Opioids exhibit their effect by action on specific opioid receptors. Opioid receptors are G-protein coupled receptors of several subtypes: μ-, κ-, and δ-receptors. Via a direct coupling of the G-protein to potassium channels (which open upon opioid binding) and calcium channels (which close upon opioid binding), opioids lower the synaptic potential and thus reduce neuronal excitability. This results in decreased release of neurotransmitters such as GABA, glutamate and substance P. The decreased GABA levels in the synapse indirectly activate dopaminergic neurons. This activation of the dopaminergic reward pathway leads to the feelings of euphoria and the ‘high’ associated with opioid use. The activated G-protein also reduces the intracellular cAMP levels. Opioids excite neurons in the periaqueductal grey matter and nucleus reticularis paragigantocellularis, which project to the nucleus raphe magnus. (see graphic below) Descending pathways from the midbrain exert a strong inhibitory effect on pain transmission in the dorsal horn (mediated by 5-HT, enkephalins and norepinephrine). Opioids also inhibit pain transmission by acting directly on the dorsal horn, and by inhibiting excitation of peripheral nociceptive afferent neurons. Common adverse effects of opioid use are sedation, constipation (due to decreased GI motility), vomiting and hypotension. In high doses, opioids can cause serious side effects such as respiratory depression and coma. Opioid dependence is very likely in case of long-term use. text-size-adjust: auto; background-color: #e4eaff;" href="https://coo.lumc.nl/trc/linkMap.aspx?linkdomain=FK&subjectID=267&link=https%3A%2F%2Fwww.farmacotherapeutischkompas.nl%2Fbladeren%2Fpreparaatteksten%2Fm%2Fmorfine&rnd=484136" target="_blank">Morphine, methadone, tramadol, fentanyl, oxycodone, pethidine, and buprenorphine are the most frequently used opioids. Formulations with controlled release of opioids are also prescribed (e.g. OxyContin) particulalry for treatment of chronic pain with malignancies.