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Journal ArticleDOI

NMP-7 inhibits chronic inflammatory and neuropathic pain via block of Cav3.2 T-type calcium channels and activation of CB2 receptors.

06 Dec 2014-Molecular Pain (BioMed Central)-Vol. 10, Iss: 1, pp 77-77
TL;DR: This work shows that NMP-7 mediates a significant analgesic effect in a model of persistent inflammatory and chronic neuropathic pain by way of T-type channel modulation and CB2 receptor activation, and provides a novel therapeutic avenue for managing chronic pain conditions via mixed CB ligands/T-type channels.
Abstract: Background: T-type calcium channels and cannabinoid receptors are known to play important roles in chronic pain, making them attractive therapeutic targets. We recently reported on the design, synthesis and analgesic properties of a novel T-type channel inhibitor (NMP-7), which also shows mixed agonist activity on CB1 and CB2 receptors in vitro. Here, we analyzed the analgesic effect of systemically delivered NMP-7 (intraperitoneal (i.p.) or intragstric (i.g.) routes) on mechanical hypersensitivity in inflammatory pain induced by Complete Freund’s Adjuvant (CFA) and neuropathic pain induced by sciatic nerve injury. Results: NMP-7 delivered by either i.p. or i.g. routes produced dose-dependent inhibition of mechanical hyperalgesia in mouse models of inflammatory and neuropathic pain, without altering spontaneous locomotor activity in the open-field test at the highest active dose. Neither i.p. nor i.g. treatment reduced peripheral inflammation per se ,a s evaluated by examining paw edema and myeloperoxidase activity. The antinociception produced by NMP-7 in the CFA test was completely abolished in CaV3.2-null mice, confirming CaV 3.2 as ak ey target. The analgesic action of intraperitoneally delivered NMP-7 was not affected by pretreatment of mice with the CB1 antagonist AM281, but was significantly attenuated by pretreatment with the CB2 antagonist AM630, suggesting that CB2 receptors, but not CB1 receptors are involved in the action of NMP-7 in vivo. Conclusions: Overall, our work shows that NMP-7 mediates a significant analgesic effect in a model of persistent inflammatory and chronic neuropathic pain by way of T-type channel modulation and CB2 receptor activation. Thus, this study provides a novel therapeutic avenue for managing chronic pain conditions via mixed CB ligands/ T-type channel blockers.

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Citations
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Journal ArticleDOI
TL;DR: An overview of calcium channels as drug targets for nervous system disorders is provided, and potential challenges and opportunities for the development of new clinically effective calcium channel inhibitors are discussed.
Abstract: Voltage-gated calcium channels are important regulators of brain, heart and muscle functions, and their dysfunction can give rise to pathophysiological conditions ranging from cardiovascular disorders to neurological and psychiatric conditions such as epilepsy, pain and autism. In the nervous system, calcium channel blockers have been used successfully to treat absence seizures, and are emerging as potential therapeutic avenues for pathologies such as pain, Parkinson disease, addiction and anxiety. This Review provides an overview of calcium channels as drug targets for nervous system disorders, and discusses potential challenges and opportunities for the development of new clinically effective calcium channel inhibitors.

301 citations

Journal ArticleDOI
TL;DR: It is suggested that drugs that affect multiple processes, rather than a single specific target, show the greatest promise for future therapeutic development.
Abstract: Injury to or disease of the nervous system can invoke chronic and sometimes intractable neuropathic pain. Many parallel, interdependent, and time-dependent processes, including neuroimmune interactions at the peripheral, supraspinal, and spinal levels, contribute to the etiology of this "disease of pain." Recent work emphasizes the roles of colony-stimulating factor 1, ATP, and brain-derived neurotrophic factor. Excitatory processes are enhanced, and inhibitory processes are attenuated in the spinal dorsal horn and throughout the somatosensory system. This leads to central sensitization and aberrant processing such that tactile and innocuous thermal information is perceived as pain (allodynia). Processes involved in the onset of neuropathic pain differ from those involved in its long-term maintenance. Opioids display limited effectiveness, and less than 35% of patients derive meaningful benefit from other therapeutic approaches. We thus review promising therapeutic targets that have emerged over the last 20 years, including Na+, K+, Ca2+, hyperpolarization-activated cyclic nucleotide-gated channels, transient receptor potential channel type V1 channels, and adenosine A3 receptors. Despite this progress, the gabapentinoids retain their status as first-line treatments, yet their mechanism of action is poorly understood. We outline recent progress in understanding the etiology of neuropathic pain and show how this has provided insights into the cellular actions of pregabalin and gabapentin. Interactions of gabapentinoids with the α2δ-1 subunit of voltage-gated Ca2+ channels produce multiple and neuron type-specific actions in spinal cord and higher centers. We suggest that drugs that affect multiple processes, rather than a single specific target, show the greatest promise for future therapeutic development.

240 citations


Additional excerpts

  • ...2 channels (Berger et al., 2014)....

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Journal ArticleDOI
TL;DR: Recent developments in the discovery of novel classes of T‐type calcium channel blockers, and their analgesic effects in animal models of pain and in clinical trials are reviewed.
Abstract: Cav3.2 T-type calcium channels are important regulators of pain signals in afferent pain pathway, and their activities are dysregulated during various chronic pain states. Therefore it stands to reason that inhibiting T-type calcium channels in dorsal root ganglion neurons and in the spinal dorsal horn can be targeted for pain relief. This is supported by early pharmacological studies with T-type channel blockers such as ethosuximide, and by analgesic effects of siRNA depletion of Cav3.2 channels. In the past five years, considerable effort has been applied towards identifying novel classes of T-type calcium channel blockers. Here we review recent developments in the discovery of novel classes of T-type calcium channel blockers, and their analgesics effects in animal models of pain and in clinical trials.

86 citations


Cites background from "NMP-7 inhibits chronic inflammatory..."

  • ...More recently, a series of novel DHP derivatives with a condensed hexahydroquinoline 1,4-DHP ring system were identified (Bladen et al., 2014)....

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Journal ArticleDOI
09 Sep 2016-PLOS ONE
TL;DR: It is concluded that activation of CB2R ameliorates DSS-induced colitis through enhancing autophagy that may inhibit NLRP3 inflammasome activation in macrophages and it is demonstrated that AMPK-mTOR-P70S6K signaling pathway was involved in thisCB2R-mediated process.
Abstract: Activation of cannabinoid receptor 2 (CB2R) ameliorates inflammation, but the underlying mechanism remains unclear. In the present study, we examined whether activation of CB2R could suppress the nucleotide-binding domain and leucine-rich repeat protein 3 (NLRP3) inflammasome. In peritoneal macrophages isolated from C57BL/6 mice, LPS/DSS challenge for 24 h increased the expression of the components of NLRP3 inflammasome NLRP3, Casp-1 p20/Casp-1 p45 ratio, proIL-1β and IL-1β and also enhanced autophagy (LC3-II/LC3-I ratio, Beclin-1 and SQSTM1). Pretreatment of peritoneal macrophages with HU 308, a selective CB2R agonist, attenuated LPS/DSS-induced NLRP3 inflammasome activation, but further enhanced autophagy. In comparison with wild-type (WT) control, peritoneal macrophages from CB2R knockout (KO) mice had more robust NLRP3 inflammasome activation and attenuated autophagy upon LPS/DSS challenge. Knockdown autophagy-related gene 5 (Atg5) with a siRNA in peritoneal macrophages attenuated the inhibitory effects of HU 308 on LPS/DSS-induced NLRP3 inflammasome activation in vitro. In vivo, HU308 treatment attenuated DSS-induced colitis mice associated with reduced colon inflammation and inhibited NLRP3 inflammasome activation in wild-type mice. In CB2R KO mice, DSS-induced inflammation and NLRP3 inflammasome activation were more pronounced than those in WT control. Finally, we demonstrated that AMPK-mTOR-P70S6K signaling pathway was involved in this CB2R-mediated process. We conclude that activation of CB2R ameliorates DSS-induced colitis through enhancing autophagy that may inhibit NLRP3 inflammasome activation in macrophages.

67 citations

Journal ArticleDOI
TL;DR: The anatomical physiology, underlying mechanisms of neuropathic pain is overviewed to provide a better understanding in the initiation, development, maintenance, and modulation of this pervasive disease, and inspire research in the unclear mechanisms as well as potential targets.

46 citations


Cites background from "NMP-7 inhibits chronic inflammatory..."

  • ...2 blocker SNI model analgesic effect (Berger et al., 2014) Suramin and the flavonoid gossypetin USP5-Cav3....

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  • ...2 T-type channel blocker, was shown to mediate a significant analgesic effect in the model of neuropathic pain (Berger et al. , 2014)....

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References
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Journal ArticleDOI
TL;DR: It is found that, in parallel with the development of diabetes-induced pain, T-type current density increased by twofold in medium-size cells from L4–L5 dorsal root ganglia (DRG) with a depolarizing shift in steady-state inactivation, and increased cellular excitability manifested as a lower threshold for burst firing in diabetic than in control cells.
Abstract: Recent data indicate that T-type Ca2+ channels are amplifiers of peripheral pain signals, but their involvement in disorders of sensory neurons such as those associated with diabetes is poorly understood. To address this issue, we used a combination of behavioral, immunohistological, molecular, and electrophysiological studies in rats with streptozotocin (N-[methylnitrosocarbamoil]-D-glucosamine)-induced early diabetic neuropathy. We found that, in parallel with the development of diabetes-induced pain, T-type current density increased by twofold in medium-size cells from L4-L5 dorsal root ganglia (DRG) with a depolarizing shift in steady-state inactivation. This not only correlated closely with more prominent afterdepolarizing potentials (ADPs) but also increased cellular excitability manifested as a lower threshold for burst firing in diabetic than in control cells. T-type currents and ADPs were potently inhibited by nickel and enhanced by L-cysteine, suggesting that the Ca(V)3.2 T-type channel isoform was upregulated. Both control and diabetic DRG cells with ADPs stained positively for isolectin B4, but only diabetic cells responded robustly to capsaicin, suggesting enhanced nociceptive function. Because increased excitability of sensory neurons may result in such pathological perceptions of pain as hyperalgesia and allodynia, upregulation of T-type Ca2+ currents and enhanced Ca2+ entry into these cells could contribute to the development of symptoms in diabetic neuropathy.

251 citations


"NMP-7 inhibits chronic inflammatory..." refers background in this paper

  • ...Conversely, increased T-type channel activity in the primary pain pathway occurs in models of chronic pain such as spinal nerve injury [25], peripheral nerve injury [26], colonic hypersensitivity [8] and diabetic neuropathy [27]....

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Journal ArticleDOI
01 Sep 2003-Pain
TL;DR: The data support the view that selective T‐ type calcium channel blockers may have significant potential in the treatment of neuropathic pain states and suggest that T‐type calcium channels may play a role in the expression of the neuropathic state.
Abstract: Experimental nerve injury results in exaggerated responses to tactile and thermal stimuli that resemble some aspects of human neuropathic pain. Neuronal hyperexcitability and neurotransmitter release have been suggested to promote such increased responses to sensory stimuli. Enhanced activity of Ca(2+) current is associated with increased neuronal activity and blockade of N- and P-types, but not L-type, calcium channels have been found to block experimental neuropathic pain. While T-type currents are believed to promote neuronal excitability and transmitter release, it is unclear whether these channels may also contribute to the neuropathic state. Rats were prepared with L(5)/L(6) spinal nerve ligation, and tactile and thermal hypersensitivities were established. Mibefradil or ethosuximide was administered either intraperitoneally, intrathecally (i.th.), or locally into the plantar aspect of the injured hindpaw. Systemic mibefradil or ethosuximide produced a dose-dependent blockade of both tactile and thermal hypersensitivities in nerve-injured rats; responses of sham-operated rats were unchanged. Local injection of mibefradil also blocked both end points. Ethosuximide, however, was inactive after local administration, perhaps reflecting its low potency when compared with mibefradil. Neither mibefradil nor ethosuximide given i.th. produced any blockade of neuropathic behaviors. The results presented here suggest that T-type calcium channels may play a role in the expression of the neuropathic state. The data support the view that selective T-type calcium channel blockers may have significant potential in the treatment of neuropathic pain states.

233 citations


"NMP-7 inhibits chronic inflammatory..." refers background in this paper

  • ...knockdown [7,8] or inhibition of the T-type calcium channel by T-type channel modulators produce significant antinociceptive effects in vivo [9-13]....

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  • ...Systemic, peripheral and intrathecal administration of T-type calcium channel blockers such as mibefradil and ethosuximide have been previously shown to reverse mechanical and thermal hypersensitivity in response to nerve injury [11]....

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  • ...Inhibition of T-type channels or in vivo antisense-mediated knockdown produces antinociception in these and other models of chronic pain [7-16]....

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Journal ArticleDOI
TL;DR: The present study reveals that the CaV3.2 subtype of T‐type Ca2+ channels are important in the peripheral processing of noxious signals, regardless of modality, duration or affected tissue type.
Abstract: Although T-type Ca2+ channels are implicated in nociception, the function of specific subtypes has not been well defined. Here, we compared pain susceptibility in mice lacking CaV3.2 subtype of T-type Ca2+ channels (CaV3.2−/−) with wild-type littermates in various behavioral models of pain to explore the roles of CaV3.2 in the processing of noxious stimuli in vivo. In acute mechanical, thermal and chemical pain tests, CaV3.2−/− mice showed decreased pain responses compared to wild-type mice. CaV3.2−/− mice also displayed attenuated pain responses to tonic noxious stimuli such as intraperitoneal injections of irritant agents and intradermal injections of formalin. In spinal nerve ligation-induced neuropathic pain, however, behavioral responses of CaV3.2−/− mice were not different from those of wild-type mice. The present study reveals that the CaV3.2 subtype of T-type Ca2+ channels are important in the peripheral processing of noxious signals, regardless of modality, duration or affected tissue type.

223 citations


"NMP-7 inhibits chronic inflammatory..." refers background in this paper

  • ...2 knockout mouse strains also show attenuated pain responses in the formalin-induced pain model [16]....

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  • ...Inhibition of T-type channels or in vivo antisense-mediated knockdown produces antinociception in these and other models of chronic pain [7-16]....

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Journal ArticleDOI
TL;DR: The finding that T-type currents are upregulated in a CCI model of peripheral neuropathy and earlier pharmacological and molecular studies suggest that T -type channels may be potentially useful therapeutic targets for the treatment of neuropathic pain associated with partial mechanical injury to the sciatic nerve.
Abstract: Recent data indicate that peripheral T-type Ca2+ channels are instrumental in supporting acute pain transmission. However, the function of these channels in chronic pain processing is less clear. T...

203 citations


"NMP-7 inhibits chronic inflammatory..." refers background in this paper

  • ...Conversely, increased T-type channel activity in the primary pain pathway occurs in models of chronic pain such as spinal nerve injury [25], peripheral nerve injury [26], colonic hypersensitivity [8] and diabetic neuropathy [27]....

    [...]

Journal ArticleDOI
03 Sep 2014-Neuron
TL;DR: Experiments reveal a cell signaling pathway that regulates T-type channel activity and their role in nociceptive signaling and reveal the role of USP5 in both inflammatory and neuropathic mouse models of mechanical hypersensitivity.

192 citations


"NMP-7 inhibits chronic inflammatory..." refers background or result in this paper

  • ...2 channel trafficking mediates analgesia in mouse models of inflammatory and neuropathic pain [17]....

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  • ...In response to CFA, these mice showed similar mechanical withdrawal thresholds relative to wild-type mice (Figure 5), as previously reported [17]....

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