|Neuropharmacology. 2017 Jun 30. pii: S0028-3908(17)30305-2. doi: 10.1016/j.neuropharm.2017.06.032. [Epub ahead of print]|
Inhibition of the endocannabinoid-regulating enzyme monoacylglycerol lipase elicits a CB1 receptor-mediated discriminative stimulus in mice.
Owens RA1, Mustafa MA1, Ignatowska-Jankowska BM1, Damaj MI2, Beardsley PM1, Wiley JL3, Niphakis MJ4, Cravatt BF4, Lichtman AH5.
Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA, USA.
Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA, USA; RTI International, 3040 Cornwallis Road, Research Triangle Park, NC, 27709-2194, USA; The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA, 92037, USA.
RTI International, 3040 Cornwallis Road, Research Triangle Park, NC, 27709-2194, USA.
The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA, 92037, USA.
Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA, USA. Electronic address: email@example.com.
Substantial challenges exist for investigating the cannabinoid receptor type 1 (CB1)-mediated discriminative stimulus effects of the endocannabinoids, 2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine (anandamide; AEA), compared with exogenous CB1 receptor agonists, such as ?9-tetrahydrocannabinol (THC) and the synthetic cannabinoid CP55,940. Specifically, each is rapidly degraded by the respective hydrolytic enzymes, monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH). Whereas MAGL inhibitors partially substitute for THC and fully substitute for CP55,940, FAAH inhibitors do not substitute for either drug. Interestingly, combined FAAH-MAGL inhibition results in full THC substitution, and the dual FAAH-MAGL inhibitor SA-57 serves as its own discriminative training stimulus. Because MAGL inhibitors fully substitute for SA-57, we tested whether the selective MAGL inhibitor MJN110 would serve as a training stimulus. Twelve of 13 C57BL/6J mice learned to discriminate MJN110 from vehicle, and the CB1 receptor antagonist rimonabant dose-dependently blocked its discriminative stimulus. CP55,940, SA-57, and another MAGL inhibitor JZL184, fully substituted for MJN110. In contrast, the FAAH inhibitor PF-3845 failed to substitute for the MJN110 discriminative stimulus, but produced a 1.6 (1.1-2.2; 95% confidence interval) leftward shift in the MJN110 dose-response curve. Inhibitors of other relevant enzymes (i.e., ABHD6, COX-2) and nicotine did not engender substitution. Diazepam partially substituted for MJN110, but rimonabant failed to block this partial effect. These findings suggest that MAGL normally throttles 2-AG stimulation of CB1 receptors to a magnitude insufficient to produce cannabimimetic subjective effects. Accordingly, inhibitors of this enzyme may release this endogenous brake producing effects akin to those produced by exogenously administered cannabinoids.
J Pharmacol Exp Ther. 2017 Aug;362(2):296-305. doi: 10.1124/jpet.117.241901. Epub 2017 Jun 7.
Cannabinoid CB2 Agonist GW405833 Suppresses Inflammatory and Neuropathic Pain through a CB1 Mechanism that is Independent of CB2 Receptors in Mice.
Li AL1, Carey LM1, Mackie K1, Hohmann AG2.
Department of Psychological and Brain Sciences (A-L L, L.M.C., K.M., A.G.H.), Program in Neuroscience (L.M.C., K.M., A.G.H.), Gill Center for Biomolecular Science (K.M., A.G.H.), Indiana University, Bloomington, Indiana.
Department of Psychological and Brain Sciences (A-L L, L.M.C., K.M., A.G.H.), Program in Neuroscience (L.M.C., K.M., A.G.H.), Gill Center for Biomolecular Science (K.M., A.G.H.), Indiana University, Bloomington, Indiana firstname.lastname@example.org.
GW405833, widely accepted as a cannabinoid receptor 2 (CB2) agonist, suppresses pathologic pain in preclinical models without the unwanted central side effects of cannabinoid receptor 1 (CB1) agonists; however, recent in vitro studies have suggested that GW405833 may also behave as a noncompetitive CB1 antagonist, suggesting that its pharmacology is more complex than initially appreciated. Here, we further investigated the pharmacologic specificity of in vivo antinociceptive actions of GW405833 in models of neuropathic (i.e., partial sciatic nerve ligation model) and inflammatory (i.e., complete Freund's adjuvant model) pain using CB2 and CB1 knockout (KO) mice, their respective wild-type (WT) mice, and both CB2 and CB1 antagonists. GW405833 (3, 10, and 30 mg/kg i.p.) dose dependently reversed established mechanical allodynia in both pain models in WT mice; however, the antiallodynic effects of GW405833 were fully preserved in CB2KO mice and absent in CB1KO mice. Furthermore, the antiallodynic efficacy of GW405833 (30 mg/kg i.p.) was completely blocked by the CB1 antagonist rimonabant (10 mg/kg i.p.) but not by the CB2 antagonist SR144528 (10 mg/kg i.p.). Thus, the antinociceptive properties of GW405833 are dependent on CB1 receptors. GW405833 (30 mg/kg i.p.) was also inactive in a tetrad of tests measuring cardinal signs of CB1 activation. Additionally, unlike rimonabant (10 mg/kg i.p.), GW405833 (10 mg/kg, i.p.) did not act as a CB1 antagonist in vivo to precipitate withdrawal in mice treated chronically with ?9-tetrahydrocannabinol. The present results suggest that the antiallodynic efficacy of GW405833 is CB1-dependent but does not seem to involve engagement of the CB1 receptor's orthosteric site.