Neuropsychopharmacology. 2015 Jun 8. doi: 10.1038/npp.2015.148. [Epub ahead of print]
A Cannabinoid CB1 Receptor Positive Allosteric Modulator Reduces Neuropathic Pain in the Mouse with no Psychoactive Effects.
Ignatowska-Jankowska BM1, Baillie GL2, Kinsey S3, Crowe M3, Ghosh S1, Allen Owens R1, Imad Damaj M1, Poklis J1, Wiley JL4, Zanda M5, Zanato C5, Greig IR5, Lichtman AH1, Ross RA2.
1Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA.
2Department of Pharmacology and Toxicology, University of Toronto and Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto.
3Department of Psychology, West Virginia University, Morgantown, WV, USA.
4Research Triangle Institute, Research Triangle Park, NC, USA.
5School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK.
The CB1 receptor represents a promising target for the treatment of several disorders including pain-related disease states. However, therapeutic applications of ?9-tetrahydrocannabinol (THC) and other CB1 orthosteric receptor agonists remain limited because of psychoactive side effects. Positive allosteric modulators (PAMs) offer an alternative approach to enhance CB1 receptor function for therapeutic gain with the promise of reduced side effects. Here we describe the development of the novel synthetic CB1 PAM, 6-methyl-3-(2-nitro-1-(thiophen-2-yl)ethyl)-2-phenyl-1H-indole (ZCZ011), which augments the in vitro and in vivo pharmacological actions of the CB1 orthosteric agonists CP55,940 and N-arachidonoylethanolamine (AEA). ZCZ011 potentiated binding of [3H]CP55,940 to the CB1 receptor as well as enhancing AEA-stimulated [35S]GTP?S binding in mouse brain membranes and ß-arrestin recruitment and ERK phosphorylation in hCB1 cells. In the whole animal, ZCZ011 is brain penetrant, increased the potency of these orthosteric agonists in mouse behavioral assays indicative of cannabimimetic activity, including antinociception, hypothermia, catalepsy, locomotor activity and in the drug discrimination paradigm. Administration of ZCZ011 alone was devoid of activity in these assays and did not produce a conditioned place preference or aversion, but elicited CB1 receptor mediated antinociceptive effects in the chronic constriction nerve injury (CCI) model of neuropathic pain and carrageenan model of inflammatory pain. These data suggest that ZCZ011 acts as a CB1 PAM and provide the first proof of principle that CB1 PAMs offer a promising strategy to treat neuropathic and inflammatory pain with minimal or no cannabimimetic side effects. |
