Opioids exert their effects on neurons by acting on opioid receptors located on neuronal cell membranes. There are three main opioid receptors designated μ (mu), δ(delta) and k (kappa) after the prototypic drugs used in the studies that led to their identification. The receptors have since been reclassified as OP³, OP², and OP¹ respectively but most references still refer to the older nomenclature. There is also a fourth receptor denoted N/OFQ which is structurally related to, but pharmacologically distinct from, the main opioid receptors.

Opioid receptors are located on both the pre and postsynaptic neurons within the peripheral and central nervous system. Agonism of pre-synaptic receptors is considered to be responsible for their major effect on the nervous system. This presynaptic activity involves inhibition of neurotransmitter release and activation of the modulating pathways to reduce the intensity of the pain signal. Postsynaptic neuronal activity involves inhibition of the ascending pain pathway; this results in a reduction in the transmission of pain signals to the thalamus and a consequent reduction in the perception of pain.

Mu (μ) receptors were named because of the high sensitivity and affinity of morphine for the receptor. All opioids, including fentanyl, are strong μ receptor agonists, although their affinities and hence potencies are variable. Mu receptors are found in several areas of the brain that have a well-established role in pain and analgesia. There is a high density of mu receptors in the descending pathways; activation of these receptors modulates the transmission of pain signals to the thalamus resulting in an analgesic effect. Mu receptors have also been shown to be involved in the regulation of respiratory and cardiovascular functions, gastro-intestinal transit, feeding, mood, temperature control, hormone secretion and immune function. This distribution of receptors directly corresponds to the undesirable effects of opioids including dyspnoea, respiratory depression, tachycardia, palpitations, hypertension, constipation, nausea and vomiting and anorexia.