In a mouse study, the endocannabinoid system was found to be required for the analgesic action of acetaminophen (paracetamol); FAAH breaks down acetaminophen to AM404 (first identified as synthetic Cannabinoid but also displaying endocannabinoid activity), which in turn blocks re-uptake of anandamide (Mallet et al., 2008).
MAGL inhibitors showed potential therapeutic action to treat cancer, neurodegenerative diseases, ischemic injuries, inflammation, pain, Anxiety, nausea and drug-withdrawal symptoms (Chen et al., 2012; Kohnz & Nomura, 2014; Mulvihill & Nomura, 2013). The analgesic effect of paracetamol thus seems to be due to increased ambient levels of anandamide.
Blocking CB1 completely prevents the analgesic action of paracetamol suggesting CB1 is required for analgesia (Bertolini et al., 2006).
Similarly, ibuprofen was found to block the breakdown/hydrolysis of anandamide (Fowler et al., 1999), which may contribute to the analgesic effect of ibuprofen (and similar substances).
Nox-induced oxyradical stress elicited the activation of DAGLβ in vitro, increasing the biosynthesis of 2-AG (Matthews et al., 2016). DAGLβ modulates pro-inflammatory signaling cascades and its inhibition reduced nociceptive behavior in models of neuropathic and inflammatory pain (Wilkerson et al., 2016).
In mice, inhibition of opioid-degrading enzymes potentiates the analgesic effect of THC, suggesting cross talk or synergy between the opioid- and endocannabinoid systems in pain management (Reche et al., 1998).
In humans, on the other hand, THC was found not so much to enhance the analgesic effect of morphine but to inhibit the experienced discomfort that is normally associated with pain (Roberts et al., 2006).
This would suggest that cannabinoids do no necessarily block pain sensation but rather dissociate negative emotions from the experienced pain.
In a rat model, THC was found to suppress muscle pain via activation of CB1 (Bagüés et al., 2014).
Several synthetic CB2 agonists have been patented for their analgesic properties, indicating a strong role for CB2 in pain management (Murineddu et al., 2012).
TRP receptors (TRPV1-4, TRPA1, TRPM8) are classically known for their role in pain sensation.
TRPs bind to most plant cannabinoids and endocannabinoids with varying affinities (De Petrocellis et al., 2011, 2012), tentatively making TRPs excellent targets and plant cannabinoids excellent substrates for pain management.
More research is required to test the therapeutic potential of cannabinoids in pain.
In patients with Chronic Widespread pain, the endocannabinoid PEA was found to provide homeostatic pain control through the PPARα receptor (Ghafouri et al., 2013).
In mice 2 mg/kg i.p. (like THC and gabapentin) CBD reduced, but did not prevent, neuropathic pain induced by cis-platin (Harris et al., 2016).
The interaction between CBG and the α2 receptor (alpha 2 adrenalin receptor) may prove effective in pain control (Giovannoni et al., 2009).
In rats, blocking GPR55 signaling reduced algesia suggesting GPR55 is a target for pain control (Deliu et al., 2015).
Bagüés, A., Martín, M.I., and Sánchez-Robles, E.M. (2014). Involvement of central and peripheral Cannabinoid receptors on antinociceptive effect of tetrahydrocannabinol in muscle pain. Eur. J. Pharmacol. 745C, 69–75.
Bertolini, A., Ferrari, A., Ottani, A., Guerzoni, S., Tacchi, R., and Leone, S. (2006). Paracetamol: new vistas of an old drug. CNS Drug Rev. 12, 250–275.
Deliu, E., Sperow, M., Console-Bram, L., Carter, R.L., Tilley, D.G., Kalamarides, D.J., Kirby, L.G., Brailoiu, G.C., Brailoiu, E., Benamar, K., et al. (2015). The Lysophosphatidylinositol Receptor GPR55 Modulates pain Perception in the Periaqueduactal Grey. Mol. Pharmacol.
Fowler, C.J., Janson, U., Johnson, R.M., Wahlström, G., Stenström, A., Norström, K., and Tiger, G. (1999). Inhibition of anandamide hydrolysis by the enantiomers of ibuprofen, ketorolac, and flurbiprofen. Arch. Biochem. Biophys. 362, 191–196.
Ghafouri, N., Ghafouri, B., Larsson, B., Stensson, N., Fowler, C.J., and Gerdle, B. (2013). Palmitoylethanolamide and stearoylethanolamide levels in the interstitium of the trapezius muscle of women with chronic widespread pain and chronic neck-shoulder pain correlate with pain intensity and sensitivity. pain 154, 1649–1658.
Giovannoni, M.P., Ghelardini, C., Vergelli, C., and Dal Piaz, V. (2009). Alpha2-agonists as analgesic agents. Med. Res. Rev. 29, 339–368.
Harris, H.M., Sufka, K.J., Gul, W., and ElSohly, M.A. (2016). Effects of Delta-9-Tetrahydrocannabinol and Cannabidiol on Cisplatin-Induced Neuropathy in Mice. Planta Med.
Mallet, C., Daulhac, L., Bonnefont, J., Ledent, C., Etienne, M., Chapuy, E., Libert, F., and Eschalier, A. (2008). endocannabinoid and serotonergic systems are needed for acetaminophen-induced analgesia. pain 139, 190–200.
Matthews, A. T., Lee, J. H., Borazjani, A., Mangum, L. C., Hou, X., & Ross, M. K. (2016). Oxyradical stress increases the biosynthesis of 2-arachidonoylglycerol: involvement of NADPH oxidase. American Journal of Physiology - Cell Physiology, 311(6), C960-C974. https://doi.org/10.1152/ajpcell.00251.2015
Murineddu, G., Asproni, B., and Pinna, G.A. (2012). A survey of recent patents on CB2 agonists in the management of pain. Recent Patents CNS Drug Discov. 7, 4–24.
De Petrocellis, L., Ligresti, A., Moriello, A.S., Allarà, M., Bisogno, T., Petrosino, S., Stott, C.G., and Di Marzo, V. (2011). Effects of cannabinoids and Cannabinoid-enriched Cannabis extracts on TRP channels and endocannabinoid metabolic enzymes. Br. J. Pharmacol. 163, 1479–1494.
De Petrocellis, L., Orlando, P., Moriello, A.S., Aviello, G., Stott, C., Izzo, A.A., and Di Marzo, V. (2012). Cannabinoid actions at TRPV channels: effects on TRPV3 and TRPV4 and their potential relevance to gastrointestinal inflammation. Acta Physiol. Oxf. Engl. 204, 255–266.
Reche, I., Ruiz-Gayo, M., and Fuentes, J.A. (1998). Inhibition of opioid-degrading enzymes potentiates delta9-tetrahydrocannabinol-induced antinociception in mice. Neuropharmacology 37, 215–222.
Roberts, J.D., Gennings, C., and Shih, M. (2006). Synergistic affective analgesic interaction between delta-9-tetrahydrocannabinol and morphine. Eur. J. Pharmacol. 530, 54–58.
Wilkerson, J. L., Ghosh, S., Bagdas, D., Mason, B. L., Crowe, M. S., Hsu, K. L., … Lichtman, A. H. (2016). Diacylglycerol lipase β inhibition reverses nociceptive behaviour in mouse models of inflammatory and neuropathic pain. British Journal of Pharmacology, 173(10), 1678-1692. https://doi.org/10.1111/bph.13469