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.
Abstract: Neuropathic pain is maladaptive pain caused by injury or dysfunction in peripheral and central nervous system, and remains a worldwide thorny problem leading to decreases in physical and mental quality of people's life. Currently, drug therapy is the main treatment regimen for resolving pain, while effective drugs are still unmet in medical need, and commonly used drugs such as anticonvulsants and antidepressants often make patients experience adverse drug reactions like dizziness, somnolence, severe headache, and high blood pressure. Thus, in this review we overview the anatomical physiology, underlying mechanisms of neuropathic pain 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. Furthermore, we summarized the existing drug therapies and new compounds that have shown antalgic effects in laboratory studies to be helpful for rational regimens in clinical treatment and promotion in novel drug discovery.
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: Genetic, electrophysiological, and pharmacological studies are elucidating the molecular mechanisms that underlie detection, coding, and modulation of noxious stimuli that generate pain.
Abstract: The nervous system detects and interprets a wide range of thermal and mechanical stimuli, as well as environmental and endogenous chemical irritants. When intense, these stimuli generate acute pain, and in the setting of persistent injury, both peripheral and central nervous system components of the pain transmission pathway exhibit tremendous plasticity, enhancing pain signals and producing hypersensitivity. When plasticity facilitates protective reflexes, it can be beneficial, but when the changes persist, a chronic pain condition may result. Genetic, electrophysiological, and pharmacological studies are elucidating the molecular mechanisms that underlie detection, coding, and modulation of noxious stimuli that generate pain.
3,394 citations
Additional excerpts
...mildly aversive stimuli, hyperalgesia [1]....
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TL;DR: 2-AG endogenously modulates several behavioral processes classically associated with the pharmacology of cannabinoids and point to overlapping and unique functions for 2-AG and anandamide in vivo, indicating a functional segregation of endocannabinoid signaling pathways in vivo.
Abstract: 2-Arachidonoylglycerol (2-AG) and anandamide are endocannabinoids that activate the cannabinoid receptors CB1 and CB2. Endocannabinoid signaling is terminated by enzymatic hydrolysis, a process that for anandamide is mediated by fatty acid amide hydrolase (FAAH), and for 2-AG is thought to involve monoacylglycerol lipase (MAGL). FAAH inhibitors produce a select subset of the behavioral effects observed with CB1 agonists, which suggests a functional segregation of endocannabinoid signaling pathways in vivo. Testing this hypothesis, however, requires specific tools to independently block anandamide and 2-AG metabolism. Here, we report a potent and selective inhibitor of MAGL called JZL184 that, upon administration to mice, raises brain 2-AG by eight-fold without altering anandamide. JZL184-treated mice exhibited a broad array of CB1-dependent behavioral effects, including analgesia, hypothermia and hypomotility. These data indicate that 2-AG endogenously modulates several behavioral processes classically associated with the pharmacology of cannabinoids and point to overlapping and unique functions for 2-AG and anandamide in vivo.
855 citations
"NMP-7 inhibits chronic inflammatory..." refers methods in this paper
...Yet, AM281 reversed the antinociceptive action of JZL184 (16 mg/kg, i.p., an irreversible inhibitor of monoacyglycerol lipase, the primary degradatory enzyme for endocannabinoid 2-arachidonoylglycerol) (Two-way ANOVA, p 0.05) (Figure 6B), thus confirming that AM281 was indeed active in vivo....
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...JZL184 was used as a positive control, and was administered 15 minutes post-AM281 treatment in the same way as NMP-7....
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...%) and PBS. Selective CB1 antagonist AM281, irreversible inhibitor of monoacylglycerol lipase JZL184 [32,33], selective CB2 antagonist AM630, and the irreversible inhibitor of fatty acid amide hydrolase URB597 [34] were provided by Cayman Chemical, and dissolved in phosphate buffered saline (PBS) and dimethyl sulfoxide (DMSO) to 5%....
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...Selective CB1 antagonist AM281, irreversible inhibitor of monoacylglycerol lipase JZL184 [32,33], selective CB2 antagonist AM630, and the irreversible inhibitor of fatty acid amide hydrolase URB597 [34] were provided by Cayman Chemical, and dissolved in phosphate buffered saline (PBS) and dimethyl sulfoxide (DMSO) to 5%....
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TL;DR: There is the need for detailed anatomical studies of brain regions important in the therapeutic actions of drugs that modify the endocannabinoid system and the determination of the localization of the enzymes that synthesize, degrade, and transport the endOCannabinoids.
Abstract: CB1 cannabinoid receptors appear to mediate most, if not all of the psychoactive effects of delta-9-tetrahydrocannabinol and related compounds. This G protein-coupled receptor has a characteristic distribution in the nervous system: It is particularly enriched in cortex, hippocampus, amygdala, basal ganglia outflow tracts, and cerebellum—a distribution that corresponds to the most prominent behavioral effects of cannabis. In addition, this distribution helps to predict neurological and psychological maladies for which manipulation of the endocannabinoid system might be beneficial. CB1 receptors are primarily expressed on neurons, where most of the receptors are found on axons and synaptic terminals, emphasizing the important role of this receptor in modulating neurotransmission at specific synapses. While our knowledge of CB1 localization in the nervous system has advanced tremendously over the past 15 years, there is still more to learn. Particularly pressing is the need for (1) detailed anatomical studies of brain regions important in the therapeutic actions of drugs that modify the endocannabinoid system and (2) the determination of the localization of the enzymes that synthesize, degrade, and transport the endocannabinoids.
604 citations
"NMP-7 inhibits chronic inflammatory..." refers background in this paper
...CB1 receptors are expressed throughout the brain and the spinal cord, where they modulate neurotransmitter release such as inhibition of glutamate release by spinal cord interneurons [29,30]....
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...However, CB1 receptors almost exclusively mediate cannabis-related psychotropic effects, catalepsy and motor ataxia [29]....
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TL;DR: The data suggest that T‐type calcium channels may play a role in chemotherapy‐induced neuropathy and moreover identify ethosuximide as a new potential treatment for chemotherapy‐ induced pain.
Abstract: Paclitaxel (Taxol) is one of the most effective and frequently used chemotherapeutics for the treatment of solid tumours. However, paclitaxel produces peripheral neurotoxicity with patients reporting sensory abnormalities and neuropathic pain during and often persisting after paclitaxel therapy. The mechanisms underlying this dose-limiting side effect are currently unknown and there are no validated drugs for its prevention or control. Male Sprague-Dawley rats received four intraperitoneal (i.p.) injections on alternate days of 2 mg/kg paclitaxel. Behavioural assessment using von Frey filaments and acetone showed that such paclitaxel treatment induced a pronounced mechanical and cold allodynia/hyperalgesia. Thus these studies aim to test potential analgesics on established paclitaxel-induced pain. Paclitaxel-induced pain appears to be relatively resistant to opioid therapy i.p. 4 mg/kg morphine was ineffective and i.p. 8 mg/kg morphine only elicited up to a 50% reversal of mechanical allodynia/hyperalgesia. Interestingly, a maximally tolerated dose (i.p. 0.2 mg/kg) of the potent NMDA receptor antagonist MK-801 produced no significant reversal of the mechanical allodynia/hyperalgesia suggesting that NMDA receptors have little role in paclitaxel-induced pain. Ethosuximide (i.p. 450 mg/kg) an anti-epileptic and relatively selective T-type calcium channel blocker elicited a near complete reversal of mechanical allodynia/hyperalgesia. Repetitive dosing with ethosuximide (i.p. 100 or 300 mg/kg daily for 3 days) showed a dose-related consistent reversal of mechanical allodynia/hyperalgesia with no evidence of tolerance. Ethosuximide (i.p. 300 mg/kg) also reversed paclitaxel-induced cold allodynia and vincristine-induced mechanical allodynia/hyperalgesia. These data suggest that T-type calcium channels may play a role in chemotherapy-induced neuropathy and moreover identify ethosuximide as a new potential treatment for chemotherapy-induced pain.
534 citations
TL;DR: It is concluded that the contribution of CB1-type receptors expressed on the peripheral terminals of nociceptors to cannabinoid-induced analgesia is paramount, which should enable the development of peripherally acting CB1 analgesic agonists without any central side effects.
Abstract: Although endocannabinoids constitute one of the first lines of defense against pain, the anatomical locus and the precise receptor mechanisms underlying cannabinergic modulation of pain are uncertain. Clinical exploitation of the system is severely hindered by the cognitive deficits, memory impairment, motor disturbances and psychotropic effects resulting from the central actions of cannabinoids. We deleted the type 1 cannabinoid receptor (CB1) specifically in nociceptive neurons localized in the peripheral nervous system of mice, preserving its expression in the CNS, and analyzed these genetically modified mice in preclinical models of inflammatory and neuropathic pain. The nociceptor-specific loss of CB1 substantially reduced the analgesia produced by local and systemic, but not intrathecal, delivery of cannabinoids. We conclude that the contribution of CB1-type receptors expressed on the peripheral terminals of nociceptors to cannabinoid-induced analgesia is paramount, which should enable the development of peripherally acting CB1 analgesic agonists without any central side effects.
511 citations
"NMP-7 inhibits chronic inflammatory..." refers background in this paper
...There is also evidence for CB1 expression on nociceptors in the periphery [31]....
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