Targeting N-type and T-type calcium channels for the treatment of pain

McGivern, Joseph G.

doi:10.1016/s1359-6446(05)03662-7

Cited by 120 publications

(92 citation statements)

References 120 publications

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“…Loperamide-induced inhibition of voltage-gated calcium channels (Church et al 1994;Hagiwara et al 2003;Reynolds et al 1984) and NMDA receptors (Church et al 1994) present both in CNS and in sensory fibers (Carlton et al 1995;Coggeshall and Carlton 1998;Davidson et al 1997;Kinkelin et al 2000) is broadly consistent with its analgesic properties, considering the well-documented efficacy of selective antagonists of voltage-gated calcium channels and NMDA receptors in treating inflammatory and neuropathic pain symptoms (Chizh and Headley 2005;McGivern 2006). Our finding of loperamide-induced inhibition of HCN channels is also consistent with HCN channels involvement in the pathophysiology of pain (Chaplan et al 2003;Hutcheon and Yarom 2000;Pape 1996;Yao et al 2003).…”

Section: Physiological Significance Of Loperamide-induced I H Inhibitionmentioning

confidence: 95%

Direct Inhibition of I_h by Analgesic Loperamide in Rat DRG Neurons

Vasilyev

Qin²,

Lu³

et al. 2007

Journal of Neurophysiology

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. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are responsible for the functional hyperpolarization-activated current (I h ) in dorsal root ganglion (DRG) neurons, playing an important role in pain processing. We found that the known analgesic loperamide inhibited I h channels in rat DRG neurons. Loperamide blocked I h in a concentration-dependent manner, with an IC 50 ϭ 4.9 Ϯ 0.6 and 11.0 Ϯ 0.5 M for large-and small-diameter neurons, respectively. Loperamideinduced I h inhibition was unrelated to the activation of opioid receptors and was reversible, voltage-dependent, use-independent, and was associated with a negative shift of V 1/2 for I h steady-state activation. Loperamide block of I h was voltage-dependent, gradually decreasing at more hyperpolarized membrane voltages from 89% at -60 mV to 4% at -120 mV in the presence of 3.7 M loperamide. The voltage sensitivity of block can be explained by a loperamide-induced shift in the steady-state activation of I h . Inclusion of 10 M loperamide into the recording pipette did not affect I h voltage for half-maximal activation, activation kinetics, and the peak current amplitude, whereas concurrent application of equimolar external loperamide produced a rapid, reversible I h inhibition. The observed loperamideinduced I h inhibition was not caused by the activation of peripheral opioid receptors because the broad-spectrum opioid receptor antagonist naloxone did not reverse I h inhibition. Therefore we suggest that loperamide inhibits I h by direct binding to the extracellular region of the channel. Because I h channels are involved in pain processing, loperamide-induced inhibition of I h channels could provide an additional molecular mechanism for its analgesic action.

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Section: Physiological Significance Of Loperamide-induced I H Inhibitionmentioning

confidence: 95%

Direct Inhibition of I_h by Analgesic Loperamide in Rat DRG Neurons

Vasilyev

Qin²,

Lu³

et al. 2007

Journal of Neurophysiology

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“…Ziconotide (Prialt Ò ), an analgesic drug that works by specifically targeting N-type calcium channels, is also approved by several government regulatory bodies worldwide, for the treatment of severe chronic pain associated with cancer, AIDS and neuropathies [11]. Based on the literature and clinical judgment of the pain management physicians, other analgesic agents are known to be infused into the cerebrospinal fluid.…”

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confidence: 99%

Stability and compatibility of drug mixtures in an implantable infusion system

Bianchi¹,

Ginggen²,

Tardy³

2008

Anaesthesia

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SummaryThis study evaluated the stability and the compatibility of mixtures of morphine sulphate, bupivacaine, and clonidine hydrochloride and of hydromorphone, bupivacaine, and clonidine hydrochloride, when used in constant flow implantable pumps under simulated clinical use conditions. The pumps were filled with drug mixtures and incubated at 37°C for a period of 90 days. Aliquots were sampled monthly from the reservoir and catheter outlet and the drug concentrations analysed using validated chromatography methods. Individual materials from the infusion system were immersed in the drug mixtures and stored at 37°C for 60 weeks and evaluated for mechanical performance for compatibility testing. Both drug mixtures were found to be stable over 90 days in the pump at 37°C. All device materials retained acceptable mechanical performance following exposure. These results demonstrate that both drug mixtures are stable when maintained at simulated body temperature in an implantable infusion system for 90 days.

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“…In the peripheral nervous system, HVA (including L-, N-, P/Q and R-type) and LVA channels have been identified in TG and DRG neurons (Borgland et al, 2001;Kim and Chung, 1999). In nociceptors, VGCCs contribute to the upstroke and duration of AP and when activated may depolarize the nociceptor and release pro-inflammatory transmitters and peptides therefore, VGCCs are important targets for the treatment of pain (Bourinet and Zamponi, 2005;McGivern, 2006;Wallace, 2000), including acute (Ogasawara et al, 2001), chronic and neuropathic pain (Snutch, 2005). In this study, LVA current was found only in about 7% (54/744) small and medium size TG neurons (data not shown), so we focused our experiment on I HVA .…”

Section: Physiological Significancementioning

confidence: 99%

Changes in osmolality modulate voltage-gated calcium channels in trigeminal ganglion neurons

Chen

Liu

2008

Brain Research

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Voltage-gated calcium channels (VGCCs) participate in many important physiological functions. However whether VGCCs are modulated by changes of osmolarity and involve in anisotonicityinduced nociception are still unknown. For this reason by using whole cell patch clamp techniques in rat and mouse trigeminal ganglion (TG) neurons we tested the effects of hypo and hypertonicity on VGCCs. We found that high voltage-gated calcium current (I HVA ) was inhibited by both hypo and hypertonicity. In rat TG neurons, the inhibition by hypotonicity was mimicked by Transient Receptor Potential Vanilloid 4 receptor (TRPV4) activator but hypotonicity did not exhibit inhibition in TRPV4 −/− mice TG neurons. Concerning the downstream signaling pathways, antagonism of PKG pathway selectively reduced the hypotonicity-induced inhibition, whereas inhibition of PLC-and PI3K-mediated pathways selectively reduced the inhibition produced by hypertonicity. In summary, although the effects of hypo-and hypertonicity show similar phenotype, receptor and intracellular signaling pathways were selective for hypo-versus hypertonicity induced inhibition of I HVA .

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Targeting N-type and T-type calcium channels for the treatment of pain

Cited by 120 publications

References 120 publications

Direct Inhibition of I_h by Analgesic Loperamide in Rat DRG Neurons

Direct Inhibition of I_h by Analgesic Loperamide in Rat DRG Neurons

Stability and compatibility of drug mixtures in an implantable infusion system

Changes in osmolality modulate voltage-gated calcium channels in trigeminal ganglion neurons

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Targeting N-type and T-type calcium channels for the treatment of pain

Cited by 120 publications

References 120 publications

Direct Inhibition of Ih by Analgesic Loperamide in Rat DRG Neurons

Direct Inhibition of Ih by Analgesic Loperamide in Rat DRG Neurons

Stability and compatibility of drug mixtures in an implantable infusion system

Changes in osmolality modulate voltage-gated calcium channels in trigeminal ganglion neurons

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Direct Inhibition of I_h by Analgesic Loperamide in Rat DRG Neurons

Direct Inhibition of I_h by Analgesic Loperamide in Rat DRG Neurons