Opioid analgesics inhibit synaptic activity partly through direct activation of opioid receptors and partly through release of the endogenous opioid peptides, which are themselves inhibitory to neurons. All 3 major opioid receptors are coupled to their effectors by G proteins and activate phospholipase C or inhibit adenylyl cyclase. At the postsynaptic level, activation of these receptors can open potassium ion channels to cause membrane hyperpolarization (inhibitory postsynaptic potentials). At the presynaptic level, opioid receptor activation can close voltage-gated calcium ion channels to inhibit neurotransmitter release.Presynaptic actions result in the inhibition of release of multiple neurotransmitters, including acetylcholine (ACh), norepinephrine, serotonin, glutamate, and substance P.