Functional Characterization and Analgesic Effects of Mixed Cannabinoid Receptor/T-type Channel Ligands

Overview

Journal Mol Pain

Date 2011 Nov 19

PMID 22093952

Citations 14

Authors

Haitao You

Vinicius M Gadotti

Ravil R Petrov

Gerald W Zamponi

Philippe Diaz

Affiliations

Soon will be listed here.

Abstract

Background: Both T-type calcium channels and cannabinoid receptors modulate signalling in the primary afferent pain pathway. Here, we investigate the analgesics activities of a series of novel cannabinoid receptor ligands with T-type calcium channel blocking activity.

Results: Novel compounds were characterized in radioligand binding assays and in vitro functional assays at human and rat CB1 and CB2 receptors. The inhibitory effects of these compounds on transient expressed human T-type calcium channels were examined in tsA-201 cells using standard whole-cell voltage clamp techniques, and their analgesic effects in response to various administration routes (intrathecally, intraplantarly, intraperitoneally) assessed in the formalin model. A series of compounds were synthesized and evaluated for channel and receptor activity. Compound NMP-7 acted as non-selective CB1/CB2 agonist while NMP4 was found to be a CB1 partial agonist and CB2 inverse agonist. Furthermore, NMP-144 behaved as a selective CB2 inverse agonist. All of these three compounds completely inhibited peak Cav3.2 currents with IC50 values in the low micromolar range. All compounds mediated analgesic effects in the formalin model, but depending on the route of administration, could differentially affect phase 1 and phase 2 of the formalin response.

Conclusions: Our results reveal that a set of novel cannabinioid receptor ligands potently inhibit T-type calcium channels and show analgesic effects in vivo. Our findings suggest possible novel means of mediating pain relief through mixed T-type/cannabinoid receptor ligands.

Citing Articles

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References

Zamponi G, Lewis R, Todorovic S, Arneric S, Snutch T . Role of voltage-gated calcium channels in ascending pain pathways. Brain Res Rev. 2009; 60(1):84-9. PMC: 2692704. DOI: 10.1016/j.brainresrev.2008.12.021. View

Khorana N, Purohit A, Herrick-Davis K, Teitler M, Glennon R . gamma-Carbolines: binding at 5-HT5A serotonin receptors. Bioorg Med Chem. 2003; 11(5):717-22. DOI: 10.1016/s0968-0896(02)00527-8. View

Ross H, Gilmore A, Connor M . Inhibition of human recombinant T-type calcium channels by the endocannabinoid N-arachidonoyl dopamine. Br J Pharmacol. 2009; 156(5):740-50. PMC: 2697747. DOI: 10.1111/j.1476-5381.2008.00072.x. View

Hsieh G, Pai M, Chandran P, Hooker B, Zhu C, Salyers A . Central and peripheral sites of action for CB₂ receptor mediated analgesic activity in chronic inflammatory and neuropathic pain models in rats. Br J Pharmacol. 2010; 162(2):428-40. PMC: 3031063. DOI: 10.1111/j.1476-5381.2010.01046.x. View

Bonjoch J, Diaba F, Pages L, Perez D, Soca L, Miralpeix M . Synthesis and structure-activity relationships of gamma-carboline derivatives as potent and selective cysLT(1) antagonists. Bioorg Med Chem Lett. 2009; 19(15):4299-302. DOI: 10.1016/j.bmcl.2009.05.094. View

Felder C, Joyce K, Briley E, Mansouri J, Mackie K, Blond O . Comparison of the pharmacology and signal transduction of the human cannabinoid CB1 and CB2 receptors. Mol Pharmacol. 1995; 48(3):443-50. View

Nackley A, Zvonok A, Makriyannis A, Hohmann A . Activation of cannabinoid CB2 receptors suppresses C-fiber responses and windup in spinal wide dynamic range neurons in the absence and presence of inflammation. J Neurophysiol. 2004; 92(6):3562-74. DOI: 10.1152/jn.00886.2003. View

Diaz P, Phatak S, Xu J, Astruc-Diaz F, Cavasotto C, Naguib M . 6-Methoxy-N-alkyl isatin acylhydrazone derivatives as a novel series of potent selective cannabinoid receptor 2 inverse agonists: design, synthesis, and binding mode prediction. J Med Chem. 2009; 52(2):433-44. DOI: 10.1021/jm801353p. View

Howlett A, Barth F, Bonner T, Cabral G, Casellas P, Devane W . International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev. 2002; 54(2):161-202. DOI: 10.1124/pr.54.2.161. View

10.

Henry D, Chavkin C . Activation of inwardly rectifying potassium channels (GIRK1) by co-expressed rat brain cannabinoid receptors in Xenopus oocytes. Neurosci Lett. 1995; 186(2-3):91-4. DOI: 10.1016/0304-3940(95)11289-9. View

11.

Orestes P, Todorovic S . Are neuronal voltage-gated calcium channels valid cellular targets for general anesthetics?. Channels (Austin). 2010; 4(6):518-22. PMC: 3021099. DOI: 10.4161/chan.4.6.12873. View

12.

Elmes S, Jhaveri M, Smart D, Kendall D, Chapman V . Cannabinoid CB2 receptor activation inhibits mechanically evoked responses of wide dynamic range dorsal horn neurons in naïve rats and in rat models of inflammatory and neuropathic pain. Eur J Neurosci. 2004; 20(9):2311-20. DOI: 10.1111/j.1460-9568.2004.03690.x. View

13.

Tjolsen A, Berge O, Hunskaar S, Rosland J, Hole K . The formalin test: an evaluation of the method. Pain. 1992; 51(1):5-17. DOI: 10.1016/0304-3959(92)90003-T. View

14.

Ibrahim M, Porreca F, Lai J, Albrecht P, Rice F, Khodorova A . CB2 cannabinoid receptor activation produces antinociception by stimulating peripheral release of endogenous opioids. Proc Natl Acad Sci U S A. 2005; 102(8):3093-8. PMC: 549497. DOI: 10.1073/pnas.0409888102. View

15.

Yu X, Cao C, Martino G, Puma C, Morinville A, St-Onge S . A peripherally restricted cannabinoid receptor agonist produces robust anti-nociceptive effects in rodent models of inflammatory and neuropathic pain. Pain. 2010; 151(2):337-344. DOI: 10.1016/j.pain.2010.07.019. View

16.

Gerard C, Mollereau C, Vassart G, Parmentier M . Molecular cloning of a human cannabinoid receptor which is also expressed in testis. Biochem J. 1991; 279 ( Pt 1):129-34. PMC: 1151556. DOI: 10.1042/bj2790129. View

17.

CHEMIN J, Monteil A, Perez-Reyes E, Nargeot J, Lory P . Direct inhibition of T-type calcium channels by the endogenous cannabinoid anandamide. EMBO J. 2001; 20(24):7033-40. PMC: 125779. DOI: 10.1093/emboj/20.24.7033. View

18.

Yao B, Hsieh G, Frost J, Fan Y, Garrison T, Daza A . In vitro and in vivo characterization of A-796260: a selective cannabinoid CB2 receptor agonist exhibiting analgesic activity in rodent pain models. Br J Pharmacol. 2007; 153(2):390-401. PMC: 2219533. DOI: 10.1038/sj.bjp.0707568. View

19.

Marger F, Gelot A, Alloui A, Matricon J, Ferrer J, Barrere C . T-type calcium channels contribute to colonic hypersensitivity in a rat model of irritable bowel syndrome. Proc Natl Acad Sci U S A. 2011; 108(27):11268-73. PMC: 3131334. DOI: 10.1073/pnas.1100869108. View

20.

Zhang J, Hoffert C, Vu H, Groblewski T, Ahmad S, ODonnell D . Induction of CB2 receptor expression in the rat spinal cord of neuropathic but not inflammatory chronic pain models. Eur J Neurosci. 2003; 17(12):2750-4. DOI: 10.1046/j.1460-9568.2003.02704.x. View