Pain, cancer, neurodegenerative diseases, ischemic injuries, inflammation, anxiety, nausea, and drug-withdrawal symptoms can possibly be treated by MAGL inhibitors, which showed potential therapeutic action (Chen et al., 2012; Kohnz & Nomura, 2014; Mulvihill & Nomura, 2013).
The analgesic action of paracetamol was shown to be prevented through blocking CB1, proposing that CB1 is needed for analgesia (Bertolini et al., 2006).
Similarly, the breakdown/hydrolysis of anandamide was shown to be blocked by ibuprofen, which may contribute to the analgesic properties of ibuprofen (Fowler et al., 1999).
In mice, the analgesic effect of THC was found to be potentiated by inhibition of opioid-degrading enzymes, proposing that there is a synergistic effect between the opioid- and endocannabinoid systems in pain management (Reche et al., 1998).
In a rat model, muscle pain was shown to be inhibited by THC through activation of CB1 (Bagüés et al., 2014).
Several synthetic CB2 agonists have obtained a patent due to their analgesic effects, showing that CB2 plays an important role in pain management (Murineddu et al., 2012).
TRP receptors are involved in pain sensation.
It was shown that there is an interaction between TRPs and cannabinoids (endo and phytocannabinoids) with varying affinities (De Petrocellis et al., 2011, 2012). This means that TRPs can be excellent targets and plant cannabinoids excellent substrates to manage pain.
In patients with Chronic Widespread pain, a decrease in pain intensity was connected to high levels of PEA via the PPARα receptor (Ghafouri et al., 2013).
In rats, algesia can be reduced through blocking GPR55 signaling, proposing that GPR55 is a target to control pain (Deliu et al., 2015).
In vivo studies aimed to evaluate nasal and transdermal permeation using rats and guinea pigs, respectively. Intranasal delivery of CBD showed a bioavailability of 34-46% with CBD being absorbed within 10 minutes. Polyethylene glycol formulation in rats showed a bioavailability of 100% and the use of enhancers did not improve bioavailability. Transdermal gel application in guinea pigs showed that the steady-state plasma concentration of CBD was sufficiently high for this administration route for CBD to be considered beneficial for treating chronic pain. Furthermore, it was demonstrated that with the use of enhancers, the steady-state concentration of CBD was increased by 3.7-fold. This shows that CBD could be successfully administered intranasally or transdermally (Paudel et al., 2010).
Paudel, Kalpana S., et al. “Cannabidiol bioavailability after nasal and transdermal application: effect of permeation enhancers.” Drug development and industrial pharmacy 36.9 (2010): 1088-1097.