Mol Pharmacol. 2015 Apr 22. pii: mol.115.098483. [Epub ahead of print]
CB1 Knockout Mice Unveil Sustained CB2-Mediated Anti-Allodynic Effects of the Mixed CB1/CB2 Agonist CP55,940 in a Mouse Model of Paclitaxel-Induced Neuropathic Pain.
Deng L1, Cornett BL1, Mackie K1, Hohmann AG2.
1Indiana University Bloomington;
2Indiana University hohmanna@indiana.edu.
Cannabinoids suppress neuropathic pain through activation of cannabinoid CB1 and/or CB2 receptors. However, unwanted CB1-mediated cannabimimetic effects limit clinical use. We asked whether CP55,940, a potent cannabinoid that binds with similar affinity to CB1 and CB2 in vitro, produces functionally separable CB1- and CB2-mediated pharmacological effects in vivo. We evaluated anti-allodynic effects, possible tolerance, and cannabimimetic effects (i.e., hypothermia, catalepsy, and CB1-dependent withdrawal signs) following systemic CP55,940 treatment in a mouse model of toxic neuropathy produced by a chemotherapeutic agent paclitaxel. The contribution of CB1 and CB2 receptors to in vivo actions of CP55,940 was evaluated using CB1 knockout (CB1KO), CB2 knockout (CB2KO), and wildtype (WT) mice. Low dose CP55,940 (0.3 mg/kg/day i.p.) suppressed paclitaxel-induced allodynia in WT and CB2KO, but not CB1KO mice. Low dose CP55,940 also produced hypothermia and rimonabant-precipitated withdrawal in WT, but not CB1KO mice. In WT mice, tolerance developed to CB1-mediated hypothermic effects of CP55,940 earlier than to anti-allodynic effects. High dose CP55,940 (10 mg/kg/day i.p.) produced catalepsy in WT mice, which precluded determination of anti-allodynic efficacy, but produced sustained CB2-mediated suppression of paclitaxel-induced allodynia in CB1KO mice; these anti-allodynic effects were blocked by the CB2 antagonist AM630. High dose CP55,940 did not produce hypothermia or rimonabant-precipitated withdrawal in CB1KO mice. Our results using the mixed CB1/CB2 agonist CP55,940 document that CB1 and CB2 receptor activations produce mechanistically distinct suppression of neuropathic pain. Our study highlights the therapeutic potential of targeting cannabinoid CB2 receptors to bypass unwanted central effects associated with CB1 receptor activation.
(Unwanted? I usually don't post abstracts from reviews, but thought that someone might find this to be of interest....)
J Neuroimmune Pharmacol. 2015 Apr 28. [Epub ahead of print]
The Antitumor Activity of Plant-Derived Non-Psychoactive Cannabinoids.
McAllister SD1, Soroceanu L, Desprez PY.
1California Pacific Medical Center Research Institute, 475 Brannan Street, Suite 220, San Francisco, CA, 94107, USA, mcallis@cpmcri.org.
As a therapeutic agent, most people are familiar with the palliative effects of the primary psychoactive constituent of Cannabis sativa (CS), ?9-tetrahydrocannabinol (THC), a molecule active at both the cannabinoid 1 (CB1) and cannabinoid 2 (CB2) receptor subtypes. Through the activation primarily of CB1 receptors in the central nervous system, THC can reduce nausea, emesis and pain in cancer patients undergoing chemotherapy. During the last decade, however, several studies have now shown that CB1 and CB2 receptor agonists can act as direct antitumor agents in a variety of aggressive cancers. In addition to THC, there are many other cannabinoids found in CS, and a majority produces little to no psychoactivity due to the inability to activate cannabinoid receptors. For example, the second most abundant cannabinoid in CS is the non-psychoactive cannabidiol (CBD). Using animal models, CBD has been shown to inhibit the progression of many types of cancer including glioblastoma (GBM), breast, lung, prostate and colon cancer. This review will center on mechanisms by which CBD, and other plant-derived cannabinoids inefficient at activating cannabinoid receptors, inhibit tumor cell viability, invasion, metastasis, angiogenesis, and the stem-like potential of cancer cells. We will also discuss the ability of non-psychoactive cannabinoids to induce autophagy and apoptotic-mediated cancer cell death, and enhance the activity of first-line agents commonly used in cancer treatment. |
