Pain, pleasure and placebo: the cannabinoids in reward processing and the perception of pain

Abstract

Chronic pain poses a complex, widespread problem that remains inadequately resolved by pain medication. Similarly, depression and addiction exist along a spectrum of reward related mood disorders that pose an ever-increasing burden on healthcare services. There is a need for a greater range of drugs to tackle these diverse health conditions and cannabinoid biology offers a unifying line of research that could invigorate the approach to treatment. Cannabinoids are known contributors to the physiological basis and emotional perception of pain, pleasure, and the placebo effect via activation of cannabinoid type 1 receptors widely expressed throughout the central nervous system. Endogenous cannabinoids -arachidonic acid derivatives synthesised on demand -are the primary contributors, but the system is also susceptible to synthetic cannabinoids and plant-derived phytocannabinoids. Targeting the endocannabinoid system pharmacologically has yielded few licenced drugs and with limited applications. The failure to provide a greater range of drugs stems partly from the limited understanding of endogenous cannabinoid biology. This review will critically evaluate current evidence of how cannabinoids influence pain, hedonic reward processing, and the placebo effect. Crucially, the endocannabinoid system must not be considered in isolation, but in the context of opioid and dopaminergic neural circuitry. As such, the most exciting pharmacological opportunities could lie as adjuncts to pre-existing drugs.