The role of the endogenous neurotransmitters associated with neuropathic pain and in the opioid crisis: The innate pain-relieving system

•Role of endogenous transmitters and receptors in the innate pain-relieving system.•Demand for pain-relieving medicines has significantly increased.•The number of analgesic drugs available for chronic pain is limited.•Major public health concern because of opioid crisis in the USA and Canada. Neuropathic pain is a chronic pain caused by central and peripheral nerve injury, long-term diabetes or treatment with chemotherapy drugs, and it is dissimilar to other chronic pain conditions. Chronic pain usually seriously affects the quality of life, and its drug treatment may result in increased costs of social and medical care. As in the USA and Canada, in Europe, the demand for pain-relieving medicines used in chronic pain has also significantly increased, but most European countries are not experiencing an opioid crisis. In this review, the role of various endogenous transmitters (noradrenaline, dopamine, serotonin, met- and leu-enkephalins, β-endorphin, dynorphins, cannabinoids, ATP) and various receptors (α2, μ, etc.) in the innate pain-relieving system will be discussed. Furthermore, the modulation of pain processing pathways by transmitters, focusing on neuropathic pain and the role of the sympathetic nervous system in the side effects of excessive opioid treatment, will be explained.