Abstract
Opioid analgesics represent a critical treatment for chronic pain in the analgesic ladder of the World Health Organization. However, their use can result in a number of unwanted side-effects including incomplete efficacy, constipation, physical dependence, and overdose liability. Cannabinoids enhance the pain-relieving effects of opioids in preclinical studies and dampen unwanted side-effects resulting from excessive opioid intake. We recently reported that a CB1 positive allosteric modulator (PAM) exhibits antinociceptive efficacy in models of pathological pain and lacks the adverse side effects of direct CB1 receptor activation. In the present study, we evaluated whether a CB1 PAM would enhance morphine’s therapeutic efficacy in an animal model of chemotherapy-induced neuropathic pain and characterized its impact on unwanted side-effects associated with chronic opioid administration. In paclitaxel-treated mice, both the CB1 PAM GAT211 and the opioid analgesic morphine reduced paclitaxel-induced behavioral hypersensitivities to mechanical and cold stimulation in a dose-dependent manner. Isobolographic analysis revealed that combinations of GAT211 and morphine resulted in anti-allodynic synergism. In paclitaxel-treated mice, a sub-threshold dose of GAT211 prevented the development of tolerance to the anti-allodynic effects of morphine over 20 days of once daily dosing. However, GAT211 did not reliably alter somatic withdrawal signs (i.e., jumps, paw tremors) in morphine-dependent neuropathic mice challenged with naloxone. In otherwise naïve mice, GAT211 also prolonged antinociceptive efficacy of morphine in the tail-flick test and reduced the overall right-ward shift in the ED50 for morphine to produce antinociception in the tail-flick test, consistent with attenuation of morphine tolerance. Pretreatment with GAT211 did not alter somatic signs of μ opioid receptor dependence in mice rendered dependent upon morphine via subcutaneous implantation of a morphine pellet. Moreover, GAT211 did not reliably alter μ-opioid receptor-mediated reward as measured by conditioned place preference to morphine. Our results suggest that a CB1 PAM may be beneficial in enhancing and prolonging the therapeutic properties of opioids while potentially sparing unwanted side-effects (e.g., tolerance) that occur with repeated opioid treatment.
Highlights
An estimated 11.2% of individuals in the United States are diagnosed with some form of chronic pain, representing an unmet clinical need for analgesics that are safe, effective and lack abuse liability (Jamison and Mao, 2015)
We demonstrated that the CB1 positive allosteric modulators (PAMs) GAT211 suppressed inflammatory pain produced by intraplantar injection of complete Freund’s adjuvant as well as chemotherapy-induced neuropathic pain produced by paclitaxel without producing tolerance (Slivicki et al, 2018b)
Adverse events associated with intake of cannabis or cannabinoids in clinical settings are rare, they produce detrimental side-effects including psychoactivity, FIGURE 6 | GAT211 does not alter conditioned place preference to morphine
Summary
An estimated 11.2% of individuals in the United States are diagnosed with some form of chronic pain, representing an unmet clinical need for analgesics that are safe, effective and lack abuse liability (Jamison and Mao, 2015). Opioid-based therapies are effective tools for pain management and remain a component of the analgesic ladder of the World Health Organization (Ballantyne et al, 2016) These therapies are plagued by a myriad of unwanted side effects including constipation, nausea, tolerance, dependence and, in extreme cases, overdose death (Gardell et al, 2006; Fields, 2011; Roques et al, 2012; Jamison and Mao, 2015). These observations highlight an urgent need to develop alternative therapies that retain or increase the beneficial efficacy of currently prescribed analgesics while reducing their detrimental side effects. A number of drug discovery efforts have focused on indirectly activating CB1 receptors as a way to circumvent these unwanted side effects
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
