NMP-7 inhibits chronic inflammatory and neuropathic pain via block of Cav3.2 T-type calcium channels and activation of CB2 receptors.
N. Daniel Berger,Vinicius M. Gadotti,Ravil R. Petrov,Kevin Chapman,Philippe Diaz,Gerald W. Zamponi +5 more
TLDR
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.read more
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A cell-permeant peptide corresponding to the cUBP domain of USP5 reverses inflammatory and neuropathic pain.
TL;DR: A crucial region in the cUBP domain of USP5 that is important for substrate recognition and binding to the III-IV linker of Cav3.2 channels can be exploited as the basis for therapeutic intervention into inflammatory and neuropathic pain.
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References
More filters
Journal ArticleDOI
Cellular and Molecular Mechanisms of Pain
TL;DR: Genetic, electrophysiological, and pharmacological studies are elucidating the molecular mechanisms that underlie detection, coding, and modulation of noxious stimuli that generate pain.
Journal ArticleDOI
Selective blockade of 2-arachidonoylglycerol hydrolysis produces cannabinoid behavioral effects
Jonathan Z. Long,Weiwei Li,Lamont Booker,James J. Burston,Steven G. Kinsey,Joel E. Schlosburg,Franciso J Pavón,Antonia Serrano,Dana E. Selley,Loren H. Parsons,Aron H. Lichtman,Benjamin F. Cravatt +11 more
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.
Book ChapterDOI
Distribution of cannabinoid receptors in the central and peripheral nervous system.
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.
Journal ArticleDOI
Ethosuximide reverses paclitaxel- and vincristine-induced painful peripheral neuropathy.
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.
Journal ArticleDOI
Cannabinoids mediate analgesia largely via peripheral type 1 cannabinoid receptors in nociceptors
Nitin Agarwal,Pal Pacher,Irmgard Tegeder,Fumimasa Amaya,Cristina E. Constantin,Gary J. Brenner,Tiziana Rubino,Christoph W. Michalski,Giovanni Marsicano,Krisztina Monory,Ken Mackie,Claudiu Marian,Sandor Batkai,Daniela Parolaro,Michael Fischer,Peter W. Reeh,George Kunos,Michaela Kress,Beat Lutz,Clifford J. Woolf,Rohini Kuner +20 more
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.
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