High and Mighty? Cannabinoids and the microbiome in pain

Within the human gut, we each harbour a unique ecosystem represented by trillions of microbes that contribute to our health and wellbeing. These gut microbiota form part of a complex network termed the microbiota-gut-brain axis along with the enteric nervous system, sympathetic and parasympathetic divisions of the autonomic nervous system, and neuroendocrine and neuroimmune components of the central nervous system. Through endocrine, immune and neuropeptide/neurotransmitter systems, the microbiota can relay information about health status of the gut. This in turn can profoundly impact neuronal signalling not only in the periphery, but also in the brain itself and thus impact on emotional systems and behavioural responses. This may be true for pain, as the top-down facilitation or inhibition of pain processing occurs at a central level, while ascending afferent nociceptive information from the viscera and systemic areas travel through the periphery and spinal cord to the brain. The endogenous cannabinoid receptors are ubiquitously expressed throughout the gut, periphery and in brain regions associated with pain responding, and represent targets for endogenous and exogenous manipulation. In this review, we will focus on the potential role of the endogenous cannabinoids in modulating microbiota-driven changes in peripheral and central pain processing. We also focus on the overlap in mechanisms whereby commensal gut microbiota and endocannabinoid ligands can regulate inflammation and further aim to exploit our understanding of their role in microbiota-gut-brain axis communication in pain processing.