Lee_2021_Br.J.Pharmacol__

The use of opioids in pain management is hampered by the emergence of analgesic tolerance, which leads to increased dosing and side effects, both of which have contributed to the opioid epidemic. One promising potential approach to limit opioid analgesic tolerance is activating the CNS endocannabinoid system, via activation of CB(1) receptors (CB(1) Rs) in the descending pain inhibitory pathway. In this review, we first discuss preclinical and clinical evidence revealing the potential of pharmacological activation of CB(1) Rs in modulating opioid tolerance, including activation by phytocannabinoids, synthetic CB(1) R agonists, endocannabinoid degradation enzyme inhibitors, and recently discovered CB(1) R positive allosteric modulators. On the other hand, as nonpharmacological pain relief is advocated by the US-NIH to combat the opioid epidemic, we also discuss contributions of peripheral neuromodulation, involving the electrostimulation of peripheral nerves, in addressing chronic pain and opioid tolerance. The involvement of supraspinal endocannabinoid systems in peripheral neuromodulation-induced analgesia is also discussed.