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A-1048400 is a novel, orally active, state-dependent neuronal calcium channel blocker that produces dose-dependent antinociception without altering hemodynamic function in rats.

Biochem Pharmacol. 2012 Feb 1;83(3):406-18

Authors: Scott VE, Vortherms TA, Niforatos W, Swensen AM, Neelands T, Milicic I, Banfor PN, King A, Zhong C, Simler G, Zhan C, Bratcher N, Boyce-Rustay JM, Zhu CZ, Bhatia P, Doherty G, Mack H, Stewart AO, Jarvis MF

Blockade of voltage-gated Ca²? channels on sensory nerves attenuates neurotransmitter release and membrane hyperexcitability associated with chronic pain states. Identification of small molecule Ca²? channel blockers that produce significant antinociception in the absence of deleterious hemodynamic effects has been challenging. In this report, two novel structurally related compounds, A-686085 and A-1048400, were identified that potently block N-type (IC??=0.8 ?M and 1.4 ?M, respectively) and T-type (IC??=4.6 ?M and 1.2 ?M, respectively) Ca²? channels in FLIPR based Ca²? flux assays. A-686085 also potently blocked L-type Ca²? channels (EC??=0.6 ?M), however, A-1048400 was much less active in blocking this channel (EC??=28 ?M). Both compounds dose-dependently reversed tactile allodynia in a model of capsaicin-induced secondary hypersensitivity with similar potencies (EC??=300-365 ng/ml). However, A-686085 produced dose-related decreases in mean arterial pressure at antinociceptive plasma concentrations in the rat, while A-1048400 did not significantly alter hemodynamic function at supra-efficacious plasma concentrations. Electrophysiological studies demonstrated that A-1048400 blocks native N- and T-type Ca²? currents in rat dorsal root ganglion neurons (IC??=3.0 ?M and 1.6 ?M, respectively) in a voltage-dependent fashion. In other experimental pain models, A-1048400 dose-dependently attenuated nociceptive, neuropathic and inflammatory pain at doses that did not alter psychomotor or hemodynamic function. The identification of A-1048400 provides further evidence that voltage-dependent inhibition of neuronal Ca²? channels coupled with pharmacological selectivity vs. L-type Ca²? channels can provide robust antinociception in the absence of deleterious effects on hemodynamic or psychomotor function.

PMID: 22153861 [PubMed – indexed for MEDLINE]

Brain-derived neurotrophic factor modulates N-methyl-D-aspartate receptor activation in a rat model of cancer-induced bone pain.

J Neurosci Res. 2012 Feb 22;

Authors: Wang LN, Yang JP, Ji FH, Zhan Y, Jin XH, Xu QN, Wang XY, Zuo JL

Brain-derived neurotrophic factor (BDNF) released within the spinal cord induces phosphorylation of N-methyl-D-aspartate (NMDA) receptors on the spinal cord neurons. This process is necessary for maintaining pain hypersensitivity after nerve injury. However, little is known about the role of BDNF and NMDA receptors in cancer-induced bone pain (CIBP), whose features are unique. This study demonstrates a critical role of the BDNF-modulated NMDA subunit 1 (NR1) in the induction and maintenance of behavioral hypersensitivity in a rat model of CIBP, both in the spinal cord and in the dorsal root ganglia (DRG). We selectively suppressed BDNF expression by RNA interference (RNAi) using intrathecal administration of BDNF small interfering RNA (siRNA). Then, we assessed mechanical threshold and spontaneous pain in CIBP rats. Real-time PCR, Western blotting, and fluorescent immunohistochemical staining were used to detect BDNF or NR1 both in vivo and in vitro. BDNF and phospho-NR1 were expressed under CIBP experimental conditions, with expression levels peaking at day 6 (BDNF) or 9 (NR1). Intrathecal BDNF siRNA prevented CIBP at an early stage of tumor growth (days 4-6). However, at later stages (days 10-12), intrathecal BDNF siRNA only attenuated, but did not completely block, the established CIBP. BDNF-induced NMDA receptor activation in the spinal cord or DRG leads to central sensitization and behavioral hypersensitivity. Thus, BDNF might provide a targeting opportunity for alleviating CIBP. © 2012 Wiley Priodicals, Inc.

PMID: 22354476 [PubMed – as supplied by publisher]

Stimulation of peripheral Kappa opioid receptors inhibits inflammatory hyperalgesia via activation of the PI3K?/AKT/nNOS/NO signaling pathway.

Mol Pain. 2012;8:10

Authors: Cunha TM, Souza GR, Domingues AC, Carreira EU, Lotufo CM, Funez MI, Verri WA, Cunha FQ, Ferreira SH

BACKGROUND: In addition to their central effects, opioids cause peripheral analgesia. There is evidence showing that peripheral activation of kappa opioid receptors (KORs) inhibits inflammatory pain. Moreover, peripheral ?-opioid receptor (MOR) activation are able to direct block PGE2-induced ongoing hyperalgesia However, this effect was not tested for KOR selective activation. In the present study, the effect of the peripheral activation of KORs on PGE2-induced ongoing hyperalgesia was investigated. The mechanisms involved were also evaluated.
RESULTS: Local (paw) administration of U50488 (a selective KOR agonist) directly blocked, PGE2-induced mechanical hyperalgesia in both rats and mice. This effect was reversed by treating animals with L-NMMA or N-propyl-L-arginine (a selective inhibitor of neuronal nitric oxide synthase, nNOS), suggesting involvement of the nNOS/NO pathway. U50488 peripheral effect was also dependent on stimulation of PI3K?/AKT because inhibitors of these kinases also reduced peripheral antinociception induced by U50488. Furthermore, U50488 lost its peripheral analgesic effect in PI3K? null mice. Observations made in vivo were confirmed after incubation of dorsal root ganglion cultured neurons with U50488 produced an increase in the activation of AKT as evaluated by western blot analyses of its phosphorylated form. Finally, immunofluorescence of DRG neurons revealed that KOR-expressing neurons also express PI3K? (? 43%).
CONCLUSIONS: The present study indicates that activation of peripheral KORs directly blocks inflammatory hyperalgesia through stimulation of the nNOS/NO signaling pathway which is probably stimulated by PI3K?/AKT signaling. This study extends a previously study of our group suggesting that PI3K?/AKT/nNOS/NO is an important analgesic pathway in primary nociceptive neurons.

PMID: 22316281 [PubMed – in process]

Block of Na(+) currents and suppression of action potentials in embryonic rat dorsal root ganglion neurons by ranolazine.

Neuropharmacology. 2012 Feb 2;

Authors: Hirakawa R, El-Bizri N, Shryock JC, Belardinelli L, Rajamani S

Ranolazine, an anti-anginal drug, reduces neuropathic and inflammatory-induced allodynia in rats. However, the mechanism of ranolazin’s anti-allodynic effect is not known. We hypothesized that ranolazine would reduce dorsal root ganglion (DRG) Na(+) current (I(Na)) and neuronal firing by stabilizing Na(+) channels in inactivated states to cause voltage- and frequency-dependent block. Therefore, we investigated the effects of ranolazine on tetrodotoxin-sensitive (TTXs) and tetrodotoxin-resistant (TTXr) I(Na) and action potential parameters of small diameter DRG neurons from embryonic rats. Ranolazine (10 and 30 ?M) significantly reduced the firing frequency of evoked action potentials in DRG neurons from 19.2 ± 1.4 to 9.8 ± 2.7 (10 ?M) and 5.7 ± 1.3 (30 ?M) Hz at a resting membrane potential of -40 mV. Ranolazine blocked TTXs and TTXr in a voltage- and frequency-dependent manner. Furthermore, ranolazine (10 ?M) blocked hNa(v)1.3 (expressed in HEK293 cells) and caused a hyperpolarizing shift in the voltage dependence of steady-state intermediate and slow inactivation Na(v)1.3 current. Taken together, the results suggest that ranolazine suppresses the hyperexcitability of DRG neurons by interacting with the inactivated states of Na(+) channels and these actions may contribute to its anti-allodynic effect in animal models of neuropathic pain.

PMID: 22313527 [PubMed – as supplied by publisher]

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