salgado C, Huguenard JR. 1996. Low-threshold calcium currents in central Moshourab R, Lewin GR, Carroll P, Valmier J, Scamps F. 2004.
nervous system neurons. Annu Rev Physiol 58:329–348.
Role of T-type calcium current in identified D-hair mechan- Huguenard JR. 2002. Block of T-Type Ca(21) Channels is an oreceptor neurons studied in vitro. J Neurosci 24:8480–8484.
important action of succinimide antiabsence drugs. Epilepsy Curr Enyeart JJ, Biagi BA, Day RN, Sheu SS, Maurer RA. 1990a.
Blockade of low and high threshold Ca21 channels by Huguenard JR, Prince DA. 1992. A novel T-type current underlies diphenylbutylpiperidine antipsychotics linked to inhibition of prolonged Ca(21)-dependent burst firing in GABAergic neurons prolactin gene expression. J Biol Chem 265:16373–16379.
of rat thalamic reticular nucleus. J Neurosci 12:3804–3817.
Enyeart JJ, Dirksen RT, Sharma VK, Williford DJ, Sheu SS. 1990b.
Ikeda H, Heinke B, Ruscheweyh R, Sandkuhler J. 2003. Synaptic Antipsychotic pimozide is a potent Ca21 channel blocker in plasticity in spinal lamina I projection neurons that mediate heart. Mol Pharmacol 37:752–757.
hyperalgesia. Science 299:1237–1240.
Enyeart JJ, Biagi BA, Mlinar B. 1992. Preferential block of T-type Ino M, Yoshinaga T, Wakamori M, Miyamoto N, Takahashi E, calcium channels by neuroleptics in neural crest-derived rat and Sonoda J, Kagaya T, Oki T, Nagasu T, Nishizawa Y, and others.
human C cell lines. Mol Pharmacol 42:364–372.
2001. Functional disorders of the sympathetic nervous system in Evans AR, Nicol GD, Vasko MR. 1996. Differential regulation of mice lacking the alpha 1B subunit (Cav 2.2) of N-type calcium evoked peptide release by voltage-sensitive calcium channels in channels. Proc Natl Acad Sci USA 98:5323–5328.
rat sensory neurons. Brain Res 712:265–273.
Itoh T, Murota I, Yoshikai K, Yamada S, Yamamoto K. 2006.
Flatters SJ, Bennett GJ. 2004. Ethosuximide reverses paclitaxel- and Synthesis of docosahexaenoic acid derivatives designed as novel vincristine-induced painful peripheral neuropathy. Pain 109: PPARgamma agonists and antidiabetic agents. Bioorg Med Chem Foong FW, Satoh M, Takagi H. 1982. A newly devised reliable Jimenez C, Bourinet E, Leuranguer V, Richard S, Snutch TP, method for evaluating analgesic potencies of drugs on trigeminal Nargeot J. 2000. Determinants of voltage-dependent inactivation pain. J Pharmacol Methods 7:271–278.
affect Mibefradil block of calcium channels. Neuropharmacology Furukawa T, Miura R, Honda M, Kamiya N, Mori Y, Takeshita S, Isshiki T, Nukada T. 2004. Identification of R( )-isomer Khosravani H, Altier C, Simms B, Hamming KS, Snutch TP, of efonidipine as a selective blocker of T-type Ca21 channels.
Mezeyova J, McRory JE, Zamponi GW. 2004. Gating effects of Br J Pharmacol 143:1050–1057.
mutations in the Cav3.2 T-type calcium channel associated with Gee NS, Brown JP, Dissanayake VU, Offord J, Thurlow R, childhood absence epilepsy. J Biol Chem 279:9681–9684.
Woodruff GN. 1996. The novel anticonvulsant drug, gabapentin Khosravani H, Bladen C, Parker DB, Snutch TP, McRory JE, (Neurontin), binds to the alpha2delta subunit of a calcium Zamponi GW. 2005. Effects of Cav3.2 channel mutations linked channel. J Biol Chem 271:5768–5776.
to idiopathic generalized epilepsy. Ann Neurol 57:745–749.
Gomora JC, Daud AN, Weiergraber M, Perez-Reyes E. 2001. Block Kim C, Jun K, Lee T, Kim SS, McEnery MW, Chin H, Kim HL, of cloned human T-type calcium channels by succinimideantiepileptic drugs. Mol Pharmacol 60:1121–1132.
Park JM, Kim DK, Jung SJ, et al. 2001. Altered nociceptiveresponse in mice deficient in the alpha(1B) subunit of the voltage- Green MW, Selman JE. 1991. Review article: the medical manage- dependent calcium channel. Mol Cell Neurosci 18:235–245.
ment of trigeminal neuralgia. Headache 31:588–592.
Kim D, Song I, Keum S, Lee T, Jeong MJ, Kim SS, McEnery MW, Guay DR. 2003. Oxcarbazepine, topiramate, zonisamide, and Shin HS. 2001. Lack of the burst firing of thalamocortical relay levetiracetam: potential use in neuropathic pain. Am J Geriatr neurons and resistance to absence seizures in mice lacking alpha(1G) T-type Ca(21) channels. Neuron 31:35–45.
Harada K, Nomura M, Nishikado A, Uehara K, Nakaya Y, Ito S.
Kim D, Park D, Choi S, Lee S, Sun M, Kim C, Shin HS. 2003.
2003. Clinical efficacy of efonidipine hydrochloride, a T-type Thalamic control of visceral nociception mediated by T-type Ca21 calcium channel inhibitor, on sympathetic activities. Circ J 67: channels. Science 302:117–119.
Kito M, Maehara, Watanabe K. 1996. Mechanisms of T-type calcium Heron SE, Phillips HA, Mulley JC, Mazarib A, Neufeld MY, channel blockade by zonisamide. Seizure 5:115–119.
Berkovic SF, Scheffer IE. 2004. Genetic variation of CACNA1 Hin idiopathic generalized epilepsy. Ann Neurol 55:595–596.
Laird MA, Gidal BE. 2000. Use of gabapentin in the treatment of neuropathic pain. Ann Pharmacother 34:802–807.
Herrero JF, Laird JM, Lopez-Garcia JA. 2000. Wind-up of spinal cord neurones and pain sensation: much ado about something? Lambert DM, Fowler CJ. 2005. The endocannabinoid system: Prog Neurobiol 61:169–203.
drug targets, lead compounds, and potential therapeutic applica-tions. J Med Chem 48:5059–5087.
Hollingshead LM, Faulds D, Fitton A. 1992. Bepridil. A review of its pharmacological properties and therapeutic use in stable Lechin F, van der Dijs B, Lechin ME, Amat J, Lechin AE, Cabrera angina pectoris. Drugs 44:835–857.
A, Gomez F, Acosta E, Arocha L, Villa S, et al. 1989. Pimozide Hord AH, Denson DD, Chalfoun AG, Azevedo MI. 2003. The effect therapy for trigeminal neuralgia. Arch Neurol 46:960–963.
of systemic zonisamide (Zonegran) on thermal hyperalgesia and Lee JH, Daud AN, Cribbs LL, Lacerda AE, Pereverzev A, Klockner mechanical allodynia in rats with an experimental mononeuro- U, Schneider T, Perez-Reyes E. 1999. Cloning and expression pathy. Anesth Analg 96:1700–1706.
of a novel member of the low voltage-activated T-type calcium Houtchens MK, Richert JR, Sami A, Rose JW. 1997. Open label channel family. J Neurosci 19:1912–1921.
gabapentin treatment for pain in multiple sclerosis. Mult Scler 3: Li CY, Song YH, Higuera ES, Luo ZD. 2004. Spinal dorsal horn calcium channel alpha2delta-1 subunit upregulation contributes Drug Dev. Res. DOI 10.1002/ddr to peripheral nerve injury-induced tactile allodynia. J Neurosci Monteil A, Chemin J, Bourinet E, Mennessier G, Lory P, Nargeot J.
2000a. Molecular and functional properties of the human Li Y, Sato T, Arita M. 1999. Bepridil blunts the shortening of action alpha(1G) subunit that forms T-type calcium channels. J Biol potential duration caused by metabolic inhibition via blockade of ATP-sensitive K(1) channels and Na(1)-activated K(1) channels.
Monteil A, Chemin J, Leuranguer V, Altier C, Mennessier G, J Pharmacol Exp Ther 291:562–568.
Bourinet E, Lory P, Nargeot J. 2000b. Specific properties of Lingamaneni R, Hemmings HC Jr. 1999. Effects of anticonvulsants T-type calcium channels generated by the human alpha 1I on veratridine- and KCl-evoked glutamate release from rat subunit. J Biol Chem 275:16530–16535.
cortical synaptosomes. Neurosci Lett 276:127–130.
Nelson MT, Joksovic PM, Perez-Reyes E, Todorovic SM. 2005. The endogenous redox agent L-cysteine induces T-type Ca21 Llinas R, Yarom Y. 1981a. Electrophysiology of mammalian inferior channel-dependent sensitization of a novel subpopulation of rat olivary neurones in vitro. Different types of voltage-dependent peripheral nociceptors. J Neurosci 25:8766–8775.
ionic conductances. J Physiol 315:549–567.
Nowycky MC, Fox AP, Tsien RW. 1985. Three types of neuronal Llinas R, Yarom Y. 1981b. Properties and distribution of ionic calcium channel with different calcium agonist sensitivity. Nature conductances generating electroresponsiveness of mammalian inferior olivary neurones in vitro. J Physiol 315:569–584.
Opler LA, Feinberg SS. 1991. The role of pimozide in clinical Luo ZD, Calcutt NA, Higuera ES, Valder CR, Song YH, Svensson psychiatry: a review. J Clin Psychiatry 52:221–233.
CI, Myers RR. 2002. Injury type-specific calcium channel alpha 2delta-1 subunit up-regulation in rat neuropathic pain models Peloquin JB, Khosravani H, Barr W, Bladen C, Evans R, Mezeyova correlates with antiallodynic effects of gabapentin. J Pharmacol J, Parker DB, Snutch TP, McRory JE, Zamponi GW. 2006.
Exp Ther 303:1199–1205.
Functional analysis of Cav3.2 T-type calcium channel mutationslinked to childhood absence epilepsy. Epilepsia 47:655–658.
Mackie K, Hille B. 1992. Cannabinoids inhibit N-type calcium channels in neuroblastoma-glioma cells. Proc Natl Acad Sci USA Perez-Reyes E. 2003. Molecular physiology of low-voltage-activated t-type calcium channels. Physiol Rev 83:117–161.
Marais E, Klugbauer N, Hofmann F. 2001. Calcium channel Perez-Reyes E, Cribbs LL, Daud A, Lacerda AE, Barclay J, alpha(2)delta subunits-structure and Gabapentin binding. Mol Williamson MP, Fox M, Rees M, Lee JH. 1998. Molecularcharacterization of a neuronal low-voltage-activated T-type calcium channel. Nature 391:896–900.
Martin RL, Lee JH, Cribbs LL, Perez-Reyes E, Hanck DA. 2000.
Ridgeway B, Wallace M, Gerayli A. 2000. Ziconotide for the Mibefradil block of cloned T-type calcium channels. J Pharmacol treatment of severe spasticity after spinal cord injury. Pain 85: Exp Ther 295:302–308.
Masumiya H, Kase J, Tanaka Y, Tanaka H, Shigenobu K. 2000.
Rowbotham M, Harden N, Stacey B, Bernstein P, Magnus-Miller L.
Frequency-dependent blockade of T-type Ca21 current by 1998. Gabapentin for the treatment of postherpetic neuralgia: efonidipine in cardiomyocytes. Life Sci 68:345–351.
a randomized controlled trial. JAMA 280:1837–1842.
Matthews EA, Dickenson AH. 2001. Effects of ethosuximide, Saddi G, Abbott FV. 2000. The formalin test in the mouse: a T-type Ca(21) channel blocker, on dorsal horn neuronal a parametric analysis of scoring properties. Pain 89:53–63.
responses in rats. Eur J Pharmacol 415:141–149.
Saegusa H, Kurihara T, Zong S, Kazuno A, Matsuda Y, Nonaka T, McCleane GJ. 1999. Intravenous infusion of phenytoin relieves Han W, Toriyama H, Tanabe T. 2001. Suppression of inflamma- neuropathic pain: a randomized, double-blinded, placebo-con- tory and neuropathic pain symptoms in mice lacking the N-type trolled, crossover study. Anesth Analg 89:985–988.
Ca21 channel. Embo J 20:2349–2356.
McCobb DP, Best PM, Beam KG. 1989. Development alters the Sakaue A, Honda M, Tanabe M, Ono H. 2004. Antinociceptive expression of calcium currents in chick limb motoneurons.
effects of sodium channel-blocking agents on acute pain in mice.
J Pharmacol Sci 95:181–188.
McCormick DA, Huguenard JR. 1992. A model of the electro- Santi CM, Cayabyab FS, Sutton KG, McRory JE, Mezeyova J, physiological properties of thalamocortical relay neurons.
Hamming KS, Parker D, Schauf CL. 1987. Zonisamide enhances J Neurophysiol 68:1384–1400.
slow sodium inactivation in Myxicola. Brain Res 413:185–188.
McGuire D, Bowersox S, Fellmann JD, Luther RR. 1997.
Schrier AD, Wang H, Talley EM, Perez-Reyes E, Barrett PQ. 2001.
Sympatholysis after neuron-specific, N-type, voltage-sensitive alpha1 H T-type Ca21 channel is the predominant subtype calcium channel blockade: first demonstration of N-channel expressed in bovine and rat zona glomerulosa. Am J Physiol Cell function in humans. J Cardiovasc Pharmacol 30:400–403.
McRory JE, Santi CM, Hamming KS, Mezeyova J, Sutton KG, Schroeder JE, Fischbach PS, McCleskey EW. 1990. T-type Baillie DL, Stea A, Snutch TP. 2001. Molecular and functional calcium channels: heterogeneous expression in rat sensory characterization of a family of rat brain T-type calcium channels.
neurons and selective modulation by phorbol esters. J Neurosci J Biol Chem 276:3999–4011.
Mimaki T, Suzuki Y, Tagawa T, Karasawa T, Yabuuchi H. 1990.
Scroggs RS, Fox AP. 1992. Calcium current variation between Interaction of zonisamide with benzodiazepine and GABA acutely isolated adult rat dorsal root ganglion neurons of different receptors in rat brain. Med J Osaka Univ 39:13–17.
size. J Physiol 445:639–658.
Mittman S, Guo J, Emerick MC, Agnew WS. 1999. Structure and Shin JB, Martinez-Salgado C, Heppenstall PA, Lewin GR. 2003.
alternative splicing of the gene encoding alpha1I, a human brain T A T-type calcium channel required for normal function of a calcium channel alpha1 subunit. Neurosci Lett 269:121–124.
mammalian mechanoreceptor. Nat Neurosci 6:724–730.
Drug Dev. Res. DOI 10.1002/ddr T-TYPE CALCIUM CHANNELS IN PAIN TREATMENT Snutch TP. 2005. Targeting chronic and neuropathic pain: the Twombly DA, Yoshii M, Narahashi T. 1988. Mechanisms of calcium N-type calcium channel comes of age. NeuroRx 2:662–670.
channel block by phenytoin. J Pharmacol Exp Ther 246:189–195.
Soldo BL, Moises HC. 1998. mu-opioid receptor activation inhibits Uchino T, Lee TS, Kaku T, Yamashita N, Noguchi T, Ono K. 2005.
N- and P-type Ca21 channel currents in magnocellular neurones Voltage-dependent and frequency-independent inhibition of of the rat supraoptic nucleus. J Physiol 513:787–804.
recombinant Cav3.2 T-type Ca21 channel by bepridil. Pharma- Staats PS, Yearwood T, Charapata SG, Presley RW, Wallace MS, Byas-Smith M, Fisher R, Bryce DA, Mangieri EA, Luther RR, van der Stelt M, Di Marzo V. 2005. Anandamide as an intracellular et al. 2004. Intrathecal ziconotide in the treatment of refractory messenger regulating ion channel activity. Prostagland Other pain in patients with cancer or AIDS: a randomized controlled Lipid Mediat 77:111–122.
trial. JAMA 291:63–70.
Vitko I, Chen Y, Arias JM, Shen Y, Wu XR, Perez-Reyes E. 2005.
Stea A, Snutch TP. 2002. Differential inhibition of T-type calcium Functional characterization and neuronal modeling of the effects channels by neuroleptics. J Neurosci 22:396–403.
of childhood absence epilepsy variants of CACNA1H, a T-type Sutton KG, Snutch TP. 2002. Gabapentin: A novel analgesic calcium channel. J Neurosci 25:4844–4855.
targeting voltage-gated Ca channels. Drug Dev Res 54:167–172.
Wang JC, Kiyosue T, Kiriyama K, Arita M. 1999. Bepridil Suzuki S, Kawakami K, Nishimura S, Watanabe Y, Yagi K, Seino M, differentially inhibits two delayed rectifier K(1) currents, I(Kr) Miyamoto K. 1992. Zonisamide blocks T-type calcium channels in and I(Ks), in guinea-pig ventricular myocytes. Br J Pharmacol cultured neurons of cerebral cortex. Epilepsy Res 12:21–27.
Takahashi Y, Hashimoto K, Tsuji S. 2004. Successful use of Yajnik S, Singh GP, Singh G, Kumar M. 1992. Phenytoin as a zonisamide for central poststroke pain. J Pain 5:192–194.
coanalgesic in cancer pain. J Pain Symptom Manage 7:209–213.
Todorovic SM, Perez-Reyes E, Lingle CJ. 2000. Anticonvulsants Yatani A, Brown AM, Schwartz A. 1986. Bepridil block of cardiac but not general anesthetics have differential blocking effects calcium and sodium channels. J Pharmacol Exp Ther 237:9–17.
on different T-type current variants. Mol Pharmacol 58:98–108.
Zamponi GW, Snutch TP. 1998. Decay of prepulse facilitation of N Todorovic SM, Jevtovic-Todorovic V, Meyenburg A, Mennerick S, Perez-Reyes E, Romano C, Olney JW, Zorumski CF. 2001. Redox type calcium channels during G protein inhibition is consistent modulation of T-type calcium channels in rat peripheral with binding of a single Gbeta subunit. Proc Natl Acad Sci USA nociceptors. Neuron 31:75–85.
Todorovic SM, Meyenburg A, Jevtovic-Todorovic V. 2004. Redox Zamponi GW, Bourinet E, Nelson D, Nargeot J, Snutch TP. 1997.
modulation of peripheral T-type Ca21 channels in vivo: alteration Crosstalk between G proteins and protein kinase C mediated by of nerve injury-induced thermal hyperalgesia. Pain 109:328–339.
the calcium channel alpha1 subunit. Nature 385:442–446.
Tsakiridou E, Bertollini L, de Curtis M, Avanzini G, Pape HC. 1995.
Zhu G, Okada M, Murakami T, Kawata Y, Kamata A, Kaneko S.
Selective increase in T-type calcium conductance of reticular 2002. Interaction between carbamazepine, zonisamide and thalamic neurons in a rat model of absence epilepsy. J Neurosci voltage-sensitive Ca21 channel on acetylcholine release in rat frontal cortex. Epilepsy Res 49:49–60.
Drug Dev. Res. DOI 10.1002/ddr

Source: https://snutchlab.msl.ubc.ca/wp-content/uploads/2012/10/2006-Drug-Dev-Res-67-Snutch-David.pdf

Zimbabwean diabetics' beliefs about health and illness : an interview study

Zimbabwean diabetics' beliefs about health and illness: an interview study Katarina Hjelm and Esther Mufunda Linköping University Post Print N.B.: When citing this work, cite the original article. Original Publication: Katarina Hjelm and Esther Mufunda, Zimbabwean diabetics' beliefs about health and illness: an interview study, 2010, BMC International Health and Human Rights, (10), 7. Copyright: BioMed Central


Amorphization of Pharmaceuticals by Co- grinding with Neusilin® Amorphization of crystalline drugs can be achieved In a previous report, we discussed solid dispersion through several methods. The most common method methods using Neusilin as an adsorption carrier to is melting and solidifi cation by rapid cooling over liquid improve dissolution and bioavailabilty of poorly water