NMP-7 inhibits chronic inflammatory and neuropathic pain via block of Cav3.2 T-type calcium channels and activation of CB2 receptors.
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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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
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
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...2 channels (Berger et al., 2014)....
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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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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
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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TL;DR: Consensus is rapidly developing that in the periphery and spinal cord the Cav3.2 T-type calcium channel isoform selectively plays a pronociceptive role and therefore represents an attractive target for future therapeutic strategies.
23 citations
"NMP-7 inhibits chronic inflammatory..." refers background in this paper
...T-type calcium channels are expressed along the primary afferent pain pathway [4-6] and these channels—in particular T-type channel subtype CaV3....
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19 citations
"NMP-7 inhibits chronic inflammatory..." refers background in this paper
...Painful diabetic neuropathies can be reversed by inhibiting T-type channels [14] as well as by CaV3....
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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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TL;DR: This work sought to determine whether NA‐5HT also modulates T‐type ICa, anandamide and N‐arachidonoyl dopamine, endocannabinoids that activate TRPV1 or are metabolized by FAAH, also inhibit T‐ type calcium channels (ICa).
Abstract: BACKGROUND AND PURPOSE N-arachidonoyl 5-HT (NA-5HT) has anti-nociceptive effects reported to be mediated by inhibitory actions at the transient receptor potential vanilloid receptor 1 (TRPV1) and fatty acid amide hydrolase (FAAH). Anandamide and N-arachidonoyl dopamine (NA-DA), endocannabinoids that activate TRPV1 or are metabolized by FAAH, also inhibit T-type calcium channels (ICa). T-type ICa are expressed by many excitable cells, including neurons involved in pain detection and processing. We sought to determine whether NA-5HT also modulates T-type ICa.
EXPERIMENTAL APPROACH Human recombinant T-type ICa (CaV3 channels) expressed in HEK 293 cells were examined using standard whole-cell voltage-clamp electrophysiology techniques.
KEY RESULTS NA-5HT completely inhibited CaV3 channels with a rank order of potency (pEC50) of CaV3.1 (7.4) > CaV3.3 (6.8) ≥ CaV3.2 (6.6). The effects of NA-5HT were voltage-dependent, and it produced significant hyperpolarizing shifts in CaV3 steady-state inactivation relationships. NA-5HT selectively affected CaV3.3 channel kinetics.
CONCLUSIONS AND IMPLICATIONS NA-5HT increases the steady-state inactivation of CaV3 channels, reducing the number of channels available to open during depolarization. These effects occur at NA-5HT concentrations at or below those at which NA-5HT affects TRPV1 receptors and FAAH. NA-5HT is one of the most potent inhibitors of T-type ICa described to date, and it is likely to exert some of its biological effects, including anti-nociception, via inhibition of these channels.
18 citations
"NMP-7 inhibits chronic inflammatory..." refers background in this paper
...Additionally, both Δ(9)-THC and cannabidiol [21] or the endogenous cannabinoid anandamide and its derivatives [20-22] inhibit T-type channel activity....
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TL;DR: It is demonstrated that triple and quadruple combinations of these endogenous ligands caused more effective antihyperalgesia compared with double combinations, reinforcing the view that complex activation and/or inhibition of different systems can be sufficiently effective in blocking nociception without adverse effects.
14 citations
"NMP-7 inhibits chronic inflammatory..." refers background in this paper
...The development of novel analgesics is paramount to the effective treatment of chronic pain, and the development of novel molecular entities targeting multiple mechanisms of pain neurobiology may be an attractive method to effectively mediate pain with lower compound doses, and reduced side effects [2]....
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