NMP-7 inhibits chronic inflammatory and neuropathic pain via block of Cab3.2 T-type calcium channels and activation of CB2 receptors

Authors

N. Daniel Berger, University of CalgaryFollow
Vinicius M. Gadotti, University of CalgaryFollow
Ravil R. Petrov, University of Montana - MissoulaFollow
Kevin Chapman, University of Calgary
Philippe Diaz, University of Montana - MissoulaFollow
Gerald W. Zamponi, University of CalgaryFollow

Document Type

Article

Publication Title

Molecular Pain

Publisher

BioMed Central Ltd.

Publication Date

12-6-2014

Volume

10

Issue

77

Disciplines

Biology | Life Sciences

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, as evaluated by examining paw edema and myeloperoxidase activity. The antinociception produced by NMP-7 in the CFA test was completely abolished in Ca_V3.2-null mice, confirming Ca_V3.2 as a key 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.

Keywords

T-type calcium channels, Neuropathic pain, Inflammatory pain, Cannabinoid receptors, Analgesia

DOI

10.1186/1744-8069-10-77

Rights

© 2014 Berger et al.; licensee BioMed Central Ltd.

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Recommended Citation

Berger et al.: NMP-7 inhibits chronic inflammatory and neuropathic pain via block of Cav3.2 T-type calcium channels and activation of CB2 receptors. Molecular Pain 2014 10:77.