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

Molecular Pain

Gerald W Zamponi¹  Philippe Diaz²  Kevin Chapman¹  Ravil R Petrov²  Vinicius M Gadotti¹  N Daniel Berger¹ 

[1] Department of Physiology and Pharmacology, Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada;Core Laboratory for Neuromolecular Production, University of Montana, Missoula, MT, USA

关键词: Analgesia;    Cannabinoid receptors;    Inflammatory pain;    Neuropathic pain;    T-type calcium channels;   

Others  :  1135553
DOI  :  10.1186/1744-8069-10-77

 received in 2014-10-09, accepted in 2014-12-02,  发布年份 2014

【 摘 要 】

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.

【 授权许可】

   
2014 Berger et al.; licensee BioMed Central Ltd.

【 图 表 】

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